abt-199 and Leukemia--Lymphocytic--Chronic--B-Cell

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in the western world. In Italy, venetoclax was approved for use in patients with CLL as monotherapy in 2017 and in combinations in 2019. As a result of this delayed approval, there are relatively few real-world studies from Italian clinical practice and much of the data are in heavily pretreated patients. We have collected the available studies in Italian routine practice. Three studies confirm the effectiveness and tolerability of this agent in patients with relapsed/refractory CLL and high-risk disease characteristics, many of whom had received prior B-cell receptor signaling treatment. Addition of rituximab to venetoclax produced more complete responses in patients with relapsed/refractory CLL, while higher disease burden and progression while receiving a prior Bruton's tyrosine kinase inhibitor were both associated with poorer outcomes in patients treated with venetoclax. Venetoclax was well-tolerated with low discontinuation rates. No studies of venetoclax plus obinutuzumab for the first-line treatment of patients with CLL were available due to the short time since approval in Italy. Several cohorts addressed the impact of COVID-19 on patient management and outcomes, suggesting that treated patients and those in clinical observation had similar rates of COVID-19-related hospital admission, intensive care unit admission, and mortality. Overall, the responses and tolerance to venetoclax observed in the Italian real-world setting confirm the tolerability and effectiveness of venetoclax regimens in high-risk patients.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; COVID-19; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Recurrence; Rituximab

Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections.. At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents.. More than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Receptors, Chimeric Antigen; Tyrosine Kinase Inhibitors; United States

There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.. Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

The availability of novel targeted agents has revolutionized the management of chronic lymphocytic leukemia (CLL). Both B-cell lymphoma 2 (BCL2) and Bruton tyrosine kinase (BTK) inhibitors are highly effective agents for CLL treatment. Several clinical trials have demonstrated the efficacy and safety of these agents in the management of newly diagnosed and relapsed/refractory CLL. This has led to two broad approaches in the frontline management of CLL, namely venetoclax-based time-limited therapy versus BTK inhibitor-based continuous therapy. In this review, we discussed why we consider venetoclax-based therapy as a suitable frontline option for patients with CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Sulfonamides

The treatment landscape for chronic lymphocytic leukemia (CLL) continues to undergo considerable evolution. Optimal selection of initial therapy from multiple effective options provides a major challenge for clinicians, who need to consider both disease and patient factors in conjunction with a view to sequencing available therapies in event of disease relapse.. We explore the most topical clinically relevant unresolved questions through discussion of important available pertinent literature and propose expert opinion based on these data. (1) Shrinking role of chemoimmunotherapy (CIT); while novel therapies are generally superior, we highlight the utility of FCR for IGHV-mutated CLL. (2) Choosing between inhibitors of Bruton's tyrosine kinase (BTKi); while efficacy between agents is likely similar there are important differences in toxicity profiles, including the incidence of cardiac arrhythmia and hypertension. (3) BTKi with or without anti-CD20 monoclonal antibodies (mAb); while obinutuzumab-acalabrutinib (AO) may confer superior progression-free survival to acalabrutinib (Acala), this is not true of rituximab (Ritux) to ibrutinib (Ib)-we highlight that potential for increased side effects should be carefully considered. (4) Continuous BTKi versus time-limited venetoclax-obinutuzumab (VenO); we propose that venetoclax (Ven)-based therapy is generally preferable to BTKi with exception of TP53 aberrant disease. (5) BTKi-Ven versus VenO as preferred time-limited therapy; we discuss comparable efficacies and the concerns about simultaneous 1L exposure to both BTKi and Ven drug classes. (6) Utility of triplet therapy (BTKi-Ven-antiCD20 mAb) versus VenO; similar rates of complete response are observed yet with greater potential for adverse events. (7) Optimal therapy for TP53 aberrant CLL; while limited data are available, there are likely effective novel therapy combinations for TP53 aberrant disease including BTKi, BTKi-Ven ± antiCD20 mAb.. Frontline therapy for CLL should be selected based on efficacy considering the patient specific biologic profile of their disease and potential toxicities, considering patient comorbidities and preferences. With the present paradigm of sequencing effective agents, 1L combinations of novel therapies should be used with caution in view of potential adverse events and theoretical resistance mechanism concerns in the absence of compelling randomized data to support augmented efficacy.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

Several chemoimmunotherapy and targeted treatment regimens are approved as front-line therapies in chronic lymphocytic leukemia. We estimated for the 10-year cost-effectiveness of these treatment regimens and the economic burden of following the estimated risk-stratified 21 040 patients with chronic lymphocytic leukemia diagnosed in 2020 for 10 years.. A Markov model with 7 exclusive health states was specified over a 10-year time horizon. Treatment effectiveness inputs were obtained from a novel network meta-analysis on the progression-free survival, overall survival curves, and time to next treatment. Costs and utilities inputs were included for each health state for each treatment and discounted at 3.0%/year. Life-years (LYs) and quality-adjusted LYs (QALYs) for each treatment were determined. Using the lowest cost regimen as reference, the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) were estimated. The 10-year per-patient cost was determined by risk status and by initial treatment.. Venetoclax-plus-obinutuzumab was the lowest cost regimen, hence the reference. Superior in effectiveness to all chemoimmunotherapies, it was cost saving. With the highest effectiveness gains at 6.26 LYs and 5.01 QALYs and despite being the most expensive regimen ($1 298 638 per patient), acalabrutinib-plus-obinutuzumab yielded the best ICER ($409 343/LY gained) and ICUR ($501 236/QALY gained). The remaining ICERs of targeted therapies ranged from $512 101/LY gained to $793 236/LY gained and the ICURs from $579 737/QALY gained to $869 300/QALY gained. The 10-year postdiagnosis low/high (venetoclax-plus-obinutuzumab/acalabrutinib-plus-obinutuzumab) economic burden ranges were $42 690 to $98 665 for low-risk, $141 339 to $326 660 for intermediate-risk, and $273 650 to $632 453 for high-risk patients.. Compared with venetoclax-plus-obinutuzumab, chemoimmunotherapies are associated with less health benefits at higher cost. The targeted therapies achieve greater benefits at higher cost.

Topics: Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cost-Benefit Analysis; Financial Stress; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Markov Chains; Pyrazines; Quality-Adjusted Life Years; Sulfonamides

Chronic lymphocytic leukaemia (CLL) constitutively overexpresses B-cell lymphoma 2 (BCL2) with consequent dysregulation of intrinsic apoptosis leading to abnormal cellular survival. Therapeutic use of BCL2 inhibitors (BCL2i, eg, venetoclax) in CLL, as both continuous monotherapy or in fixed duration combination, has translated scientific rationale into clinical benefit with significant rates of complete responses, including those without detectable minimal residual disease. Unlike with chemotherapy, response rates to venetoclax do not appear to be influenced by pre-existing chromosomal abnormalities or somatic mutations present, although the duration of response observed remains shorter for those with traditional higher risk genetic aberrations. This review seeks to describe both the disease factors that influence primary venetoclax sensitivity/resistance and those resistance mechanisms that may be acquired secondary to BCL2i therapy in CLL. Baseline venetoclax-sensitivity or -resistance is influenced by the expression of BCL2 relative to other BCL2 family member proteins, microenvironmental factors including nodal T-cell stimulation, and tumoral heterogeneity. With selection pressure applied by continuous venetoclax exposure, secondary resistance mechanisms develop in oligoclonal fashion. Those mechanisms described include acquisition of BCL2 variants, dynamic aberrations of alternative BCL2 family proteins, and mutations affecting both BAX and other BH3 proteins. In view of the resistance described, this review also proposes future applications of BCL2i therapy in CLL and potential means by which BCL2i-resistance may be abrogated.

Topics: Antineoplastic Agents; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2

Here we describe the rationale and design of MAJIC, a phase III, prospective, multicenter, randomized trial comparing the combination of the BTK inhibitor acalabrutinib plus the BCL2 inhibitor venetoclax versus the combination of venetoclax plus obinutuzumab as frontline treatment for chronic lymphocytic leukemia or small lymphocytic lymphoma. In both treatment arms, disease response (assessed by International Workshop on Chronic Lymphocytic Leukemia criteria) and minimal residual disease will be used to guide therapy duration, with all patients ultimately discontinuing treatment after a maximum of 2 years. The primary end point is progression-free survival. Key secondary end points include rates of undetectable minimal residual disease, overall response and overall survival. This study will address key unanswered questions in frontline chronic lymphocytic leukemia/small lymphocytic lymphoma therapy by investigating the optimal duration of finite treatment and identifying the optimal venetoclax doublet regimen.. This article describes the design of the MAJIC clinical trial, which investigates two different treatment combinations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have not received treatment for their disease previously. Patients will be randomized (put into a group by chance) to receive either acalabrutinib + venetoclax (AV) or venetoclax + obinutuzumab (VO). VO is already an approved initial treatment option for CLL/SLL. Acalabrutinib is also an approved initial treatment option when given by itself, but the AV combination is not yet approved. We are doing this study to better understand and directly compare how well AV and VO work when used for the treatment of CLL/SLL. A test done on the blood and bone marrow called ‘minimal residual disease’ will be used to help guide the length of time that patients receive treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multicenter Studies as Topic; Neoplasm, Residual; Prospective Studies; Randomized Controlled Trials as Topic

Treatment options with targeted agents have changed the treatment landscape of CLL profoundly. Besides chemoimmunotherapy, treatment regimen approved for frontline therapy include continuous treatment with BTK inhibitors like ibrutinib and acalabrutinib or fixed-duration regimen like venetoclax-obinutuzumab with the approval of venetoclax-ibrutinib to be awaited. Although these agents have usually manageable side effects, toxicities might limit choices for the individual patient. We here discuss latest trial data and propose a treatment algorithm for frontline treatment of CLL according to fitness and relevant genetic risk factors like IGHV mutational status and TP53 aberrations.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.. 维奈克拉在非霍奇金淋巴瘤治疗中的研究进展.. 细胞凋亡异常与血液肿瘤的发生密切相关，BCL-2作为细胞固有程序性死亡的关键抗凋亡蛋白，近年来成为血液肿瘤治疗的热点。维奈克拉是美国食品和药物管理局批准的一种口服小分子选择性BCL-2抑制剂，用于治疗慢性淋巴细胞白血病患者或小淋巴细胞淋巴瘤患者以及不适合进行化疗的老年急性髓系白血病患者。此外，在非霍奇金淋巴瘤患者的治疗中也显示出良好的临床应用前景，这是维奈克拉临床应用的新拓展。本文就BCL-2蛋白家族在非霍奇淋巴瘤细胞凋亡调控中的作用、BCL-2抑制剂的开发以及维奈克拉治疗非霍奇金淋巴瘤的最新研究进展作一综述.

Topics: Aged; Antineoplastic Agents; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Recently, the use of novel targeted drugs significantly improved the overall response rate (ORR) and survival of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). The treatment of R/R CLL has been gradually developed from traditional chemotherapy to targeted therapy. Venetoclax has been proved to be effective for R/R CLL as a single agent or in combination with various regimens. However, the data from clinical studies were still limited, especially since a large number of studies were single arms. Considering that there were few kinds of research in this regard and the data were not uniform, a meta-analysis was conducted to describe ORR and undetectable minimal residual disease (uMRD) of venetoclax in patients with R/R CLL. The pooled cumulative prevalence of total ORR was 82% (95% CI 77-87%), and the pooled ORR in venetoclax + anti-CD20 antibody-based group was 89% (95% CI 83-94%). There were significant differences among venetoclax monotherapy group, venetoclax + ibrutinib group and venetoclax + anti-CD20 group with pooled uMRD of 39% (95% CI 31-47%), 57% (95% CI 50-64%) and 43% (95% CI 19-70%), respectively (P = 0.004 < 0.05). Pooled ORR of patients with high-risk cytogenetic in venetoclax monotherapy group was 73% (95% CI 61-83%). No significant difference was observed in comparison with patients without high-risk cytogenetic who received the same treatment (P = 0.518). Our research results indicate that venetoclax combined with anti-CD20 monoclonal antibody may be an effective treatment for patients with R/R CLL, especially for CLL patients with high-risk cytogenetic factors. Furthermore, ibrutinib in combination with venetoclax showed a longer remission time, the deeper remission degree and uMRD-negative rate gradually increased with the extension of the treatment time.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Sulfonamides

In the last decade, the treatment of chronic lymphocytic leukemia (CLL) has shifted away from chemoimmunotherapy toward targeted novel agents such as small molecule inhibitors and antibodies. Here, we give an overview of the pharmacology of venetoclax and obinutuzumab and the evidence from early phase to Phase III trials that have shaped how they are used in the treatment of CLL. Venetoclax, an oral anti-apoptotic BCL-2 inhibitor, in combination with a CD20 antibody has shown superiority to chemoimmunotherapy in treatment-naive and relapsed/refractory CLL. Obinutuzumab is a novel anti-CD20 monoclonal antibody that has been safely combined with novel agents including venetoclax and Bruton tyrosine kinase inhibitors and has shown superiority over rituximab when combined with chlorambucil.

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Interactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Sulfonamides

Available targeted agents (TAs) for the upfront therapy of chronic lymphocytic leukemia (ie, ibrutinib, acalabrutinib, venetoclax) have rarely been compared in head-to-head clinical trials. In search of data for evidence-based treatment decisions, a systematic literature review and network meta-analysis was performed.. The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA).. Only 3 trials were suitable for the base-case network analysis (ILLUMINATE, ELEVATE-TN, and CLL14). Regarding progression-free survival (PFS), fixed-effect analyses comparing ibrutinib-obinutuzumab (IO) with venetoclax-obinutuzumab (VO) (relative risk [RR], 1.52; 95% confidence interval [CI], 0.82-2.81), acalabrutinib (A) with IO (RR, 0.87; 95% CI, 0.47-1.61), and A with VO (RR, 0.57; 95% CI, 0.32-1.01) revealed that the upper limit of the 95% CI for RR did exceed the 1.0 value. This indicates a lack of significant difference in PFS for IO, VO, and A. In contrast, acalabrutinib plus obinutuzumab (AO) improved PFS in comparison with IO (RR, 0.43; 95% CI, 0.22-0.87) and VO (RR, 0.29; 95% CI, 0.15-0.56). No differences in the frequency of adverse events was observed across different TAs. Also, the analysis of PFS in relationship with high-risk genetic features (ie, TP53 aberrations, IGHV unmutated, 11q deletion) showed similar results for different TAs. However, patients with unmutated IGHV status fared better with AO than with VO in terms of PFS.. This systematic review and network meta-analysis indicated that upfront AO prolongs PFS in comparison with IO and VO, whereas no differences are observed between IO, VO, and single-agent A. Hopefully, ongoing studies will further delineate the position of different TAs in chronic lymphocytic leukemia therapy based on effectiveness, availability, safety, cost, and treatment objectives.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Mutation; Network Meta-Analysis; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazines; Randomized Controlled Trials as Topic; Sulfonamides; Tumor Suppressor Protein p53

Clinical research of chronic lymphocytic leukaemia (CLL) has been advancing at an unprecedented pace. Several randomized studies in the current era of oral targeted agents seem to have skipped one step and proceeded directly to combinations with antibodies, omitting the testing of novel-agent monotherapy. Thus, the ibrutinib + rituximab combination was used as the experimental arm in a major trial for untreated fit patients while two other trials subsequently showed that addition of rituximab to ibrutinib does not produce any meaningful benefit. Similarly, two large trials omitted venetoclax monotherapy and proceeded directly to venetoclax + rituximab or obinutuzumab versus chemoimmunotherapy. While such trials are undoubtedly cheaper, quicker and easier to manage, they leave the CLL community with uncertainty regarding the real role of the monoclonal antibody components. Thus, we are left with regimens which are undoubtedly effective, but might actually be unnecessarily toxic and expensive. The solution to this problem is simple: future randomized trials should be carefully designed in a 'step by step' fashion which would provide the CLL community with simple yet robust answers regarding efficacy of novel regimens so that these can be introduced to practice following the best principles of evidence-based medicine.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Randomized Controlled Trials as Topic; Rituximab; Sulfonamides

Venetoclax, an oral, BCL-2 inhibitor, is approved by the FDA for treatment of CLL in all lines of therapy. Data from landmark studies, including the CLL14 and MURANO trials, demonstrated marked improvement in clinical outcomes compared to chemoimmunotherapy when venetoclax was used in combination with CD20 monoclonal antibodies for fixed treatment duration.. This article reviews the mechanism of action of venetoclax and discusses how curtailing the BCL signaling pathway undermines CLL pathophysiology. The authors also give their clinical experience with the drug, with emphasis on assessing and managing the risk of venetoclax-associated tumor lysis syndrome (TLS).. Venetoclax has positioned itself as one of the primary treatment options for CLL, given the consistent efficacy and deep remissions it has elicited across multiple settings of the disease with a time-limited schedule. Accurate TLS risk evaluation and stringent adherence to the dose-escalation protocols will help optimize patient outcomes. Finally, we expect that current and future studies will (1) ascertain the ideal treatment duration using the minimal residual disease state as a guide and (2) help us understand the optimal role of venetoclax in combination or in sequence with other novel targeted therapies in the treatment of CLL.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease and facilitating time-limited treatment without chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins, and genomic instability. Although most commonly observed in heavily pretreated patients with disease refractory to fludarabine and harboring complex karyotype, Richter transformation presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors, allogeneic stem cell transplantation, chimeric antigen receptor T cells, and venetoclax retreatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practicing clinicians.

Topics: Allografts; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Suppressor Protein p53

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Sulfonamides; Therapies, Investigational

The Bcl-2 family members rigorously regulate cell endogenous apoptosis, and targeting anti-apoptotic members is a hot topic in design of anti-cancer drugs. At present, FDA and EMA have approved Bcl-2 inhibitor Venetoclax (ABT-199) for treating chronic lymphocytic leukemia (CLL). However, inhibitors of anti-apoptotic protein BCL2A1/Bfl-1 have not been vigorously developed, and no molecule with ideal activity and selectivity has been found yet. Here we review the biological function and protein structure of Bfl-1, discuss the therapeutic potential and list the currently reported inhibitory peptides and small molecules. This will provide a reference for Bfl-1 targeting drug discovery in the future.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Minor Histocompatibility Antigens; Models, Molecular; Molecular Structure; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Targeting BCR and BCL-2 signaling is a widely used therapeutic strategy for chronic lymphocytic leukemia. C481S mutation decreases the covalent binding affinity of ibrutinib to BTK, resulting in reversible rather than irreversible inhibition. In addition to BTK, mutations in PLCG2 have been demonstrated to mediate acquired ibrutinib resistance. Venetoclax, a highly selective BCL2 inhibitor, has high affinity to the BH3-binding grove of BCL2. Mutation in BCL2 (Gly101Val) decreases the affinity of BCL2 for venetoclax and confers acquired resistance in cell lines and primary patient cells. This review discusses the common mechanisms of resistance to targeted therapies in chronic lymphocytic leukemia.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Genomics; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcr; Sulfonamides

The Bruton's tyrosine kinase inhibitors (BTKis) ibrutinib and acalabrutinib have led to durable responses for patients with both treatment-naïve and relapsed/refractory chronic lymphocytic leukemia (CLL). Many patients, however, ultimately discontinue BTKis due to toxicity or progressive CLL. This article reviews the two most common reasons for ibrutinib and acalabrutinib discontinuation, including adverse events as well as CLL progression. The data for specific CLL-directed therapies following BTKi discontinuation, including venetoclax, phosphatidylinositol 3-kinase inhibitors, cellular therapies, and ongoing clinical trials, are reviewed. An evidence-based sequencing algorithm for treatment of CLL following BTKi discontinuation is proposed.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Network Meta-Analysis; Receptors, Antigen, B-Cell; Rituximab; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

The treatment landscape in relapsed/refractory chronic lymphocytic leukaemia (CLL) has rapidly evolved over the past five years, with one such emergent treatment being the BCL2 inhibitor, venetoclax. This oral treatment has demonstrated significant clinical advantages in indicated patients, but rapid tumour debulking can lead to a treatment-related risk of the acute condition known as tumour lysis syndrome (TLS). Here, I present real patient cases to show how I have used the recommended predose monitoring and prophylactic procedures to mitigate the risk of TLS. I also used the ramp-up dose escalation schedule of venetoclax therapy initiation to safely take patients through the treatment, successfully providing them with sustained clinical benefits.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Sulfonamides; Tumor Lysis Syndrome

Tumour lysis syndrome is a complication of chemotherapy for haematological malignancies; in particular, aggressive leukaemias and lymphomas. For haematological malignancies, targeted therapies, such as small molecule inhibitors and monoclonal antibodies, have a high anti-tumour activity, are well tolerated, and have a low incidence of associated tumour lysis syndrome. The BCL-2 inhibitor venetoclax has a high anti-tumour activity in chronic lymphocytic leukaemia, achieving deep remissions by potently inducing apoptosis and increasing the risk for tumour lysis syndrome. In this Viewpoint, we discuss the pathophysiology, risk factors, monitoring, changes in laboratory parameters, and clinical manifestations of tumour lysis syndrome, and the prophylaxis and treatments available for this complication. Prophylaxis and treatment strategies have been implemented as standard of care in patients receiving venetoclax to minimise the risk of both laboratory and clinical manifestations of tumour lysis syndrome.

Topics: Acute Kidney Injury; Allopurinol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Hyperphosphatemia; Hyperuricemia; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm Proteins; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Renal Dialysis; Risk Factors; Severity of Illness Index; Sulfonamides; Tumor Lysis Syndrome; Urate Oxidase

Over the last years, targeted anticancer therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). Here we give an overview of novel targeted agents used in therapy of chronic lymphocytic leukemia, as well as efforts to overcome resistance development, focusing on approved drugs since they gained high relevance in clinical practice.. Novel agents moved to the forefront as a treatment strategy of CLL due to their outstanding efficacy, almost irrespectively of the underlying genetic features. Inhibition of Bruton's tyrosine kinase (BTK), a key molecule in the B cell receptor pathway, achieved dramatic efficacy even in poor-risk and chemo-refractory patients. Further success was accomplished with venetoclax, which specifically inhibits anti-apoptotic BCL2 and induces apoptosis of CLL cells. Inhibition of BTK or BCL2 is very effective and induces prolongation of progression-free and overall survival. Approved combination treatments such as venetoclax or ibrutinib with obinutuzumab show high responses rates and long remission durations. However, evolution and selection of subclones with continuous treatment leads to resistance towards these novel drugs and disease relapse. Hence, comparison of sequential treatment with combinations and discontinuation of therapy are important aspects which need to be investigated.

Topics: Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Combined Modality Therapy; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Advances in the molecular biology of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and development of molecularly targeted therapies have resulted in treatment innovations. Therapeutic approaches for previously untreated CLL/SLL patients are changing from chemoimmunotherapy (CIT) to molecularly targeted drugs. The aim of therapy for CLL patients has been to control the disease; however, FCR (fludarabine, cyclophosphamide, rituximab) has improved outcomes and reduced the high incidence of undetectable minimum/measurable residual disease (MRD) in previously untreated CLL patients with no 17p deletion/TP53 disruption and mutated immunoglobulin heavy chain gene (IGHV). Patients achieving undetectable MRD in the bone marrow are expected to be cured. BTK inhibitors and BCL-2 inhibitors are effective for CLL/SLL patients. However, atrial fibrillation and bleeding are associated with the BTK inhibitor, ibrutinib, while tumor lysis syndrome is an adverse event (AE) of the BCL-2 inhibitor, venetoclax. Although these novel targeted drugs are very useful, they are also expensive. Emergence of resistant clones of CLL cells must also be addressed. Therefore, treatments of indefinite duration until progression have been replaced by fixed-duration treatments. This review introduces advances in the treatment of previously untreated CLL/SLL patients in Europe and the United States.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sulfonamides; Vidarabine

In patients with recurrent chronic lymphocytic leukemia (CLL), treatment with targeted agents such as Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax is rapidly replacing chemo-immunotherapy regimens. Venetoclax has demonstrated efficacy as monotherapy in patients with previously treated CLL and has been evaluated in combination with the anti-CD20 monoclonal antibody rituximab.. This review focuses on the activity and toxicity of the time-limited combination of venetoclax plus rituximab for the treatment of relapsed or refractory CLL, presenting clinical trial results and data from correlative studies, with the aim of highlighting the strengths of this treatment approach and discuss weaknesses and possible areas of improvement. Data from PubMed indexed papers as well as from abstracts presented at major international conferences are included.. Deep responses with venetoclax-based regimens have been shown to allow time-limited treatment and prolonged remission off-therapy in patients with CLL. The clinical benefit of venetoclax and rituximab over chemo-immunotherapy has been demonstrated in recurrent CLL. Potential advantages of time-limited treatment approaches include avoidance of long-term toxicities, high drug costs, and the selection of resistant subclones.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Neoplasm Grading; Neoplasm Staging; Prognosis; Recurrence; Retreatment; Rituximab; Sulfonamides; Treatment Outcome

Two major advances were made in the treatment of chronic lymphocytic leukaemia (CLL): the addition of the antibody rituximab to chemotherapy two decades ago and the introduction of the targeted agents during the last few years. Four targeted drugs with different mechanisms of action were added to the armamentarium of CLL treatment: the anti-CD20 antibody obinutuzumab, the two kinase inhibitors ibrutinib and idelalisib, which target the Bruton tyrosine kinase (BTK) and Phosphatidylinositiol-3-Kinase (PI3K) respectively in the B-cell receptor signalling pathway, as well as the Bcl2-antagonist venetoclax.Recently, the combination of venetoclax/obinutuzumab was approved for the first-line treatment of all CLL patients based on a phase-III trial in elderly unfit patients. This combination was shown to be clearly superior to chlorambucil/obinutuzumab and should become the preferred first-line treatment for the so called "slow-go" patients. Other options for these elderly, unfit patients are continuous ibrutinib or chlorambucil/obinutuzumab. Although data from phase-III studies are not yet available, venetoclax/obintuzumab may also be offered to younger, fit patients. Established therapeutic options for these so called "go go" patients are ibrutinib, fludarabin/cyclophosphamide/rituximab or bendemustine/rituximab (if > 65 years). Patients with the high-risk parameters deletion 17p or TP53mutation are known to poorly respond to chemo(immuno)therapy and should receive either ibrutinib or venetoclax/obinutuzumab.Thus, a choice has to be made between a continuous monotherapy with ibrutinib or a time-limited combination with either venetoclax/obinutuzumab (12 months) or chemoimmunotherapy (usually 6 months). In addition to disease-related factors (e. g. presence of deletion 17p/TP53 mutation, IgHV mutational status, prior therapies), comorbidities, co-medication and the specific side effects of the CLL therapies (myelosuppression, infections and secondary malignancies for chemoimmunotherapy; cardiac toxicity, bleeding and autoimmune disease for ibrutinib; tumour-lysis syndromes and infections for venetoclax) the patient's expectations need to be considered.. Die Aktualisierung der IWCLL-Kriterien ließ die Kriterien für die Diagnosestellung der CLL unberührt: In der Regel genügt weiterhin ein Blutausstrich und eine Immunphänotypisierung.. Auch die Kriterien für die Therapieeinleitung blieben unverändert: Nur Patienten mit symptomatischer, fortgeschrittener Erkrankung sollen behandelt werden. Die Untersuchung auf Vorliegen einer Deletion 17p und/oder TP53-Mutation als wichtigster ungünstiger Prognosefaktor und prädiktiver Faktor ist essenziell vor Einleitung jeder neuen Therapie. Die Bedeutung des Mutationsstatus der variablen Region des Immunglobulin-Schwerkettengens (IgHV) hat deutlich zugenommen.. Die Kombination des Bcl2-Antagonisten Venetoclax mit dem Antikörper Obinutuzumab wurde kürzlich für die Erstlinientherapie der CLL zugelassen. Aufgrund der klaren Überlegenheit gegenüber Chlorambucil/Obinutuzumab bei den unfitten, älteren Patienten sollte Venetoclax/Obinutuzumab von nun an die bevorzugte Behandlungsoption bei dieser Patientengruppe sein. Als Chemotherapie-freie und zeitlich limitierte Behandlung wird Venetoclax/Obinutuzumab auch bei den Hochrisikopatienten mit Deletion 17p/TP53-Mutation und bei den jüngeren, fitten Patienten künftig eine wichtige Option neben der Dauertherapie mit Ibrutinib darstellen. Bei Letzteren kann bei Vorliegen eines mutierten IgHV-Status auch eine Chemoimmuntherapie mit Rituximab, kombiniert mit Fliudarabin/Cyclophosphamid oder Bendamustin, erfolgen.. Auch in der Rezidiv-Situation werden vorzugsweise die zielgerichteten Substanzen eingesetzt unter Berücksichtigung der zyto- und molekulargenetischen Risikofaktoren der CLL, der Patientencharakteristiken, der Tiefe und Dauer des Ansprechens sowie Verträglichkeit der vorangegangenen Therapie(n).

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Comorbidity; Drug Approval; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Piperidines; Prognosis; Purines; Quinazolinones; Rituximab; Smith-Magenis Syndrome; Sulfonamides

Venetoclax is a selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2（BCL-2）and has great potential in treating a variety of hematological tumors. In recent years, domestic and foreign scholars have tried to use venetoclax singal or in combination with some drugs to treat the patients with hematological tumors, including elderly acute myeloid leukemia（AML）patients un suitable for intensive chemotherapy, relapsed or refractory chronic lymphocytic leukemia（CLL）, Non-Hodgkin's lymphoma（NHL）and multiple myeloma（MM）patients, these studies have achieved good results．At the same time，some scholars found that the secondary drug-resistance occurred in some patients who continuous treated with Venetoclax, and explored the Venetoclax-resistant mechanism. In this review, the research advance of Venetoclax in hematological tumors and the mechanisms of drug resistance are summarized and discussed briefly.. Venetoclax在血液肿瘤中的最新研究进展.. Venetoclax是抗凋亡蛋白B细胞淋巴瘤因子-2（BCL-2）的一种选择性小分子抑制剂，在治疗多种血液肿瘤方面具有巨大潜力。近年来，有国内外学者尝试将Venetoclax单药应用或联合用药治疗血液恶性肿瘤患者，包括不适合进行强化化疗的老年急性髓系白血病（AML）患者，复发或难治性的慢性淋巴细胞白血病（CLL）、非霍奇金淋巴瘤（NHL）和多发性骨髓瘤（MM）患者，这些研究均取得较好的疗效。与此同时，有学者发现部分持续服药患者对Venetoclax产生了继发性耐药并探讨了产生耐药的机制。本文就Venetoclax在血液恶性肿瘤中的最新研究进展及患者产生耐药性的机制作一综述。.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

The optimal chemotherapy-free regimens for treatment-naive CLL still remains undefined. We searched relevant published reports. Three trials with 1017 subjects were identified. In the network meta-analysis, acalabrutinib plus obinutuzumab (Aca + Obi) improved PFS than ibrutinib plus obinutuzumab (Ibu + Obi) (HR:0.43,

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Network Meta-Analysis; Piperidines; Prospective Studies; Pyrazines; Sulfonamides

Treatment outcomes of chronic lymphocytic leukemia (CLL) have improved since chemoimmunotherapy and novel drugs became available for CLL treatment; therefore, more sensitive methods to evaluate residual CLL cells in patients are required. Measurable residual disease (MRD) has been assessed in several clinical trials on CLL using flow cytometry, real-time quantitative PCR (RQ-PCR) with allele-specific oligonucleotide (ASO) primers, and high-throughput sequencing. MRD assessment is useful to predict the treatment outcomes in the context of chemotherapy and treatment with novel drugs such as venetoclax. In this review, we discuss major techniques for MRD assessment, data from relevant clinical trials, and the future of MRD assessment in CLL treatment.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Flow Cytometry; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Real-Time Polymerase Chain Reaction; Sulfonamides

Venetoclax (Venclexta

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Progression-Free Survival; Sulfonamides

The treatment of chronic lymphocytic leukemia (CLL) embodies one of the great success stories in translational research, with the development of therapies aimed at disrupting crucial pathways that allow for the survival and proliferation of the malignant clone. The arrival of targeted agents into our armamentarium, along with the advent of novel monoclonal antibodies that can achieve deeper remissions, has steered the field to a new treatment paradigm. Given the panoply of therapeutic options available, the question arises whether chemotherapy still has a role in the management of CLL. The novel targeted agents, which include the Bruton's tyrosine kinase inhibitors, ibrutinib and acalabrutinib, along with the B-cell lymphoma-2 inhibitor, venetoclax, are highly effective in achieving a response with improved remission duration and survival, particularly in high-risk patients. Despite this major progress, the new agents bring a unique set of toxicities unlike those associated with cytotoxic chemotherapy. There is a paucity of head-to-head comparisons among all of the novel agents, because their approval was based on randomization against traditional chemoimmunotherapeutic regimens. Parallel to the increase in the number of available targeted agents, there has been a significant improvement in quality of life and life expectancy of the patients with a CLL diagnosis over the last decade. Our review will examine whether "chemotherapy-free" frontline treatment approaches are worth the associated risks. Our goal is to help identify optimal treatment strategies tailored to the individual by reviewing available data on monotherapy vs combination strategies, depth of response, treatment duration, and potential toxicities.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pyrazines; Rituximab; Sulfonamides

Novel agents, including Bruton's tyrosine kinase inhibitors (BTKi; ibrutinib, acalabrutinib), venetoclax, and phosphatidylinositol 3-kinase inhibitors (PI3Ki; idelalisib, duvelisib), have fundamentally changed the chronic lymphocytic leukemia (CLL) treatment landscape, allowing for a chemotherapy-free paradigm for many. Randomized trials that demonstrated efficacy of these agents in the relapsed/refractory setting rarely included patients with prior novel agent exposure. Herein, we review available data, including single-arm prospective studies and retrospective cohorts, on outcomes for novel agent approaches after novel agent exposure. We examine data for subsequent treatment options in 3 specific scenarios: (1) progression of disease while receiving BTKi, (2) progression of disease after discontinuation of BTKi for intolerance, and (3) after treatment with venetoclax. Data are most robust for venetoclax-based regimens after progression on BTKi. For patients who experience progression of disease after discontinuation of BTKi for intolerance, venetoclax-based regimens and retreatment with BTKi (depending on severity of initial intolerance) are 2 data-driven options. After frontline venetoclax/obinutuzumab, subsequent treatment approaches depend on whether patients experience progression of disease during or after discontinuation of their fixed duration frontline regimen and whether venetoclax/obinutuzumab was discontinued for intolerance. After progression of disease while on venetoclax, we recommend BTKi as second-line therapy. For patients who experience progression after completion or premature discontinuation (because of intolerance) of fixed duration venetoclax/obinutuzumab, either BTKi or retreatment with venetoclax (with aggressive supportive care if prior intolerance) are reasonable considerations. Subsequent lines of therapy in these scenarios include PI3Ki and consideration of cellular therapies. Finally, clinical trial enrollment for interested patients in any line of therapy is recommended.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Sulfonamides

Chronic lymphocytic leukemia is one of the most common lymphoid malignancies. Often treatment modalities are tailored to individual patients based on age, presence of comorbidities and cytogenetics. The advent of ibrutinib has significantly changed the management of the disease in all patient groups and has had the largest impact on clinical practice to date. Over the last 15 years, a series of trials have established that chemoimmunotherapy improves both progression-free survival and overall survival compared to chemotherapy alone. Despite its proven role, efficacy of ibrutinib has not been well established in young, fit patients and in comparison with standard care and as combination therapy with other agents such as venetoclax. New data have strengthened the role of ibrutinib in the front-line setting and establish its place in therapy. In addition, combination therapies are geared to achieve negative minimal residual disease and allow patients to potentially be off of therapy. The management of this leukemia has extensively changed over the past years, and this review article will aim to highlight key trials that have changed practice and led to guideline updates. It is not unlikely that treatment modalities will continue to improve in light of new data.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sulfonamides

This review summarizes the role of BCL-2 in the pathogenesis of CLL, and the clinical data evaluating safety and efficacy of venetoclax, in treatment of patients with CLL, in the context of other available targeted agents.. Venetoclax, alone or in combination with other targeted agents results in high rate of durable responses and undetectable measurable residual disease. Venetoclax maintains activity across all clinical and biologic subgroups, including those with high risk disease, including CLL with chromosome 17p deletion. TLS risk can be mitigated with risk stratification and five-week administration ramp-up schedule. Venetoclax, a novel, orally bioavailable inhibitor of BCL-2 has demonstrated substantial clinical activity in the treatment of CLL. In combination with other targeted agents it can induce high disease response rates and potentially lead to MRD-negative durable remissions.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Aberrations; Disease Progression; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Genetic Predisposition to Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides; Treatment Outcome

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Recurrence; Remission Induction; Sulfonamides; Survival Analysis

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Practice Guidelines as Topic; Prognosis; Sulfonamides; Time Factors

Chronic lymphocytic leukemia has a highly variable disease course across patients, thought to be driven by the vast inter- and intrapatient molecular heterogeneity described in several large-scale DNA-sequencing studies conducted over the past decade. Although the last 5 years have seen a dramatic shift in the therapeutic landscape for chronic lymphocytic leukemia, including the regulatory approval of several potent targeted agents (ie, idelalisib, ibrutinib, venetoclax), the vast majority of patients still inevitably experience disease recurrence or persistence. Recent genome-wide sequencing approaches have helped to identify subclonal populations within tumors that demonstrate a broad spectrum of somatic mutations, diverse levels of response to therapy, patterns of repopulation, and growth kinetics. Understanding the impact of genetic, epigenetic, and transcriptomic features on clonal growth dynamics and drug response will be an important step toward the selection and timing of therapy.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Epigenesis, Genetic; Gene Expression Regulation, Leukemic; Genome-Wide Association Study; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides; Transcriptome; Whole Genome Sequencing

The management of chronic lymphocytic leukemia (CLL) has undergone dramatic changes over the previous 2 decades with the introduction of multiple new therapies and new combinations. Management of the newly diagnosed asymptomatic patient has not significantly changed outside of the development of a number of prognostic factors and the CLL International Prognostic Index, which is helpful in discussions regarding prognosis and likelihood of requiring treatment. When therapy is required, initial treatment of most patients now includes either the Bruton tyrosine kinase inhibitor ibrutinib or the B-cell lymphoma 2 inhibitor venetoclax in combination with obinutuzumab. Current frontline trials are focused on the optimal sequencing or combination of targeted therapies. In this review, we will discuss the management of previously untreated CLL with an emphasis on the clinical trials that have formed the standard of care, as well as those newer studies that are likely to form the next generation of therapy.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides

By using chronic lymphocytic leukemia as target for discovery in cancer pathogenesis we discovered that the great majority of CLLs (75-85%) carry a deletion of miR-15a and miR-16-1 at 13q14. We also discovered that miR-15/16 are negative regulators of the BCL2 oncogene. Thus the loss of the two negative regulators causes BCL2 overexpression and leukemia. A corollary of this is that CLL is very sensitive to the anti BCL2 drug venetoclax that can induce complete remission in CLL patients. Since leukemia patients may carry billions of leukemia cells, it is quite likely that some (few) of the leukemic cells are resistant to venetoclax. Thus, since microRNAs have multiple targets, we looked for other proteins that may be overexpressed in CLL because of the low of miR-15/16. We discovered that ROR1 an embryonal antigen expressed on most (∼ 90%) CLL, but not on normal B cell, is also regulated by miR-15/16. Thus CLL cells are also sensitive to monoclonal antibodies against ROR1. Venetoclax and monoclonal antibodies against ROR1 act synergistically in killing CLL cells.

Topics: Animals; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Receptor Tyrosine Kinase-like Orphan Receptors; RNA, Neoplasm; Sulfonamides

Venetoclax, an antagonist of BCL-2 protein plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). It has been approved by the FDA for the treatment of relapsed/refractory CLL with del17p, and by the EMA for patients with del17p/TP53 mutation who have failed a BCR inhibitor, or in patients without those aberrations who have failed previous therapy, regardless of their genetic/molecular profile. Venetoclax in combination with rituximab has been also approved for the treatment of CLL after at least 1 prior therapy, regardless of del17p. Areas covered: This article reviews the chemical structure, mechanisms of action, pharmacokinetic, and the clinical applications of venetoclax in monotherapy and in combined treatment of CLL. Publications dated 2010 through March 2019 were obtained from the MEDLINE database. The proceedings of the American Society of Hematology held during the last five years were also included. Expert opinion: Venetoclax shows high efficacy, a favorable toxicity profile, and a high rate of minimal residual disease negativity, which is thought to have an impact on overall survival. It is efficient in patients with del17p/TP53 mutations, the incidence of which increases during clonal CLL evolution, and after the failure of BCR pathway inhibitors.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sulfonamides

Studies presented in patents show that a novel chemotherapeutic agent, venetoclax, might be useful in additional therapeutic indications. Venetoclax is approved in America for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Venetoclax selectively inhibits the B-cell lymphoma-2 (Bcl-2) protein, an anti-apoptotic protein that can be overexpressed in most B-cell lymphoid malignancies.. This is a review of all the patents granted until November 2018, with venetoclax in the examples or claim section of the patent document. The patents include the synthesis, polymorphism, formulations,. The approved indications for treatment with venetoclax are limited but expanding rapidly. Studies suggest that venetoclax might be useful in several other therapeutic indications, mostly other hematological malignancies. Numerous studies use venetoclax in combinations with other therapeutic agents. Such combinational treatment shows promising results in additional indications as well as drug-resistant cancers. Venetoclax is an interesting new therapeutic involved in a variety of clinical research. Patent applications in recent years even include venetoclax in somewhat exotic fields such as type 1 diabetes, asthma, and Zika virus treatment.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Patents as Topic; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; United States; United States Food and Drug Administration

More effective therapies are emerging, with better toxicity profiles, and are being incorporated into modern treatment algorithms of chronic lymphocytic leukemia at various stages of the disease, including for patients harboring Del17p and/or aberrant TP53. Ibrutinib, an inhibitor of Bruton's tyrosine kinase, has demonstrated impressive response rates in the relapsed/refractory setting, including in the setting of Del17p and/or TP53 mutations. Venetoclax, an inhibitor of BCL-2 known to play an important role in regulating cell death, has been approved recently for treatment of patients with chronic lymphocytic leukemia with Del17p who have received at least one prior therapy. Unfortunately, a cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. However, hematopoietic cell allografting is limited by the availability of suitable donors and significant morbidity and mortality. Recent clinical practice recommendations by the American Society for Blood and Marrow Transplantation have relegated the role of transplantation to later stages of the disease. In patients with evidence of Richter syndrome, frontline consolidation allogeneic hematopoietic cell transplantation remains the most desirable approach owing to the limited activity of ibrutinib or other novel therapies. Further therapeutic advances would require enrolling these patients in large clinical trials that evaluate novel therapies alone or in combination with traditional chemotherapies or even in the setting of posttransplant consolidation/maintenance.

Topics: Adenine; Allografts; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Smith-Magenis Syndrome; Sulfonamides; Tumor Suppressor Protein p53

Patients with chronic lymphocytic leukemia with the 17p deletion have a poor prognosis and treatment options are limited. Venetoclax, a novel B-cell lymphoma-2 inhibitor, has been approved for treatment-experienced chronic lymphocytic leukemia patients with the 17p deletion. A phase 1 dose-escalation study to 400 mg daily showed overall response rates across all doses of 79% with a complete response achieved in 20%. A phase 2 multicenter open-label study demonstrated overall response rate of 79.4% of patients (95% confidence interval 70.5-86.6) with median duration of follow-up of 12.1 months (IQR 10.1-14.2). Tumor lysis syndrome has been observed during initiation and titration. Assessing risk of tumor lysis syndrome prior to therapy initiation is essential to provide appropriate prophylactic medications. Neutropenia, potentially warranting dose reduction or discontinuation, has been observed. Venetoclax has demonstrated activity in other leukemias, multiple myeloma, and lymphomas. Venetoclax has shown response, and is well tolerated in patients with highly resistant chronic lymphocytic leukemia. It has the potential to be part of the treatment armamentarium for other malignancies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Sulfonamides; Tumor Lysis Syndrome

The landscape of chronic lymphocytic leukemia (CLL) treatment has changed considerably since the first reported assessment of minimal residual disease (MRD) by flow cytometry in 1992. Chemoimmunotherapy (CIT) combinations have become the standard of care for most patients, and novel targeted agents are rapidly being incorporated into the front-line and relapsed settings. Minimal residual disease status has been shown to be a predictor of both progression-free survival (PFS) and overall survival (OS) at the time of response assessment following CIT, but less is known about the relationship between MRD and outcomes after novel oral therapeutics. Herein, we review current methods for MRD testing and present relevant clinical data for MRD for current treatment regimens focusing on novel oral agents as monotherapies and in combination.. Flow cytometry and polymerase chain reaction are the 2 methods most frequently used to measure MRD, although high-throughput sequencing and more specific assays are being refined. Minimal residual disease status is an independent predictor of PFS and OS for patients receiving CIT, and emerging data for venetoclax suggest a relationship between MRD negativity and outcomes. The prognostic value of MRD status for kinase inhibitors remains unknown.. Minimal residual disease as a clinical trial end point must be validated in prospective studies prior to being used as a surrogate for survival. Given the heterogeneity of CLL biology and therapies, this validation must be regimen specific. Minimal residual disease assessments should be performed in clinical trial patients with both partial and complete responses. Following CIT, MRD status has prognostic value in all responders and this observation is important to validate with novel agents because most patients obtain partial remission. Further research is required to validate the use of MRD status as a decision point in guiding therapy in clinical practice.

Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drugs, Investigational; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Prognosis; Protein Kinase Inhibitors; Sulfonamides; Treatment Outcome

In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis. In 2002, we studied 13q deletions in chronic lymphocytic leukemia (CLL) and found that the microRNA cluster miR-15a/miR-16-1 (miR-15/16) is deleted by 13q deletions. In 2005, we discovered that miR-15/16 function as tumor suppressors by directly targeting BCL2. Thus the loss of two negative regulators of BCL2 expression results in overexpression of BCL2. Very recently, a specific BCL2 inhibitor ABT-199 (Venetoclax) was developed and approved by FDA for CLL treatment. Thus it took 32 years from fundamental discovery of a critical oncogene to the development of a drug capable to cure CLL. In this review, we discuss the discovery, functions and clinical relevance of miR-15/16 and BCL2.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 13; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy.. We review key features of ibrutinib, along with problems of its use, discuss the potential and drawbacks of second generation molecules, and discuss combination therapies currently in development.. BTK inhibitors have been a major therapeutic advance in older/unfit patients and those with high-risk and/or relapsed CLL, but require indefinite maintenance therapy and risk of developing treatment resistance or adverse events requiring treatment cessation increases over time. Novel combination strategies are currently being evaluated (e.g. the combination of ibrutinib with venetoclax), which may achieve greater depth of remission, remove the need for indefinite maintenance treatment and potentially replace chemoimmunotherapy in the first-line setting.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Sulfonamides

Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities. The anticipated licensed indication specified that venetoclax-eligible del(17p)/TP53 patients should have not responded to, or be deemed unsuitable for, B-cell receptor inhibitor (BCRi) therapy, and that non-del(17p)/TP53 patients should have not responded to both chemoimmunotherapy and BCRi therapy. The three trials were heterogeneous in terms of both del(17p)/TP53 status and previous exposure to BCRi therapy. The M13-982 study investigated 158 R/R CLL patients with the 17p deletion, but only a small number had received previous BCRi therapy; the M12-175 study investigated 67 patients with CLL or small lymphocytic lymphoma, some with the 17p deletion, but very few previously treated with BCRi therapy; and the M14-032 study included 105 patients previously treated with BCRi therapy (either idelalisib or ibrutinib), some of whom had unknown mutation status. The ERG concluded that the study populations did not directly conform to those specified in the licensed indication or in the NICE scope. Outcomes reported included overall response rate (ORR), duration of response, progression-free survival (PFS) and overall survival (OS); adverse events were reported for the pooled population of all three studies, as well as separately for each study. The median PFS was 41.4 and 27.2 months among patients in the M12-175 and M13-982 trials, respectively, whereas the median PFS was not reached in the M14-032 trial. Some results were designated academic in confidence and cannot be reported here. The submission provided a de novo partitioned survival cost-effectiveness model with three health states: pre-progression, post-progression and dead. Transition probabilities between health states were estimated using Weibull models for PFS and OS. The ERG judged the model structure to be appropriate. Venetoclax was compared with best supportive care (BSC) in patients with or without del(17p)/TP53 mu

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cost-Benefit Analysis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Economic; Sulfonamides; Technology Assessment, Biomedical

Important advances in understanding the pathogenesis of chronic lymphocytic leukaemia in the past two decades have led to the development of new prognostic tools and novel targeted therapies that have improved clinical outcome. Chronic lymphocytic leukaemia is the most common type of leukaemia in developed countries, and the median age at diagnosis is 72 years. The criteria for initiating treatment rely on the Rai and Binet staging systems and on the presence of disease-related symptoms. For many patients with chronic lymphocytic leukaemia, treatment with chemotherapy and anti-CD20 monoclonal antibodies is the standard of care. The impressive efficacy of kinase inhibitors ibrutinib and idelalisib and the BCL-2 antagonist venetoclax have changed the standard of care in specific subsets of patients. In this Seminar, we review the recent progress in the management of chronic lymphocytic leukaemia and highlight new questions surrounding the optimal disease management.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Diagnosis, Differential; Genetic Predisposition to Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Risk Factors; Sulfonamides; Survival Analysis; Treatment Outcome

Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, thus inducing excessive toxicity, the highly selective BCL2 inhibitor venetoclax (ABT-199, Venclexta™) has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens. Sensitivity to venetoclax is not common in lymphomas, but promising outcomes have been achieved in the mantle cell lymphoma group. Venetoclax is also active in multiple myeloma patients, especially in those with translocation t(11;14), even if high-risk features such as del17p are also present. Surprisingly, positive results are being obtained in elderly acute myeloid leukemia patients, in whom inhibition of BCL2 is able to substantially increase the efficacy of low-dose cytarabine or hypomethylating agents. Here, we provide a summary of available results from clinical trials and describe a specific mechanism of action that stands behind the efficacy of venetoclax in hematological malignancies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Signal Transduction; Sulfonamides

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile. Areas covered: This article covers the biology of apoptosis in CLL from a translational viewpoint and deals with the mode of action of BCL2 inhibitors, in particular venetoclax. On this biological rationale, the review then focuses on the results obtained in clinical trials with venetoclax in CLL. Expert commentary: The availability of venetoclax represents a major advance in CLL treatment and offers new opportunities to further improve the results obtained until now by combining venetoclax with other agents. Venetoclax has achieved responses also in patients with TP53 disruption. These results strongly suggest that the mechanism by which venetoclax kills CLL cells might overcome a dysfunctional TP53 that is a major hallmark of chemorefractoriness to conventional antineoplastic agents.

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides; Tumor Suppressor Protein p53

Although the therapy of chronic lymphocytic leukemia (CLL) has changed rapidly over the last 5 years, the key considerations in selecting a therapy for a previously treated patient with CLL continue to include the nature of the prior therapy and the duration of prior remission to that therapy, the prognostic features of the disease, and the health and comorbidities of the patient in question. For patients treated initially with chemoimmunotherapy, randomized trials have demonstrated the benefit of targeted therapy. Retrospective data suggest that ibrutinib is preferred as a first kinase inhibitor, whereas recent data with venetoclax and rituximab may challenge the choice of ibrutinib as a first novel agent in the relapsed setting. Data on sequencing of novel agents remain quite sparse, consisting of 1 prospective trial that demonstrated the efficacy of venetoclax in patients who have experienced progression with a kinase inhibitor, as well as a retrospective real-world analysis supporting this observation. Novel agents in advanced clinical development include primarily next-generation Bruton's tyrosine kinase and phosphatidylinositol 3-kinase δ inhibitors, with other classes still in phase 1 trials. Clinical trials of combination time-limited therapies with the goal of deep remission and discontinuation are also in progress.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Rituximab; Sulfonamides

Defects in apoptotic cell death can promote cancer and impair responses of malignant cells to anti-cancer therapy. Pro-survival BCL-2 proteins prevent apoptosis by keeping the cell death effectors, BAX and BAK, in check. The BH3-only proteins initiate apoptosis by neutralizing the pro-survival BCL-2 proteins. Structural analysis and medicinal chemistry led to the development of small-molecule drugs that mimic the function of the BH3-only proteins to kill cancer cells. The BCL-2 inhibitor venetoclax has been approved for treatment of refractory chronic lymphocytic leukemia and this drug and inhibitors of pro-survival MCL-1 and BCL-XL are being tested in diverse malignancies.

Topics: Antineoplastic Agents; Apoptosis; bcl-X Protein; Biomimetic Materials; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Bruton's tyrosine kinase (BTK), a mediator in B cell receptor signaling has been successfully exploited as a therapeutic target in treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a BTK inhibitor that has shown excellent efficacy in treatment-naïve, heavily pre-treated, and high-risk CLL/SLL. With remarkable efficacy, good oral bioavailability, and modest adverse events profile, ibrutinib use is likely to continue to increase. As data with ibrutinib use in CLL matures, concerns regarding adverse events and drug resistance have emerged. New insights into mechanisms of ibrutinib resistance in CLL have uncovered potential therapeutic targets. Several promising novel agents are currently in early phases of development for overcoming ibrutinib resistance in CLL/SLL. We provide a comprehensive analysis of emerging adverse events profile of ibrutinib, summarize our current understanding of ibrutinib resistance in CLL, and review promising novel therapeutic tools to overcome this challenge.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Diarrhea; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Nausea; Piperidines; Protein-Tyrosine Kinases; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Sulfonamides

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Interactions; Food-Drug Interactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides

The therapy for chronic lymphocytic leukemia (CLL) is undergoing a major transformation. However, the seminal progresses realized to date with the use of novel agents, leave many practical questions unanswered. Areas covered: This review focuses on the recent data of the literature of small-kinase inhibitor (KI) molecules and how results of KI clinical trials may translate into current clinical practice. Several questions such as the advantage of combining small-KI molecules with anti-CD20 monoclonal antibodies or with chemo-immunotherapy in comparison to targeted agents alone are discussed. Expert commentary: Nowadays the challenge is to apply the principles of chemotherapy to combine different targeted agents with nonoverlapping toxicities. This approach is not likely to immediately change the standard of care, however, it raises relevant questions concerning the optimal strategy for incorporating novel agents in the treatment of CLL. Given the increasing number of patients who have access to treatment with small-KI molecules, generally administered over an extended duration, more sustainable pricing for such therapies is needed.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sulfonamides

Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients. New options include two agents targeting B cell receptor (BCR) signaling pathways (ibrutinib and idelalisib) and a B cell lymphoma-2 (BCL-2) inhibitor (venetoclax). Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative option for younger patients with a suitable donor.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Drug Therapy; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Recurrence; Sulfonamides; Transplantation, Homologous

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Prognosis; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Remission Induction; Sulfonamides; Tumor Suppressor Protein p53

Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy. New targeted therapies have recently been approved in the treatment of CLL, including the oral kinase inhibitors, idelalisib and ibrutinib, and the B-cell lymphoma-2 protein inhibitor, venetoclax. Several others are also under development, and combination strategies of these agents are being explored. This review examines the diagnosis, prevention, and management of TLS and summarizes the TLS experience in CLL clinical trials with newer targeted agents. Overall, the risk of TLS is small, but the consequences may be fatal; therefore, patients should be monitored carefully. Therapies capable of eliciting rapid response and combination regimens are increasingly being evaluated for treatment of CLL, which may pose a higher risk of TLS. For optimal management, patients at risk for TLS require prophylaxis and close monitoring with appropriate tests and appropriate management to correct laboratory abnormalities, which allows for safe and effective disease control.. Tumor lysis syndrome (TLS) is a potentially fatal condition observed with hematologic malignancies, caused by release of cellular components in the bloodstream from rapidly dying tumor cells. The frequency and severity of TLS is partly dependent upon the biology of the disease and type of therapy administered. Novel targeted agents highly effective at inducing rapid cell death in chronic lymphocytic leukemia (CLL) may pose a risk for TLS in patients with tumors characterized by rapid growth, high tumor burden, and/or high sensitivity to treatment. In this review, prevention strategies and management of patients with CLL who develop TLS are described.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Purines; Quinazolinones; Risk Factors; Sulfonamides; Tumor Burden; Tumor Lysis Syndrome

Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
.. The aim was to describe treatment management considerations when caring for patients using venetoclax.
.. A review was done of safety and management considerations based on current clinical practice and 240 patients with CLL who received venetoclax monotherapy on clinical trials from 2011-2016.
.. Common adverse events were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. Because of rapid tumor reduction with venetoclax, nurses should be aware of the potential for tumor lysis syndrome (TLS) and the need to educate patients on steps to minimize risks, including gradual dose ramp-up, adequate hydration, and use of prophylactic antihyperuricemia agents. Following implementation of these risk-reducing measures, no clinical TLS events were reported in ongoing trials.

Topics: Adult; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Sulfonamides; Tumor Lysis Syndrome

With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Smith-Magenis Syndrome; Sulfonamides

The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Drug Design; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies.. A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta.. Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified.. Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations.. Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Sulfonamides; Treatment Outcome; Tumor Burden; Tumor Lysis Syndrome

Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacologic mimic of the proteins that initiate apoptosis (a so-called BH3 mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells, which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a phase I study, including complete remissions in 20% of patients. Its use was approved by the FDA in April 2016 for patients with previously treated del(17p) CLL on the basis of a single-arm phase II trial demonstrating a 79% response rate and an estimated 1-year progression-free survival of 72% with 400 mg/day continuous therapy. This review focuses on venetoclax, its mechanism of action, pharmacology, and clinical trial data and seeks to place it in the context of rapid advances in therapy for patients with relapsed CLL, especially those with del(17p) CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local; Prognosis; Proto-Oncogene Proteins c-bcl-2; Remission Induction; Sulfonamides

The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.

Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides

The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-X

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Biomimetics; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Small-molecule BH3 mimetics are designed to mimic the BH3 domain of BH3-only BCL-2 family members which are antagonists of the prosurvival members (such as BCL-2, BCL-XL and MCL-1). The BH3 mimetics are intended to bind with high affinity to prosurvival proteins, in order to inhibit their functional activity and hence to induce apoptosis in cancer cells. Both navitoclax (BCL-2/BCL-XL antagonist) and ABT-199/venetoclax (BCL-2-selective inhibitor) have demonstrated therapeutic efficacy especially in chronic lymphocytic leukemia (CLL). However, these BH3 mimetics cannot antagonize the prosurvival protein MCL-1 that is overexpressed and involved in therapeutic resistance in CLL. Furthermore, until now, none of the reported small-molecule MCL-1 inhibitors bound to their target with high affinity. The first MCL-1-selective BH3 mimetics capable of high-affinity binding and inducing apoptosis in cancer cells through an on-target mechanism have just been identified. This discovery should advance the translational research to implement novel drugs in treating CLL.

Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Fragments; Proto-Oncogene Proteins; Sulfonamides

During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. The advent of oral targeted therapies, particularly ibrutinib and idelalisib, has provided generally well-tolerated and highly effective additional options that have come into widespread use in the relapsed setting. Additional agents are advancing in clinical development, with the BCL-2 inhibitor venetoclax likely to be approved by the U.S. Food and Drug Administration (FDA) in 2016. With the development of these novel therapies for patients with relapsed CLL, many unanswered questions remain, including the optimal sequence (first vs. second line), duration, discontinuation, and combination of these agents. In addition, recent publications show the emergence of a pattern of treatment resistance in certain subgroups of patients with del(17p) and complex karyotype that needs further study and improvement. Because the field of CLL management has become much more complex, we focus here on understanding the recent data and discuss many of the questions and controversies important for how we approach patients with CLL.

Topics: Adenine; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sulfonamides; Vidarabine

Venetoclax (ABT-199) is a small-molecule selective oral inhibitor of the antiapoptotic protein Bcl-2 that promotes programmed cell death of chronic lymphocytic leukemia (CLL) cells regulating the release of proapoptotic factors, such as Smac/Diablo, apoptosis-inducing factor (AIF) and cytochrome c. In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval to venetoclax for patients diagnosed with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy. This review will focus on the mechanism of action, preclinical studies and clinical development of venetoclax both as a monotherapy and in combination with other drugs for CLL in the current milieu of therapy dominated by novel tyrosine kinase inhibitors such as ibrutinib and idelalisib.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Given the current dynamics in the development of novel agents for CLL therapy, the task to find optimal, non-toxic combinations has become the primary goal. This article gives an update of the most interesting novel drugs. The strategy of the German CLL Study Group to use these agents in combinations is described in detail, highlighting the strategy and first results of a recently started series of phase II combination trials, the BXX series using agents such as bendamustine, idelalisib, ibrutinib, obinutuzumab, ofatumumab and venetoclax.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Precision Medicine; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Risk Factors; Sulfonamides

Novel therapies targeting various kinases downstream of the B-cell receptor have emerged along with monoclonal antibodies and BCL-2 antagonists, and are changing the therapeutic landscape of chronic lymphocytic leukemia. However, cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Access to allogeneic hematopoietic cell transplantation has expanded considerably with availability of reduced intensity conditioning regimens which is capable offering durable remissions even in poor-risk disease. Encouraging data from ibrutinib and venetoclax in Del17p is challenging the notion of disease eradication as the ultimate therapeutic goal to a new concept of merely disease control. By favoring the non-transplant approach, patients should be aware that there are no established salvage therapies, yet, to rescue disease progression after ibrutinib. When disease eradication is the desirable approach, a reduced intensity conditioning allogeneic hematopoietic cell transplant is the preferred choice at this time.

Topics: Adenine; Allografts; Antibodies, Monoclonal; Antibodies, Neoplasm; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Smith-Magenis Syndrome; Sulfonamides

Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy.

Topics: Adenine; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Flavonoids; Humans; Immunologic Factors; Indolizines; Isoquinolines; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyridinium Compounds; Pyrimidines; Quinazolinones; Receptors, Antigen, T-Cell; Sulfonamides; Thalidomide

The last several years have seen an explosion of novel therapies for chronic lymphocytic leukemia (CLL). These include the antibody obintutuzumab (GA-101), as well as small-molecule inhibitors of key pathways involved in the pathogenesis of CLL, specifically the B-cell receptor (BCR) pathway (especially Bruton's tyrosine kinase [BTK] and P13K), and the antiapoptotic pathway (especially BCL-2). We will consider each in turn, focusing on the molecules most advanced in clinical development. There has also been extensive development in rewiring the patient's own immune system to treat CLL. This has been done through modifying autologous T cells to express a chimeric antigen receptor (CAR). Thus far all CAR-T preparations have targeted the CD19 antigen. This is a good rational for B-cell malignancies as CD19 expression is limited to B-cell malignancies and normal B cells. The in vivo amplification of the transduced T cells relies on signaling and co-signaling domains and provides significant killing of CLL cells. As exciting as these novel agents and approaches are, they obviously beg the question, will chemotherapy as a treatment for CLL soon be obsolete? Although chemotherapy is associated with known short-term toxicities, it has the advantage of being completed in a short period of time and being relatively inexpensive in comparison to novel therapies. In addition, long-term follow-up of results with chemoimmunotherapy have now identified a group of patients whose remissions are maintained for more than 10 years. An important question that will arise going forward is how to incorporate novel agents without eliminating the long term benefits possible with chemoimmunotherapy in a subset of patients with CLL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antibodies, Monoclonal, Humanized; Antigens, CD19; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Immunotherapy; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Small Molecule Libraries; Sulfonamides; Vidarabine

ABT-199, a second-generation BH3 mimetic, is an orally bioavailable, small molecule inhibitor that selectively targets B-cell lymphoma/leukemia 2 (Bcl-2). Bcl-2 is a key protein that inhibits the intrinsic mitochondrial pathway of apoptosis. First-generation BH3 mimetics such as navitoclax (ABT-263) had a broad range of inhibitory activity against Bcl-2 family members, including Bcl-2, Bcl-XL, and Bcl-w. This drug demonstrated antitumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL); however, on-target Bcl-XL inhibition led to dose-dependent thrombocytopenia and posed a barrier to maximizing the activity of this agent. Through an elegant reengineering of navitoclax, ABT-199 was developed as a Bcl-2-selective small molecule inhibitor. In preclinical studies, ABT-199 was shown to have greater than 100-fold selectivity for Bcl-2 over Bcl-XL. This selectivity has been consistent with the early results of the ongoing phase 1 clinical trial of ABT-199 in which the drug has demonstrated high rates of activity in relapsed/refractory CLL and NHL without dose-dependent thrombocytopenia. On-target tumor lysis syndrome (TLS) has been observed in a subset of patients treated with ABT-199, but changes in initial dosing and stepwise dose escalation have now been implemented to mitigate this risk. Ongoing correlative studies are being performed to help identify patients with the highest chance of response and the greatest risk for TLS.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The failure of apoptosis (programmed cell death) underpins the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein BCL2. Because abnormally high levels of BCL2 sustain these tumors, there has been much interest in targeting BCL2 as a novel approach to treating various hematologic malignancies. One such approach is the development of BH3 mimetic compounds, small molecules that mimic the action of the BH3-only proteins, natural antagonists of BCL2 and its pro-survival relatives. These compounds act by restoring the ability of a cell to undergo apoptotic cell death. Some of them have shown very encouraging results in early-phase clinical trials that are currently underway, particularly in patients with chronic lymphocytic leukemia and some non-Hodgkin lymphomas, diseases marked by BCL2 overexpression. In this review, we discuss the rationale behind targeting BCL2, highlight the recent findings from clinical trials, and pinpoint the next steps in the clinical development of this interesting and promising class of targeted agents, particularly for the treatment of lymphoid malignancies.

Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Hematologic Neoplasms; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

The development of targeted treatment of chronic lymphocytic leukaemia (CLL) is changing the prognostic outlook for CLL patients. The B-cell antigen receptor pathway is identified as pivotal for CLL pathogenesis and CLL cell proliferation. Inhibition of this pathway by ibrutinib (Bruton's tyrosin kinase inhibition) and idelalisib (phosphatidylinositol 3-kinase inhibition) has recently shown impressive clinical results, also for CLL patients with relapsed/refractory disease and unfavourable prognostic markers. Apoptosis induction by inhibition of BCL2 with ABT-199 is reported with likewise promising clinical results.

Topics: Adenine; Aminopyridines; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Oxazines; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Signal Transduction; Sulfonamides

The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of front-line, fixed-duration venetoclax and rituximab (VenR) in combination in young (≤65 years), fit patients with chronic lymphocytic leukemia and unmutated IGHV and/or TP53 disruption. Treatment consisted of the venetoclax ramp-up, six monthly courses of the VenR combination, followed by six monthly courses of venetoclax as a single agent. A centralized assessment of minimal residual disease (MRD) was performed by allele-specific oligonucleotide polymerase chain reaction assay on the peripheral blood and bone marrow at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range, 38-65), 96% had unmutated IGHV, 12% had TP53 disruption, and 4% had mutated IGHV with TP53 disruption. The overall response rate at the EOT was 94.7%, with a complete remission rate of 76%. MRD was undetectable in the peripheral blood of 69.3% of patients and in the bone marrow of 58.7% of patients. The 12-month MRD-free survival in the 52 patients with undetectable MRD in the peripheral blood at the EOT was 73.1%. After a median follow-up of 20.8 months, no cases of disease progression were observed. Three patients had died, two due to COVID-19 and one due to tumor lysis syndrome. The first report of the VERITAS study shows that front-line VenR was associated with a high rate of complete remissions and durable response with undetectable MRD in young patients with chronic lymphocytic leukemia and unfavorable genetic characteristics. ClinicalTrials.gov identifier: NCT03455517.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; COVID-19; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Neoplasm, Residual; Rituximab

Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized (1:1) to receive either 1-year venetoclax-obinutuzumab (Ven-Obi, 216 patients) or chlorambucil-Obi (Clb-Obi, 216 patients) therapy (NCT02242942). The primary endpoint was investigator-assessed progression-free survival (PFS); secondary endpoints included minimal residual disease (MRD) and overall survival. RNA sequencing of CD19-enriched blood was conducted for exploratory post-hoc analyses. After a median follow-up of 65.4 months, PFS is significantly superior for Ven-Obi compared to Clb-Obi (Hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p < 0.0001). At 5 years after randomization, the estimated PFS rate is 62.6% after Ven-Obi and 27.0% after Clb-Obi. In both arms, MRD status at the end of therapy is associated with longer PFS. MRD + ( ≥ 10

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Transcriptome

Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking.. In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have. A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%).. Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

Topics: Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Rituximab

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.

Topics: Abnormal Karyotype; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Karyotype; Karyotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis

Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma.. We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 10. Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis).. A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable.. Juno Therapeutics, a Bristol-Myers Squibb Company.

Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Remission Induction; Sulfonamides

We evaluated immune cell subsets in patients with chronic lymphocytic leukemia (CLL) who received first-line therapy with 3 cycles of ibrutinib then 13 cycles of ibrutinib plus venetoclax in the minimal residual disease (MRD) cohort of the CAPTIVATE study (NCT02910583). Patients with Confirmed undetectable MRD (uMRD) were randomly assigned to placebo or ibrutinib groups; patients without Confirmed uMRD were randomly assigned to ibrutinib or ibrutinib plus venetoclax groups. We compared immune cell subsets in samples collected at 7 time points with age-matched healthy donors. CLL cells decreased within 3 cycles after venetoclax initiation; from cycle 16 onward, levels were similar to healthy donor levels (HDL; ≤0.8 cells per μL) in patients with Confirmed uMRD and slightly above HDL in patients without Confirmed uMRD. By 4 months after cycle 16, normal B cells had recovered to HDL in patients randomly assigned to placebo. Regardless of randomized treatment, abnormal counts of T cells, classical monocytes, and conventional dendritic cells recovered to HDL within 6 months (median change from baseline -49%, +101%, and +91%, respectively); plasmacytoid dendritic cells recovered by cycle 20 (+598%). Infections generally decreased over time regardless of randomized treatment and were numerically lowest in patients randomly assigned to placebo within 12 months after cycle 16. Sustained elimination of CLL cells and recovery of normal B cells were confirmed in samples from patients treated with fixed-duration ibrutinib plus venetoclax in the GLOW study (NCT03462719). These results demonstrate promising evidence of restoration of normal blood immune composition with ibrutinib plus venetoclax.

Topics: Humans; Immune Reconstitution; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines

In the GLOW study, fixed-duration ibrutinib-venetoclax showed superior progression-free survival versus chlorambucil-obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia who were older or had comorbidities, or both, at a median follow up of 27·7 months. In this Article, we report updated outcomes from GLOW after a 46-month median follow-up.. GLOW was a randomised, multicentre, phase 3 study done at 67 hospital centres across 14 countries. Patients aged 65 years and older or 18-64 years with previously untreated chronic lymphocytic leukaemia and a cumulative illness rating scale score of more than 6 or creatinine clearance less than 70 mL/min, or both, and an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) via an interactive web system with permuted blocks (block size of four) and stratified by IGHV mutational status and the presence of del11q aberration to the ibrutinib-venetoclax group (three cycles of ibrutinib lead-in [420 mg/day, orally], followed by 12 cycles of ibrutinib plus venetoclax [400 mg/day, orally, including a 5-week dose ramp-up]) or the chlorambucil-obinutuzumab group (six cycles of chlorambucil [0·5 mg/kg, orally, on days 1 and 15 of each cycle], and obinutuzumab [1000 mg, intravenously, on days 1 (or 100 mg on day 1 and 900 mg on day 2), 8, and 15 of cycle 1 and day 1 of cycles 2-6]). The primary endpoint was progression-free survival in the intention-to-treat population, assessed by an independent review committee. The safety population included all randomised patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov (NCT03462719) and the EU Clinical Trials Register (EudraCT 2017-004699-77).. Between May 4, 2018, and April 5, 2019, 211 patients (122 [58%] were male and 89 [42%] were female) were randomly assigned to receive ibrutinib-venetoclax (n=106) or chlorambucil-obinutuzumab (n=105). At a median of 46 months (IQR 43-47) of follow-up, progression-free survival remained superior for the ibrutinib-venetoclax group (hazard ratio 0·214 [95% CI 0·138-0·334]; p<0·0001); 42-month progression-free survival rates were 74·6% (95% CI 65·0-82·0) for ibrutinib-venetoclax and 24·8% (16·5-34·1) for chlorambucil-obinutuzumab. Following the primary analysis, one patient in the chlorambucil-obinutuzumab group had a serious adverse event of myelodysplastic syndrome. Treatment-related deaths were reported in one patient receiving ibrutinib-venetoclax (cardiac failure, pneumonia, and sinus node dysfunction) and in one patient receiving chlorambucil-obinutuzumab (pneumonia). There were 15 deaths in the ibrutinib-venetoclax group (of which three were due to post-treatment infections) and 30 deaths in the chlorambucil-obinutuzumab group (of which 10 were due to post-treatment infections).. After 4 years of follow-up, ibrutinib-venetoclax continues to significantly prolong progression-free survival (vs chemoimmunotherapy) in patients with previously untreated chronic lymphocytic leukaemia, supporting its use as a first-line option.. Janssen Research & Development and Pharmacyclics.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Pneumonia

The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Myelopoiesis; Myeloproliferative Disorders; Neoplasms, Second Primary; Sulfonamides; Vidarabine

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local; Quality of Life; Sulfonamides; Treatment Outcome

Richter syndrome (RS) of chronic lymphocytic leukemia (CLL) is typically chemoresistant, with a poor prognosis. We hypothesized that the oral Bcl-2 inhibitor venetoclax could sensitize RS to chemoimmunotherapy and improve outcomes. We conducted a single-arm, investigator-sponsored, phase 2 trial of venetoclax plus dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (VR-EPOCH) to determine the rate of complete response (CR). Patients received R-EPOCH for 1 cycle, then after count recovery, accelerated daily venetoclax ramp-up to 400 mg, then VR-EPOCH for up to 5 more 21-day cycles. Responders received venetoclax maintenance or cellular therapy off-study. Twenty-six patients were treated, and 13 of 26 (50%) achieved CR, with 11 achieving undetectable bone marrow minimal residual disease for CLL. Three additional patients achieved partial response (overall response rate, 62%). Median progression-free survival was 10.1 months, and median overall survival was 19.6 months. Hematologic toxicity included grade ≥3 neutropenia (65%) and thrombocytopenia (50%), with febrile neutropenia in 38%. No patients experienced tumor lysis syndrome with daily venetoclax ramp-up. VR-EPOCH is active in RS, with deeper, more durable responses than historical regimens. Toxicities from intensive chemoimmunotherapy and venetoclax were observed. Our data suggest that studies comparing venetoclax with chemoimmunotherapy to chemoimmunotherapy alone are warranted. This trial was registered at www.clinicaltrials.gov as #NCT03054896.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neutropenia; Prednisone; Progression-Free Survival; Sulfonamides; Vincristine

Despite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Piperidines; Sulfonamides; Survival Rate

Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.. We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).. Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.. Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse.. F Hoffmann-La Roche.

Topics: Adolescent; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Sulfonamides

Acquired T-cell dysfunction is characteristic of chronic lymphocytic leukemia (CLL) and is associated with reduced efficacy of T cell-based therapies. A recently described feature of dysfunctional CLL-derived CD8 T cells is reduced metabolic plasticity. To what extend CD4 T cells are affected and whether CD4 T-cell metabolism and function can be restored upon clinical depletion of CLL cells are currently unknown. We address these unresolved issues by comprehensive phenotypic, metabolic, transcriptomic, and functional analysis of CD4 T cells of untreated patients with CLL and by analysis of the effects of venetoclax plus obinutuzumab on the CD4 population. Resting CD4 T cells derived from patients with CLL expressed lower levels of GLUT-1 and displayed deteriorated oxidative phosphorylation (OXPHOS) and overall reduced mitochondrial fitness. Upon T-cell stimulation, CLL T cells were unable to initiate glycolysis. Transcriptome analysis revealed that depletion of CLL cells in vitro resulted in upregulation of OXPHOS and glycolysis pathways and restored T-cell function in vitro. Analysis of CD4 T cells from patients with CLL before and after venetoclax plus obinutuzumab treatment, which led to effective clearance of CLL in blood and bone marrow, revealed recovery of T-cell activation and restoration of the switch to glycolysis, as well as improved T-cell proliferation. Collectively, these data demonstrate that CLL cells impose metabolic restrictions on CD4 T cells, which leads to reduced CD4 T-cell functionality. This trial was registered in the Netherlands Trial Registry as #NTR6043.

Topics: Bridged Bicyclo Compounds, Heterocyclic; CD4-Positive T-Lymphocytes; Glycolysis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Oxidative Stress; Sulfonamides

With the advent of highly efficacious time-limited combination treatments of targeted agents in chronic lymphocytic leukemia (CLL), minimal residual disease (MRD) assessment has gained importance as a measure for therapeutic success and as a surrogate for progression-free survival. The currently most widely used method is multicolor flow cytometry, which detects circulating CLL cells in the peripheral blood. However, it seems to be less sensitive for the detection of MRD in the lymph node compartment.. To evaluate whether a cell-free approach can overcome this limitation, we performed serial assessments of circulating tumor DNA (ctDNA) in patients with CLL treated with obinutuzumab, acalabrutinib, and venetoclax in the phase II CLL2-BAAG trial. Patient-specific variability, diversity, joining (VDJ) rearrangements as well as somatic driver mutations were tracked before, during and after treatment by digital droplet PCR in blood plasma. Furthermore, these were systematically compared to matched flow cytometry data.. In the 381 sample pairs, ctDNA and flow cytometry yielded highly concordant results. However, clone-specific ctDNA was detected in 44 of 152 samples (29%) that were assessed as undetectable MRD (uMRD) by flow cytometry (defined as less than one CLL cell in 10,000 normal leukocytes). 29 ctDNA-negative samples showed detectable MRD >10-4 by flow cytometry. Also, somatic driver mutations were detected with a similar sensitivity compared with patient-specific VDJ rearrangements in plasma. In patients with predominantly nodal residual disease, ctDNA compared favorably with 4-color flow cytometry and seemed to more accurately reflect the entire disease burden across compartments.. On the basis of these findings, ctDNA-based MRD assessment appears to be a promising method to complement cell-based MRD approaches like flow cytometry that focus on circulating CLL cells in the peripheral blood.

Topics: Antibodies, Monoclonal, Humanized; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Circulating Tumor DNA; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Pyrazines; Sulfonamides

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years' follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10-7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Recurrence; Rituximab; Sulfonamides

Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group.. HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (<10. Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34·4 months (IQR 30·6-37·9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89-100). Infections (in 130 [58%] of 225 patients), neutropenia (in 91 [40%] patients), and gastrointestinal adverse events (in 53 [24%] patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib.. These data point to a favourable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population.. AbbVie and Janssen.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

This study aims to investigate pharmacokinetics (PK) and exposure-response parameters of the 400 mg once-daily venetoclax dose regimen in combination with obinutuzumab, which was approved for the first-line (1L) treatment of chronic lymphocytic leukemia (CLL) based on data from the phase 3 CLL14 study and the phase 1b dose-finding GP28331 study.. Parameter estimates and uncertainty, which were estimated by a previously developed population PK (popPK) model, were used as informative priors for this analysis. They were re-estimated, and then used to evaluate additional covariate effects, describe venetoclax PK when administered with obinutuzumab, and provide empirical Bayes estimates of PK parameters and exposure. Exposure-progression-free survival (PFS) and exposure-safety relationships were assessed using data from CLL14, with steady-state nominal venetoclax exposure (C. PK data from 274 patients (CLL14, n = 194; GP28331, n = 80) were included. The final model provided good fit of the observed data. Obinutuzumab co-administration, history of prior treatments, and disease severity at baseline had no appreciable influence on venetoclax steady-state exposure. No significant correlations were observed between venetoclax exposure and PFS, or between venetoclax exposure and the probability of treatment-emergent grade ≥ 3 neutropenia, grade ≥ 3 thrombocytopenia, grade ≥ 3 infections, and SAEs. Median dose intensities for venetoclax and obinutuzumab remained similar across venetoclax exposure tertiles.. PopPK and exposure-efficacy, exposure-safety, and exposure-tolerability analyses support the 400 mg once-daily venetoclax dose plus obinutuzumab for 1L treatment in patients with CLL.. ClinicalTrials.gov Identifiers NCT02242942 and NCT02339181.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Although BTK inhibitors provide long-term disease-control in patients with chronic lymphocytic leukaemia, they need to be combined with BCL2 inhibitors or antibodies to achieve deep responses with undetectable minimal residual disease (uMRD), which allows for time-limited treatment. This trial aims to evaluate the triple combination of obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine.. This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m. Between Jan 14, 2019, and June 25, 2020, 45 evaluable patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled; 13 (29%) were female, 32 (71%) were male, 21 (47%) had already received a targeted agent, and 14 (32%) had del(17)(p13.1) or TP53 mutation. Ethnicity-race data was not collected. At data cutoff (Feb 25, 2021), all patients had completed the induction treatment. 34 patients (76%; 95% CI 61-87, p=0·26) had uMRD in peripheral blood after 6 months of triple therapy. Until data cutoff, 32 (71%) patients started maintenance and nine (28%) were able to stop with uMRD. After a median observation time of 13·8 months (IQR 10·4-18·4), there were two (4%) Richter transformations, but no progressions and no deaths observed. The most common adverse events of grade 3 and 4 during the entire treatment were thrombocytopenia and neutropenia (12 [27%] of 45 patients each), tumour lysis syndrome and infections (five [11%] of 45 patients each, grade 3 adverse events only), infusion-associated reactions (four [9%] of 45 patients) and anaemia (four [9%] of 45 patients).. With 76% of patients achieving uMRD in peripheral blood, this trial did not reach the prespecified activity threshold. Triple therapy with obinutuzumab, acalabrutinib, and venetoclax after an optional debulking with bendamustine regimen requires further evaluation in larger trials to define its value compared with double treatment with a BTK or BCL2 inhibitor combined with obinutuzumab or a combination of the two oral targeted drugs. Until these trials show a clear benefit, the use of the triple combination in routine practice cannot be recommended.. Acerta, AstraZeneca, F Hoffmann-La Roche, and AbbVie.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cytoreduction Surgical Procedures; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm, Residual; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Sulfonamides

Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax-obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.. In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3-7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as <1 chronic lymphocytic leukaemia cell per 10 000 leucocytes as measured by four-colour flow cytometry), at cycle 16 day 1. Safety and activity endpoints were assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT03580928, and is ongoing.. Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57-70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27·6 months (IQR 25·1-28·2). At cycle 16 day 1, 14 (38% [95% CI 22-55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3-4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study.. Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib-venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261).. AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Boston; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Progression-Free Survival; Pyrazines; Remission Induction; Sulfonamides; Time Factors

CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL).. Previously untreated CLL patients age < 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety.. One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n = 43) or ibrutinib (n = 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Median follow-up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, -1.6 to 10.9];. The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.

Topics: Adenine; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Piperidines; Sulfonamides; Survival Analysis

We hypothesised that combining zanubrutinib with obinutuzumab and venetoclax (BOVen) as an initial therapy for chronic lymphocytic leukaemia and small lymphocytic lymphoma would lead to high rates of undetectable minimal residual disease (MRD), and we explored MRD as a biomarker for directing treatment duration.. This multicenter, investigator-initiated, single-arm, phase 2 trial took place at two two academic medical centres in the USA. Patients were eligible for the primary cohort if they had treatment-naive chronic lymphocytic leukaemia or small lymphocytic lymphoma, required therapy, and were at least 18 years of age with an Eastern Cooperative Oncology Group performance status up to 2. BOVen was administered in 28 day cycles (oral zanubrutinib at 160 mg twice per day starting in cycle 1 on day 1; intravenous obinutuzumab at 1000 mg on day 1 [split over day 1 with 100 mg and day 2 with 900 mg for an absolute lymphocyte count >25 000 cells per μL or lymph nodes >5 cm in diameter], day 8, and day 15 of cycle 1, and day 1 of cycles 2-8; and oral venetoclax ramp up to 400 mg per day starting in cycle 3 on day 1) and discontinued after 8-24 cycles when prespecified undetectable MRD criteria were met in the peripheral blood and bone marrow. The primary endpoint was the proportion of patients that reached undetectable MRD in both the peripheral blood and bone marrow (flow cytometry cutoff less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes [<10. Between March 14, 2019, and Oct 10, 2019, 47 patients were screened for eligibility, and 39 patients were enrolled and treated. Median age was 62 years (IQR 52-70) with 30 (77%) of 39 male participants and nine (23%) of 39 female participants. 28 (72%) of 39 patients had unmutated immunoglobulin heavy-chain variable-region and five (13%) of 39 had 17p deletion or TP53 mutation. After a median follow-up of 25·8 months (IQR 24·0-27·3), 33 (89%) of 37 patients (95% CI 75-97) had undetectable MRD in both blood and bone marrow, meeting the prespecified undetectable MRD criteria to stop therapy after a median of ten cycles (IQR 8-12), which includes two cycles of zanubrutinib and obinutuzumab before starting venetoclax. After median surveillance after treatment of 15·8 months (IQR 13·0-18·6), 31 (94%) of 33 patients had undetectable MRD. The most common adverse events were thrombocytopenia (23 [59%] of 39), fatigue (21 [54%]), neutropenia (20 [51%]), and bruising (20 [51%]), and the most common adverse event at grade 3 or worse was neutropenia (seven [18%]) in the intention-to-treat population. One death occurred in a patient with intracranial haemorrhage on day 1 of cycle 1 after initiating intravenous heparin for pulmonary emboli.. BOVen was well tolerated and met its primary endpoint, with 33 (89%) of 37 previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma reaching undetectable MRD in both peripheral blood and bone marrow despite a median treatment duration of only 10 months, owing to our undetectable MRD-driven treatment discontinuation design. These data support further evaluation of the BOVen regimen in chronic lymphocytic leukaemia and small lymphocytic lymphoma with treatment duration guided by early MRD response kinetics.. Beigene, Genentech (Roche), Grais-Cutler Fund, Lymphoma Research Fund, Lymphoma Research Foundation, American Cancer Society, Farmer Family Foundation, and the National Instititutes of Health and National Cancer Institute.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax-rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax-rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Kinetics; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Rituximab; Sulfonamides

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Protein Kinase Inhibitors; Sulfonamides; Treatment Outcome

Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have limited treatment options. Venetoclax is a potent BCL-2 inhibitor that induces apoptosis in CLL cells. This open-label, phase 1/2 study (NCT02265731) evaluated the safety, pharmacokinetics, and efficacy of venetoclax in Japanese patients with R/R CLL/SLL. Patients enrolled in phase 1 received 400 mg/day venetoclax monotherapy. Patients enrolled in phase 2 received 400 mg/day venetoclax, plus rituximab. Venetoclax was administered with a weekly stepwise ramp-up in doses. In phase 2, efficacy was evaluated by objective response rate (ORR). Twelve patients were enrolled, six in each arm. The most common grade ≥ 3 adverse events were neutropenia (83%), lymphopenia (67%), leukopenia (33%), and thrombocytopenia (17%). Patients receiving venetoclax monotherapy achieved an ORR of 100%, including a complete remission (CR) rate of 17%. Patients receiving combination therapy had an ORR of 67% and a CR rate of 50%. The venetoclax pharmacokinetics profile in Japanese patients was similar to that of Western patients. Venetoclax 400 mg/day monotherapy or in combination with rituximab was well-tolerated and induced promising responses in Japanese patients with R/R CLL/SLL. Although patient numbers were small, the safety profile was largely consistent with other Western studies. Clinical trial registration: clinicaltrials.gov; NCT02265731.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Diseases; Humans; Japan; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Nausea; Neoplasm Proteins; Progression-Free Survival; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sulfonamides; Treatment Outcome

Venetoclax (Ven), an orally administered, potent BCL-2 inhibitor, has demonstrated efficacy in chronic lymphocytic leukaemia (CLL) in combination with rituximab (R) or obinutuzumab (G). Our aim was to investigate the addition of bendamustine (B) to these Ven-containing regimens in relapsed/refractory (R/R) or first-line (1L) CLL. This multi-arm, non-randomized, open-label, phase 1b study was designed to evaluate the maximum tolerated dose (MTD) and safety/tolerability of Ven with BR/BG, with 3+3 dose-escalation followed by safety expansion. Patients received Ven (schedule A) or BR/BG first (schedule B) to compare safety and determine dose/schedule for expansion. Six Ven-BR/-BG cycles were to be administered, then Ven monotherapy until disease progression (R/R) or fixed-duration 1-year treatment (1L). Overall, 33 R/R and 50 1L patients were enrolled. No dose-limiting toxicities were observed (doses 100-400-mg), and the MTD was not reached. Safety was similar between schedules; no tumour lysis syndrome (TLS) occurred during dose-finding. Schedule B and Ven 400-mg were chosen for expansion. The most frequent grade 3-4 toxicity was neutropenia: R/R 64%, 1L Ven-BR 85%, 1L Ven-BG 55%. Grade 3-4 infection rate was: R/R 27%, 1L Ven-BR 0%, 1L Ven-BG 27%. During expansion, one clinical and two laboratory TLS cases occurred. Fewer than half the patients completed six combination therapy cycles with all study drugs; rates of bendamustine discontinuation were high. Overall response rate was 91% in R/R and 100% in 1L patients (16/49 1L patients received Ven for >1 year). In conclusion, addition of bendamustine to Ven-R/-G increased toxicity without apparent efficacy benefit.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Autoimmune Diseases; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Purines; Quinazolinones; Sulfonamides

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex vivo and in vivo efficacy of the dual phosphatidylinositol 3-kinase-δ/γ (PI3K-δ/γ) inhibitor duvelisib (Duv) and the Bcl-2 inhibitor venetoclax (Ven) using 4 different RS patient-derived xenograft (PDX) models. Ex vivo exposure of RS cells to Duv, Ven, or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. Although RS1316, IP867/17, and RS9737 cells express PI3K-δ, PI3K-γ, and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-γ and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with the Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof of concept of the efficacy of dual targeting of PI3K-δ/γ and Bcl-2 in RS and providing an opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are under way. This trial was registered at www.clinicaltrials.gov as #NCT03892044.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Class I Phosphatidylinositol 3-Kinases; Class Ib Phosphatidylinositol 3-Kinase; Female; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice; Proto-Oncogene Proteins c-bcl-2; Purines; Sulfonamides; Xenograft Model Antitumor Assays

Chronic lymphocytic leukemia (CLL)-related symptoms impair the well-being of patients, making improvement of health-related quality of life (QoL) a goal of treatment. The CLL14 trial demonstrated higher efficacy of fixed-duration venetoclax-obinutuzumab (Ven-Obi) compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated CLL. To assess patients' QoL, the following patient-reported outcomes (PRO) measures were assessed: the M.D. Anderson Symptom Inventory (MDASI) core instrument and CLL module and the EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). At treatment start, physical functioning (mean 75.9 [standard deviation (SD) ± 20.1] in the Clb-Obi arm and 76.9 [±19.4] in the Ven-Obi arm), role functioning (73.6 [±27.86] and 72.6 [±26.9]) and GHS/QoL (63.6 [±21.0] and 60.3 [±20.5]) were comparable between treatment arms per EORTC QLQ-C30 scale scores. Baseline levels of physical and role functioning were maintained throughout treatment and follow-up, with no relevant improvement or deterioration. On average, patients treated with Ven-Obi showed a meaningful improvement of GHS/QoL during treatment and follow-up by at least eight points at cycle three, whereas improvement was delayed until cycle eight with Clb-Obi. According to MDASI scores, CLL symptoms (1.5 [±1.2] and 1.6 [±1.3]), core cancer symptoms (1.5 [±1.4] and 1.8 [±1.7]) and symptom interference (2.1 [±2.3] and 2.3 [±2.3]) were generally low and comparable between treatment arms at baseline and were maintained throughout treatment and follow-up. This analysis demonstrates that the higher efficacy of Ven-Obi is not associated with QoL impairment and that Ven-Obi achieves early relief of CLL-related symptoms in elderly unfit patients.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Patient Reported Outcome Measures; Quality of Life; Sulfonamides

Fifty-one of 189 evaluable patients from 3 prospective phase 2 trials evaluating a sequential targeted treatment had high-risk chronic lymphocytic leukemia (CLL) with a 17p deletion, TP53 mutation, or both. Twenty-seven patients started treatment with bendamustine debulking before induction and maintenance treatment, which was ibrutinib/ofatumumab (IO) in 21 patients, ibrutinib/obinutuzumab (IG) in 13, and venetoclax/obinutuzumab (AG) in 17. The primary end point was overall response rate after 8 months of induction treatment, which was 81%, 100%, and 94% for IO, IG, and AG, respectively. Minimal residual disease (MRD) was undetectable (uMRD) in peripheral blood (<10-4 by flow cytometry) in 0%, 23%, and 82% of patients, respectively. Median progression-free survival (PFS) was 45 months. Seventeen patients discontinued maintenance treatment due to uMRD: 9 progressed, 2 died without progression (median PFS, 28 months after discontinuation of treatment), and 6 remained in remission after a median observation time of 46 months (range, 6-47 months) after treatment discontinuation. Thus, MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce deep and durable remissions in CLL patients with high-risk genetic lesions, which can persist after treatment discontinuation (due to a predefined fixed-duration or MRD-guided early termination). The median PFS was 45 months. These trials were registered at www.clinicaltrials.gov as #NCT02345863, #NCT02401503, and #NCT02689141.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Female; Gene Deletion; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Piperidines; Progression-Free Survival; Prospective Studies; Sulfonamides; Tumor Suppressor Protein p53

Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax.. To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax.. A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older.. Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4.. Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.. Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation.. The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL.. ClinicalTrials.gov Identifier: NCT02756897.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Sulfonamides

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (<10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all >2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recurrence; Rituximab; Sulfonamides; Survival Rate

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Protein Kinase Inhibitors; Purines; Quinazolinones; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Venetoclax is a cytochrome P450, family 3, subfamily A (CYP3A) substrate and was shown to inhibit P-gp efflux transporters in vitro. To quantify the impact of CYP3A inhibition by ritonavir on venetoclax disposition and P-gp inhibition by venetoclax on digoxin pharmacokinetics, two semimechanistic drug-drug interaction (DDI) models of venetoclax were developed using clinical data from healthy volunteers who received subtherapeutic doses of venetoclax with ritonavir 50-100 mg or digoxin 0.5 mg. These models were then used to assess the magnitude of interaction at therapeutic venetoclax doses and to explore various clinical dosing strategies that maintain venetoclax and digoxin concentrations within their respective therapeutic windows. Simulations demonstrated that venetoclax dose reductions of at least 75% are needed when venetoclax is coadministered with ritonavir and administering digoxin at least 2 hours before venetoclax would minimize DDI. Semimechanistic modeling leveraging clinical data is a plausible approach to predict DDI and propose dose adjustments, and administration time of interacting drugs.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP3A Inhibitors; Digoxin; Dose-Response Relationship, Drug; Drug Interactions; Female; Healthy Volunteers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Biological; Ritonavir; Sulfonamides

Topics: Adenine; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Betacoronavirus; Bridged Bicyclo Compounds, Heterocyclic; Coronavirus Infections; COVID-19; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Pandemics; Piperidines; Pneumonia, Viral; Prognosis; Pyrazoles; Pyrimidines; Rituximab; SARS-CoV-2; Sulfonamides

Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Because ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment, combined with dissecting functional interactions of Bcl-2 family members, in an in vitro model of venetoclax resistance. In the PB, recent LN emigrants had higher Bcl-XL and Mcl-1 expression than did cells immigrating back to the LN. Under ibrutinib treatment, this distinction collapsed; significantly, the pretreatment profile reappeared in patients who relapsed on ibrutinib. However, in response to venetoclax, Bcl-2 members displayed an early increase, underlining the different modes of action of these 2 drugs. Profiling by BH3 mimetics was performed in CLL cells fully resistant to venetoclax due to CD40-mediated induction of Bcl-XL, Mcl-1, and Bfl-1. Several dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL cells. Lastly, we demonstrated that proapoptotic Bim interacts with antiapoptotic Bcl-2 members in a sequential manner: Bcl-2 > Bcl-XL > Mcl-1 > Bfl-1. Combined, the data indicate that Bcl-XL is more important in venetoclax resistance than is Mcl-1 and provide biological rationale for potential synergy between ibrutinib and venetoclax.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy.. This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety.. The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed.. The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; CD4 Lymphocyte Count; Cognition; Female; Follow-Up Studies; Humans; Hypertension; Hyponatremia; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Neutropenia; Piperidines; Progression-Free Survival; Quality of Life; Remission Induction; Retreatment; Sulfonamides; Survival Rate; Thrombocytopenia; Young Adult

Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.. CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942.. Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma).. 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia.. F Hoffmann-La Roche and AbbVie.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Progression-Free Survival; Sulfonamides; Treatment Outcome

In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics.. Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed.. Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (. Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Exportin 1 Protein; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Karyopherins; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Receptor, Notch1; Receptors, Cytoplasmic and Nuclear; Rituximab; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53

Literature is scarce on the combination treatment of ibrutinib and venetoclax (IV) is scarce in relapsed or refractory chronic lymphocytic leukaemia (RR-CLL). Especially, the possibility of stopping ibrutinib in RR-CLL patients in deep remission is unclear.. In the HOVON 141/VISION trial, patients with RR-CLL are treated with 12 cycles of IV after a short induction with ibrutinib. Patients reaching undetectable minimal residual disease (uMRD) after 12 cycles of IV are randomised 1:2 to continue ibrutinib or stop treatment. The persistence of uMRD after stopping IV is studied. In addition, in patients who become positive for MRD again after stopping, IV treatment is reinitiated. The efficacy of this approach with regard to progression-free survival 12 months after randomisation is the primary endpoint of the study.. This protocol respects the Helsinki declaration and has been approved by the ethical committee of the Amsterdam Medical Center. Study findings will be disseminated through peer-reviewed papers. All patients who fulfil the inclusion criteria and no-exclusion criteria, and have signed the informed consent form are included in the study.. ClinicalTrials.gov Registry (NCT03226301).

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Creatinine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Prospective Studies; Receptor Tyrosine Kinase-like Orphan Receptors; Recurrence; Sulfonamides; Tumor Suppressor Protein p53

The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixed-duration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes.. Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status-at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter-were secondary end points.. Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 10. With all patients having finished treatment, continued benefit was observed for venetoclax-rituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Progression-Free Survival; Recurrence; Rituximab; Sulfonamides; Time Factors

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Sulfonamides

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics.. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods.. Venetoclax maximum observed plasma concentration (C. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Case-Control Studies; Female; Half-Life; Hepatic Insufficiency; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Safety; Sulfonamides

To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Sulfonamides

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination.. We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated. A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated. In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Topics: Adenine; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Induction Chemotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Count; Male; Middle Aged; Mutation; Neoplasm, Residual; Neutropenia; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Sulfonamides

Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax-rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure-response analysis.. Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure-response analysis.. The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21-39%). Apparent central volume of distribution was 30% lower (95% CI 22-38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes.. The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure-response evaluation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Models, Biological; Rituximab; Sex Factors; Sulfonamides; Time Factors; Tissue Distribution

The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy.. CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival.. In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events.. The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Sulfonamides

Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.. In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282.. Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred.. The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019.. AbbVie, Genentech.

Topics: Adenine; Administration, Oral; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Sulfonamides; Time Factors; Treatment Outcome; United States

B-cell receptor pathway inhibitors (BCRis) have transformed treatment of chronic lymphocytic leukemia (CLL); however, the efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRis is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi before enrollment. Venetoclax was initiated at 20 mg daily, followed by intrapatient ramp-up to 400 mg daily. Primary objectives included efficacy (objective response rate [ORR]) and safety of venetoclax. The study enrolled 36 patients who previously received idelalisib (ORR, 67% [24/36]); 2 patients achieved complete remission, and 1 had complete remission with incomplete bone marrow recovery. Median progression-free survival (PFS) has not yet been reached; estimated 12-month PFS was 79%. The most common adverse events (AEs; all grades) were neutropenia (56%), diarrhea (42%), upper respiratory tract infection (39%), thrombocytopenia (36%), nausea (31%), fatigue (28%), cough (22%), rash (22%), and anemia (22%). Grade 3 or 4 AEs were primarily hematologic (neutropenia [50%], thrombocytopenia [25%], and anemia [17%]). No patients experienced tumor lysis syndrome. Venetoclax demonstrated promising clinical activity and favorable tolerability in patients with CLL whose disease progressed during or after idelalisib therapy. This trial was registered at www.clinicaltrials.gov as #NCT02141282.

Topics: Administration, Oral; Aged; Aged, 80 and over; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Purines; Quinazolinones; Recurrence; Sulfonamides; Survival Rate

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 (PD-L1) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mutation; Neoplasm Proteins; Sulfonamides

Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity.. This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Humans; Induction Chemotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Maintenance Chemotherapy; Molecular Targeted Therapy; Neoplasm, Residual; Purines; Quinazolinones; Sulfonamides; Treatment Outcome

Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.. In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival.. After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients).. Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Neutropenia; Recurrence; Rituximab; Sulfonamides; Tumor Lysis Syndrome; Young Adult

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia.. Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87-99) had responded, including all 34 patients in the treatment-naive cohort and 26 [90%] of 29 relapsed or refractory patients. The most common grade 3-4 adverse events during debulking were neutropenia and anaemia (five [11%] of 47 patients each), and thrombocytopenia and infection (three [6%] each). The most common grade 3-4 adverse events during induction were neutropenia (29 [44%] of 66 patients), infection (nine [14%]), thrombocytopenia (eight [12%]), infusion-related reactions (five [8%]), and secondary primary malignancy (four [6%]). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not.. The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation.. F Hoffmann-La Roche and AbbVie.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Germany; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Prospective Studies; Sulfonamides; Time Factors; Treatment Outcome

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Sulfonamides

Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp-up period to reach 1.89 µg/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 µg/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P≥0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Sulfonamides

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.. The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).. A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection).. Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5-88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events.. The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neutropenia; Recurrence; Sulfonamides; Treatment Outcome

Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Purines; Sulfonamides; Tumor Cells, Cultured

New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Recurrence; Remission Induction; Sulfonamides; Tumor Lysis Syndrome

Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia.. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment.. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their relationship to treatment, with the most common (≥5% of patients) being pyrexia and autoimmune haemolytic anaemia (seven [7%] each), pneumonia (six [6%]), and febrile neutropenia (five [5%]). 11 patients died in the study within 30 days of the last dose of venetoclax; seven due to disease progression and four from an adverse event (none assessed as treatment related).. Results of this trial show that venetoclax monotherapy is active and well tolerated in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia, providing a new therapeutic option for this very poor prognosis population. Additionally, in view of the distinct mechanism-of-action of venetoclax, combinations or sequencing with other novel targeted agents should be investigated to further advance treatment of del(17p) chronic lymphocytic leukaemia.. AbbVie and Genentech.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Salvage Therapy; Sulfonamides; Survival Rate

Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Dietary Fats; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Models, Biological; Predictive Value of Tests; Sulfonamides

Inhibition of B-cell receptor (BCR) signaling pathways in chronic lymphocytic leukemia (CLL) provides significant clinical benefit to patients, mainly by blocking adhesion of CLL cells in the lymph node microenvironment. The currently applied inhibitors ibrutinib and idelalisib have limited capacity however to induce cell death as monotherapy and are unlikely to eradicate the disease. Acquired resistance to therapy in CLL is often caused by mutations in the response network being targeted, both for DNA damage or BCR signaling pathways. Thus, drugs with dual targeting capacity could offer improved therapeutic value. Here, the potency of CC-115, a novel inhibitor of mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK), was evaluated in primary CLL cells in vitro and in CLL patients. Combined TORK and DNA-PK inhibition in vitro resulted in caspase-dependent cell killing irrespective of p53, ATM, NOTCH1, or SF3B1 status. Proliferation induced by CD40(+) interleukin-21 stimulation was completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could be reverted by CC-115. BCR-mediated signaling was inhibited by CC-115 and also in CLL samples obtained from patients with acquired resistance to idelalisib treatment. Clinical efficacy of CC-115 was demonstrated in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations; all but 1 patient had a decrease in lymphadenopathy, resulting in 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. In conclusion, these preclinical results, along with early promising clinical activity, suggest that CC-115 may be developed further for treatment of CLL. The trial was registered at www.clinicaltrials.gov as #NCT01353625.

Topics: Bridged Bicyclo Compounds, Heterocyclic; DNA-Activated Protein Kinase; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplasm Proteins; Nuclear Proteins; Purines; Pyrazines; Quinazolinones; Sulfonamides; TOR Serine-Threonine Kinases; Triazoles; Tumor Cells, Cultured; Vidarabine

In chronic lymphocytic leukemia, growing evidence has accumulated about long-term outcomes of first-line treatments. Our objective was to perform indirect comparisons across first-line treatments.. We applied the Shiny method, an artificial intelligence technique that analyses Kaplan-Meier curves and reconstructs patient-level data. Reconstructed patient data were then evaluated through standard survival statistics and indirect head-to-head comparisons. The endpoint was progression-free survival (PFS).. Seven first-line treatments were studied (1983 patients). Three treatments based on either ibrutinib or venetoclax (i.e., ibrutinib monotherapy, ibrutinib+ rituximab/obinutuzumab, and venetoclax+obinutuzumab) showed a very similar survival pattern. The PFS for these three treatments was significantly better than that of the remaining four treatments (fludarabine+cyclophosphamide+rituximab, chlorambucil+obinutuzumab, bendamustine+rituximab, and chlorambucil monotherapy). Regarding chlorambucil+ obinutuzumab, a significant between-trial variability was found.. Long-term results are particularly favorable to ibrutinib (alone or in combination) and discourage further use of chlorambucil. As in other studies based on the Shiny method, the multi-treatment Kaplan-Meier graph summarized the available evidence in comparative terms. The evidence generated this way contributes to define the place in therapy of individual agents.

Topics: Antineoplastic Combined Chemotherapy Protocols; Artificial Intelligence; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Progression-Free Survival; Rituximab

Topics: Apoptosis; Biphenyl Compounds; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Interferon-gamma; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Recurrence, Local; Nitrophenols; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor

In the last few years, BTK inhibitors, PI3K inhibitors, and venetoclax have been approved for clinical use against chronic lymphocytic leukemia (CLL), both as single agents, and in combination. This article summarizes recent achievements in the treatment of patients with CLL, and pays special attention to novel targeted drugs and monoclonal antibodies (Mabs). A literature search was conducted of the PubMed and Google Scholar databases. Rituximab and obinutuzumab have been combined with chemotherapy, and more recently, with BTK inhibitors, PI3K inhibitors, and venetoclax. These agents have demonstrated high activity in treatment naïve (TN) and relapsed or refractory (RR) CLL. Immunochemotherapy regimens are currently considered in TN younger patients with

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Phosphatidylinositol 3-Kinases; Recurrence

Efficacy of venetoclax plus obinutuzumab (VenO) compared with chlorambucil plus obinutuzumab (ClbO) for treatment-naïve adult patients with chronic lymphocytic leukemia (CLL) with coexisting medical conditions was investigated in CLL14 (NCT02242942). Our aim was to evaluate the cost-effectiveness of VenO versus ClbO for these patients from a Dutch societal perspective.. A 3-state partitioned survival model was constructed to evaluate the cost-effectiveness of VenO. The outcome of the analysis was the incremental cost-effectiveness ratio (ICER) with effectiveness measured in quality-adjusted life-years (QALYs) gained. Uncertainty was explored through deterministic and probabilistic sensitivity analyses, scenario analyses, and value of information analysis (VOI).. The base case resulted in a discounted ICER -49 928 EUR/QALY gained (with incremental negative costs and positive effects). None of the ICERs resulted from deterministic sensitivity and scenario analyses exceeded the chosen willingness-to-pay threshold of 20 000 EUR/QALY, and > 99% of the iterations in the probabilistic sensitivity analysis were cost-effective. VOI analyses showed a maximum expected value of eliminating all model parameter uncertainty of 183 591 EUR.. Our study demonstrated VenO being dominant over ClbO in treatment-naïve adult patients with CLL assuming a Dutch societal perspective. We concluded that our results are robust as tested through sensitivity and scenario analyses. Additionally, the VOI analyses confirmed that our current evidence base is strong enough to generate reliable results for our study. Nevertheless, further research based on real-world data or longer follow-up period could further contribute to the robustness of the current study's conclusions.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Cost-Benefit Analysis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Quality-Adjusted Life Years

Venetoclax is an effective treatment for certain blood cancers, such as chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). However, most patients relapse while on venetoclax and further treatment options are limited. Combining venetoclax with immunotherapies is an attractive approach; however, a detailed understanding of how venetoclax treatment impacts normal immune cells in patients is lacking. In this study, we performed deep profiling of peripheral blood (PB) cells from patients with CLL and AML before and after short-term treatment with venetoclax using mass cytometry (cytometry by time of flight) and found no impact on the concentrations of key T-cell subsets or their expression of checkpoint molecules. We also analyzed PB from patients with breast cancer receiving venetoclax long-term using a single-cell multiomics approach (cellular indexing of transcriptomes and epitopes by sequencing) and functional assays. We found significant depletion of B-cell populations with low expression of MCL-1 relative to other immune cells, attended by extensive transcriptomic changes. By contrast, there was less impact on circulating T cells and natural killer (NK) cells, with no changes in their subset composition, transcriptome, or function following venetoclax treatment. Our data indicate that venetoclax has minimal impact on circulating T or NK cells, supporting the rationale of combining this BH3 mimetic drug with cancer immunotherapies for more durable antitumor responses.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Rituximab; Splenomegaly

Preventing or overcoming resistance to the Bcl-2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti-apoptotic Bcl-2 members through signalling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non-canonical NF-κB activation and subsequent Bcl-XL induction. Moreover, the T cell-derived cytokines IL-21 and IL-4 differentially affect Bcl-XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl-XL is regulated in the context of JAK-STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL-21/STAT3 signalling in the NF-κB-mediated expression of Bcl-XL, whereas IL-4/STAT6 further promoted the expression of Bcl-XL. In comparison, Bfl-1, another NF-κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl-XL transcription by binding to its promoter without disrupting the DNA-binding activity of NF-κB. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK-STAT signalling and NF-κB, in which STAT3 inhibited canonical NF-κB by accelerating nuclear export, and STAT6 promoted non-canonical NF-κB. Finally, NF-κB inducing kinase (NIK) inhibition interrupted the NF-κB/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL, thereby revealing new potential therapeutic targets.

Topics: Apoptosis; Drug Resistance, Neoplasm; Humans; Interleukin-4; Leukemia, Lymphocytic, Chronic, B-Cell; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Tumor Microenvironment

The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B-cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real-world' cohort.. We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax.. Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person-years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4-15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07-2.31, p = .018) and 1.3 (1.05-1.62, p = .016) respectively].. The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Retrospective Studies

Patients with synchronous malignancies can be problematic to diagnose and manage because workup and therapeutic targeting for each individual malignancy must be coordinated carefully. This report presents a patient with concurrent chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) managed with concomitant venetoclax and imatinib. Because imatinib is a moderate cytochrome P450 3A4 inhibitor, close monitoring is required when using with a substrate of 3A4 such as venetoclax. Although the target dose of venetoclax is 400 mg, it was capped at 100 mg due to the interaction. Despite the interaction and possible enhancement of toxicities, the patient has tolerated therapy well, and both diseases have responded to this novel approach. In addition, because aberrant BCL-2 activity has been implicated in CML, the use of venetoclax may contribute to success in the management of this patient's CML. This case report represents the safe concomitant use of venetoclax and imatinib in a patient with synchronous CML and CLL.

Topics: Antineoplastic Agents; Humans; Imatinib Mesylate; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Topics: Anemia, Hemolytic, Autoimmune; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Spain

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

This retrospective, observational study evaluated patterns of inpatient versus outpatient tumour lysis syndrome (TLS) monitoring during venetoclax ramp-up in 170 patients with chronic lymphocytic leukaemia. The primary outcome was clinical/biochemical TLS. Two clinical and four biochemical TLS occurred (4.1%). Five of the six events occurred in high-risk patients, four occurred at 20 mg dose and three at the 6-h time-point. Inpatient versus outpatient TLS rates within the high-risk subgroup were 15% and 8%. Risk category was the only predictor of TLS events in multivariate analysis. Outpatient escalation did not associate with clinically meaningful TLS events, suggesting outpatient escalation has manageable associated TLS risks, including in high-risk cohorts. These observations require confirmation in larger studies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retrospective Studies; Tumor Lysis Syndrome

This study assessed treatment discontinuation patterns and reasons among chronic lymphocytic leukemia (CLL) patients initiating first-line (1L) and second-line (2L) treatments in real-world settings.. Using deidentified electronic medical records from the CLL Collaborative Study of Real-World Evidence, premature treatment discontinuation was assessed among FCR, BR, BTKi-based, and BCL-2-based regimen cohorts.. Of 1364 1L patients (initiated in 1997-2021), 190/13.9% received FCR (23.7% discontinued prematurely); 255/18.7% received BR (34.5% discontinued prematurely); 473/34.7% received BTKi-based regimens, of whom 28.1% discontinued prematurely; and 43/3.2% received venetoclax-based regimens, of whom 16.3% discontinued prematurely (venetoclax monotherapy: 7/0.5%, of whom 42.9% discontinued; VG/VR: 36/2.6%, of whom 11.1% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 25/13.2%; BR: 36/14.1%; BTKi-based regimens: 75/15.9%) and disease progression (venetoclax-based: 3/7.0%). Of 626 2L patients, 20/3.2% received FCR (50.0% discontinued); 62/9.9% received BR (35.5% discontinued); 303/48.4% received BTKi-based regimens, of whom 38.0% discontinued; and 73/11.7% received venetoclax-based regimens, of whom 30.1% discontinued (venetoclax monotherapy: 27/4.3%, of whom 29.6% discontinued; VG/VR: 43/6.9%, of whom 27.9% discontinued). The most common reasons for treatment discontinuation were adverse events (FCR: 6/30.0%; BR: 11/17.7%; BTKi-based regimens: 60/19.8%; venetoclax-based: 6/8.2%).. The findings of this study highlight the continued need for tolerable therapies in CLL, with finite therapy offering a better tolerated option for patients who are newly diagnosed or relapsed/refractory to prior treatments.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.

Topics: Bridged Bicyclo Compounds, Heterocyclic; CD40 Antigens; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Biosynthesis; Proto-Oncogene Proteins c-bcl-2; Toll-Like Receptor 9; Tumor Microenvironment; Up-Regulation

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual

Although BCL2 mutations are reported as later occurring events leading to venetoclax resistance, many other mechanisms of progression have been reported though remain poorly understood. Here, we analyze longitudinal tumor samples from 11 patients with disease progression while receiving venetoclax to characterize the clonal evolution of resistance. All patients tested showed increased in vitro resistance to venetoclax at the posttreatment time point. We found the previously described acquired BCL2-G101V mutation in only 4 of 11 patients, with 2 patients showing a very low variant allele fraction (0.03%-4.68%). Whole-exome sequencing revealed acquired loss(8p) in 4 of 11 patients, of which 2 patients also had gain (1q21.2-21.3) in the same cells affecting the MCL1 gene. In vitro experiments showed that CLL cells from the 4 patients with loss(8p) were more resistant to venetoclax than cells from those without it, with the cells from 2 patients also carrying gain (1q21.2-21.3) showing increased sensitivity to MCL1 inhibition. Progression samples with gain (1q21.2-21.3) were more susceptible to the combination of MCL1 inhibitor and venetoclax. Differential gene expression analysis comparing bulk RNA sequencing data from pretreatment and progression time points of all patients showed upregulation of proliferation, B-cell receptor (BCR), and NF-κB gene sets including MAPK genes. Cells from progression time points demonstrated upregulation of surface immunoglobulin M and higher pERK levels compared with those from the preprogression time point, suggesting an upregulation of BCR signaling that activates the MAPK pathway. Overall, our data suggest several mechanisms of acquired resistance to venetoclax in CLL that could pave the way for rationally designed combination treatments for patients with venetoclax-resistant CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Exome Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Chronic lymphocytic leukemia (CLL) is an immunosuppressive disease characterized by increased infectious morbidity and inferior antitumor activity of immunotherapies. Targeted therapy with Bruton's tyrosine kinase inhibitors (BTKis) or the Bcl-2 inhibitor venetoclax has profoundly improved treatment outcomes in CLL. To overcome or prevent drug resistance and extend the duration of response after a time-limited therapy, combination regimens are tested. Anti-CD20 antibodies that recruit cell- and complement-mediated effector functions are commonly used. Epcoritamab (GEN3013), an anti-CD3×CD20 bispecific antibody that recruits T-cell effector functions, has demonstrated potent clinical activity in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma. Development of CLL therapy is ongoing. To characterize epcoritamab-mediated cytotoxicity against primary CLL cells, peripheral blood mononuclear cells from treatment-naive and BTKi-treated patients, including patients progressing on therapy, were cultured with epcoritamab alone or in combination with venetoclax. Ongoing treatment with BTKi and high effector-to-target ratios were associated with superior in vitro cytotoxicity. Cytotoxic activity was independent of CD20 expression on CLL cells and observed in samples from patients whose condition progressed while receiving BTKi. Epcoritamab induced significant T-cell expansion, activation, and differentiation into Th1 and effector memory cells in all patient samples. In patient-derived xenografts, epcoritamab reduced the blood and spleen disease burden compared with that in mice receiving a nontargeting control. In vitro, the combination of venetoclax with epcoritamab induced superior killing of CLL cells than either agent alone. These data support the investigation of epcoritamab in combination with BTKis or venetoclax to consolidate responses and target emergent drug-resistant subclones.

Topics: Animals; Antibodies, Bispecific; Antineoplastic Agents; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Mice; Proto-Oncogene Proteins c-bcl-2

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment.. Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10. Ibrutinib + venetoclax achieved deeper uMRD (<10. Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Progression-Free Survival

The CAPTIVATE study investigated first-line ibrutinib plus venetoclax for chronic lymphocytic leukemia in 2 cohorts: minimal residual disease (MRD)-guided randomized discontinuation (MRD cohort) and Fixed Duration (FD cohort). We report outcomes of fixed-duration ibrutinib plus venetoclax in patients with high-risk genomic features [del(17p), TP53 mutation, and/or unmutated immunoglobulin heavy chain (IGHV)] in CAPTIVATE.. Patients received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day). FD cohort patients (n = 159) received no further treatment. Forty-three MRD cohort patients with confirmed undetectable MRD (uMRD) after 12 cycles of ibrutinib plus venetoclax received randomized placebo treatment.. Of 195 patients with known status of genomic risk features at baseline, 129 (66%) had ≥1 high-risk feature. Overall response rates were >95% regardless of high-risk features. In patients with and without high-risk features, respectively, complete response (CR) rates were 61% and 53%; best uMRD rates: 88% and 70% (peripheral blood) and 72% and 61% (bone marrow); 36-month progression-free survival (PFS) rates: 88% and 92%. In subsets with del(17p)/TP53 mutation (n = 29) and unmutated IGHV without del(17p)/TP53 mutation (n = 100), respectively, CR rates were 52% and 64%; uMRD rates: 83% and 90% (peripheral blood) and 45% and 80% (bone marrow); 36-month PFS rates: 81% and 90%. Thirty-six-month overall survival (OS) rates were >95% regardless of high-risk features.. Deep, durable responses and sustained PFS seen with fixed-duration ibrutinib plus venetoclax are maintained in patients with high-risk genomic features, with similar PFS and OS to those without high-risk features. See related commentary by Rogers, p. 2561.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines

In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin heavy chain variable (IGHV) unmutated status, del(17p), and/or TP53 mutation had similar efficacy and safety outcomes compared with patients without a higher-risk feature when treated with fixed-duration ibrutinib and venetoclax. See related article by Allan et al., p. 2593.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperidines

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Fatigue; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Quality of Life

The final analysis of the open-label, multicenter phase 2 CLL2-GIVe trial shows response and tolerability of the triple combination of obinutuzumab, ibrutinib, and venetoclax (GIVe regimen) in 41 previously untreated patients with high-risk chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation. Induction consisted of 6 cycles of GIVe; venetoclax and ibrutinib were continued up to cycle 12 as consolidation. Ibrutinib was given until cycle 15 or up to cycle 36 in patients not achieving a complete response and with detectable minimal residual disease. The primary end point was the complete remission rate at cycle 15, which was achieved at 58.5% (95% CI, 42.1-73.7; P < .001). The last patient reached the end of the study in January 2022. After a median observation time of 38.4 months (range, 3.7-44.9), the 36-month progression-free survival was 79.9%, and the 36-month overall survival was 92.6%. Only 6 patients continued ibrutinib maintenance. Adverse events of concern were neutropenia (48.8%, grade ≥3) and infections (19.5%, grade ≥3). Cardiovascular toxicity grade 3 occurred as atrial fibrillation at a rate of 2.4% between cycles 1 and 12, as well as hypertension (4.9%) between cycles 1 and 6. The incidence of adverse events of any grade and grade ≥3 was highest during induction and decreased over time. Progressive disease was observed in 7 patients between cycles 27 and 42. In conclusion, the CLL2-GIVe regimen is a promising fixed-duration, first-line treatment for patients with high-risk CLL with a manageable safety profile.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

BTK (Bruton's tyrosine kinase) inhibitors are highly effective front-line therapy for CLL (chronic lymphocytic leukemia) due to high response rates and prolonged progression-free survival, even in patients with high-risk disease features. They are also generally well tolerated, with the newer BTK inhibitors demonstrating better tolerability than ibrutinib while maintaining efficacy. Adverse effects such as bleeding or infections are usually manageable with supportive care or dose adjustments. Orally administered BTK inhibitors do not require intensive or inpatient monitoring and improve quality-of-life outcomes. Moreover, the established activity of venetoclax in the setting of BTK inhibitor failure is also reassuring as a salvage option. Nevertheless, the advantage of venetoclax as a time-limited treatment option is substantial, despite its inferior progression-free survival, since these patients can get another challenge with a reasonable chance of success. BTK inhibitors after venetoclax may be effective, but long-term data is limited. Given these reasons, BTK inhibitors remain the preferred treatment option as initial therapy for patients with CLL, especially those with del17p or TP53 mutations.

Topics: Agammaglobulinaemia Tyrosine Kinase; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Sulfonamides

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Suppressor Protein p53

The results of the MURANO trial showed encouraging progression-free survival (PFS) and overall survival (OS) in relapsed/refractory chronic lymphocytic leukemia (RR-CLL) patients treated with venetoclax-rituximab (VEN-R). A retrospective analysis was performed to evaluate the efficacy and safety of VEN-R within the Polish Adult Leukemia Study Group (PALG) centers. The study group included 117 patients with RR-CLL (with early relapse after immunochemotherapy or bearing TP53 aberrations) treated with VEN-R in 2019-2023 outside clinical trials. Patients were treated with a median of 2 (range 1-9) previous lines of therapy. Twenty-two participants were previously treated with BTKi (18.8% out of 117). The median follow-up was 20.3 months (range 0.27-39.1). The overall response rate (ORR) was 95.3% in the group of patients in whom a response to treatment was assessed and 86.3% for all patients. Twenty patients (17.1% out of 117) achieved a complete response (CR), 81 (69.2%) achieved a partial response (PR), and in 5 patients (4.3%), disease progression was noted (assessed as the best response during treatment). The median PFS in the whole cohort was 36.97 (95% CI 24.5, not reached) months, and the median OS was not reached (95% CI 27.03, not reached). Thirty-six patients died during the follow-up, 10 (8.5%; 27.8% of deaths) due to COVID-19 infection. All grade neutropenia (n = 87/117, 74.4%; grade 3 or higher n = 67/117, 57.3%) was the most common treatment adverse event. Forty-five patients (38.5%) remained on treatment, and twenty-two (18.8%) completed 24 months of therapy, while it was discontinued in fifty cases (42.7%). In this real-world setting of early access in very high-risk RR-CLL patients, the VEN-R regimen was associated with shorter median PFS compared with the results of the MURANO trial. This outcome, however, could be attributed to patients' exposure to SARS-CoV-2 infection and the aggressive course of the disease as very high-risk patients, after multiple lines of prior therapies, were included in the Polish Ministry of Health reimbursement program.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; COVID-19; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Poland; Recurrence; Retrospective Studies; Rituximab; SARS-CoV-2; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

It is well established that inflammation and platelets promote multiple processes of cancer malignancy. Recently, platelets have received attention for their role in carcinogenesis through the production of microvesicles or platelet-derived microparticles (PMPs), which transfer their biological content to cancer cells. We have previously characterized a new subpopulation of these microparticles (termed mito-microparticles), which package functional mitochondria. The potential of mitochondria transfer to cancer cells is particularly impactful as many aspects of mitochondrial biology (i.e., cell growth, apoptosis inhibition, and drug resistance) coincide with cancer hallmarks and disease progression. These metabolic aspects are particularly notable in chronic lymphocytic leukemia (CLL), which is characterized by a relentless accumulation of proliferating, immunologically dysfunctional, mature B-lymphocytes that fail to undergo apoptosis. The present study aimed to investigate the role of PMPs on CLL metabolic plasticity leading to cancer cell phenotypic changes.. CLL cell lines were co-incubated with different concentrations of human PMPs, and their impact on cell proliferation, mitochondrial DNA copy number, OCR level, ATP production, and ROS content was evaluated. Essential genes involved in metabolic-reprogramming were identified using the bioinformatics tools, examined between patients with early and advanced CLL stages, and then validated in PMP-recipient CLLs. Finally, the impact of the induced metabolic reprogramming on CLLs' growth, survival, mobility, and invasiveness was tested against anti-cancer drugs Cytarabine, Venetoclax, and Plumbagin.. The data demonstrated the potency of PMPs in inducing tumoral growth and invasiveness in CLLs through mitochondrial internalization and OXPHOS stimulation which was in line with metabolic shift reported in CLL patients from early to advanced stages. This metabolic rewiring also improved CLL cells' resistance to Cytarabine, Venetoclax, and Plumbagin chemo drugs.. Altogether, these findings depict a new platelet-mediated pathway of cancer pathogenesis. We also highlight the impact of PMPs in CLL metabolic reprogramming and disease progression.

Topics: Antineoplastic Agents; Cell-Derived Microparticles; Cytarabine; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

To evaluate the time to discontinuation (TTD) and baseline characteristics among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) treated with first-line (1L) venetoclax + obinutuzumab (VO) in the United States.. A nationwide electronic health record-derived database was used to select adults with CLL/SLL initiating a 1L venetoclax-based regimen between April 11, 2016-July 31, 2020. Study measures included TTD (defined as >120-day treatment gap or switching therapy) and baseline characteristics by discontinuation status.. A total of 113 patients receiving 1L VO on/before July 31, 2020 were eligible for analysis (mean age: 65.9 years; 31.9% women). During the first 60 days post-treatment initiation, 3.5% had tumor lysis syndrome (TLS). The proportion of patients using corticosteroids, anti-hyperuricemics, and anti-emetics was higher during the first 60 days post-treatment initiation (100.0%, 78.8%, and 52.2%, respectively) than the period from day 61 onward (67.0%, 45.5%, and 33.9%, respectively). Mean (median) duration of active treatment was 11.6 (12.1) months; 16.8% discontinued treatment before completing 12 cycles, 68.1% completed ≥12 cycles (among which 29.9% completed ≥15 cycles), and 15.0% who did not discontinue treatment were censored before completing 12 cycles. Kaplan-Meier analysis showed that median TTD was 13.8 months. Relative to those completing ≥12 cycles, patients discontinuing treatment before completing the prescribed 12 cycles were older (70.4 vs. 65.1 years) and had poorer renal function (36.8% vs. 13.0% with creatinine clearance <60 mL/min).. A small proportion of CLL/SLL patients who were older and had poorer baseline renal function discontinued 1L VO prior to completing 12 treatment cycles. Additionally, treatment utilization, including medications related to TLS mitigation and management, was more intense during the initiation phase of VO. Further research with longer follow-up to assess long-term outcomes of VO treatment after early discontinuation is warranted.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male

Topics: Humans; Karyotype; Karyotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; East Asian People; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab

Topics: Antibodies, Monoclonal, Humanized; Humans; Leukemia, Lymphocytic, Chronic, B-Cell

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Topics: Aged; Frailty; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Quality of Life

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Sulfonamides

Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Phenotype; Phosphatidylinositol 3-Kinases; Sulfonamides; Tumor Microenvironment

Venetoclax in combination with rituximab (VEN + R) demonstrated prolonged overall survival (OS) and progression-free survival (PFS) for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) in comparison to standard chemoimmunotherapy [bendamustine + rituximab (BR)]. We conducted a cost-effectiveness and budget impact analysis comparing VEN + R versus six comparators from the Swiss healthcare payer perspective.. A three-state partitioned survival model, developed in accordance with NICE and ISPOR decision modelling guidelines, was adapted to Switzerland. Model inputs were informed by the MURANO trial (survival data, patient characteristics), publicly available Swiss sources (drug prices, inpatient and outpatient costs), Swiss National Institute of Cancer Epidemiology and Registration data (incidence and prevalence values), and Swiss medical expert feedback. We used published (dis-)utility values and adverse event probabilities.. Over a lifetime, VEN + R resulted in an expected gain of 2.60 quality-adjusted life years (QALYs) per patient and incremental costs of Swiss Francs (CHF) 147,851 compared to BR, leading to an incremental cost-effectiveness ratio of CHF 56,881/QALY gained. Other treatment strategies (for example ibrutinib versus VEN + R) resulted in higher costs and lower QALYs. Results were not different for subgroups of patients with/without deletion of chromosome 17p/tumour protein 53 mutation. In scenario analysis, changes in post-progression treatment costs demonstrated a high impact on results. We estimated an expected value of perfect information of CHF 3,318/patient. A moderate VEN + R uptake was estimated to save CHF 12.3 million during 5 years.. Using a threshold of CHF 100,000 per QALY, VEN + R was projected to be cost-effective vs BR.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cost-Benefit Analysis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Quality-Adjusted Life Years; Rituximab; Sulfonamides; Switzerland

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Sulfonamides

Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Retrospective Studies; Sulfonamides; Survival Rate

Chronic lymphocytic leukemia (CLL) is commonly treated with the B-cell lymphoma 2 inhibitor (BCL-2) venetoclax. Venetoclax is associated with an increased risk of tumor lysis syndrome in this patient population. Because venetoclax undergoes CYP3A4 metabolism, strong CYP3A4 inhibitors are contraindicated during the ramp-up phase of venetoclax in patients with CLL.. Our case report describes a 58 year old male initially diagnosed with CLL in 2013, whose first-line treatment consisted of ibrutinib. The patient developed a central nervous system (CNS) aspergillosis infection in 2018, and was initiated on voriconazole. He was subsequently under active surveillance until his disease progressed. The patient was started on venetoclax therapy, while on concomitant voriconazole, for management of his CLL.. The patient's initial venetoclax dose was 10 mg daily, and he received rasburicase on day 1 of therapy. He tolerated a modified ramp-up phase without complication. After receiving 9 days of inpatient therapy, the patient was discharged on 50 mg of venetoclax to continue outpatient dose escalation. His dose was ultimately escalated to 100 mg daily.. Although this report describes the safe administration of venetoclax with voriconazole, extreme caution should be exercised when administering venetoclax with any strong CYP3A4 inhibitor during the ramp-up phase in patients with CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Sulfonamides; Voriconazole

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Sulfonamides

Venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (r/r CLL). Tumour lysis syndrome (TLS) is a serious toxicity associated with venetoclax, and real-world studies suggest that the incidence may be higher than in clinical trials. The purpose of this study is to describe the incidence of venetoclax toxicities in British Columbia (BC).. Retrospective review of electronic medical charts for patient characteristics and clinical outcomes of patients treated with venetoclax for r/r CLL in BC. Patients were classified according to their risk for developing TLS. The incidence of TLS was categorized based on laboratory metrics or clinical diagnosis. Other non-TLS toxicities were also collected.. Of 33 patients identified, 40%, 33%, and 27% were at low, intermediate, and high risk for TLS, respectively. Laboratory TLS occurred in 1/33 patients (3%), and no clinical TLS was reported. Grade 3 or 4 toxicities occurred in 19/33 patients (58%). Of these, neutropenia was the most common, occurring in 16 patients (84%) followed by thrombocytopenia, which occurred in 8 patients (42%).. The incidence of TLS in patients treated with venetoclax for r/r CLL in BC was lower than in other real-world studies. Findings may warrant further investigation to determine if the higher incidence of TLS in real-world reports may be mitigated through modifying TLS risk categorization and associated prophylactic measures. Neutropenia was the most common grade 3 or 4 venetoclax toxicity reported, and the incidence in BC is comparable to other centres.

Topics: Antineoplastic Agents; British Columbia; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Recurrence; Tumor Lysis Syndrome

Venetoclax is a BCL-2 inhibitor approved for treatment of adult patients with chronic lymphocytic leukemia (CLL). Due to significant risk of tumor lysis syndrome (TLS) upon treatment initiation, a 5-week dose ramp-up is recommended. University of North Carolina Medical Center (UNCMC) utilizes a novel interdisciplinary model of care involving clinical pharmacists (CPs) who oversee the 5-week ramp-up to minimize treatment-related adverse events. The aim of this study was to investigate the effects of a pharmacist-led venetoclax initiation protocol on patient outcomes. The primary objective was to determine the incidence of venetoclax-induced TLS during dose ramp-up in patients managed by a CP. In this cohort (

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; COVID-19; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pandemics; Sulfonamides

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and fadraciclib efficiently abrogated the protective effect. Further, fadraciclib was synergistic with the Bcl-2 antagonist venetoclax, inducing more profound CLL cell death, especially in samples with 17p deletion. While fadraciclib, venetoclax, and the combination each had distinct kinetics of cell death induction, their activities were reversible, as no additional cell death was induced upon removal of the drugs. The best combination effects were achieved when both drugs were maintained together. Altogether, this study provides a rationale for the clinical development of fadraciclib in CLL, either alone or in combination with a Bcl-2 antagonist.

Topics: Adenosine; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Roscovitine; Sulfonamides; Tumor Microenvironment

Although the BH3-mimetic venetoclax is highly cytotoxic for chronic lymphocytic leukemia (CLL) cells, some patients with CLL fail to clear minimal residual disease (MRD). We examined the CLL cells of seven such patients (CLL1-7) and found each had high-level expression of ROR1. By examining the CLL cells from such patients prior to therapy at SC1 and then more than 1 year later (Sample Collection 2 (SC2)), when they had progressive increases in MRD despite continued venetoclax therapy, we found the levels of ROR1 expressed on CLL cells at SC2 were significantly higher than that on CLL cells collected at SC1. At SC2, we also observed upregulation of genes induced by Wnt5a-induced ROR1 signaling, including BCL2L1. Transduction of the CLL-cell-line MEC1 to express ROR1 enhanced expression of target genes induced by ROR1-signaling, increased expression of BCL-XL, and enhanced resistance to venetoclax, even in MEC1 made to express mutant forms of BCL2, which are associated with venetoclax resistance. Treatment of primary CLL cells with Wnt5a also increased their resistance to venetoclax, an effect that could be inhibited by the anti-ROR1 mAb (UC-961, zilovertamab). Collectively, these studies indicate that Wnt5a-induced ROR1-signaling can enhance resistance to venetoclax therapy.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Receptor Tyrosine Kinase-like Orphan Receptors; Sulfonamides

Patients with chronic lymphocytic leukemia (CLL) relapsing on ibrutinib are often treated with the Bcl-2 inhibitor venetoclax. However, the transition from one agent to another poses some clinical challenges due to disease flares sometimes occurring right after ibrutinib interruption. Here, we describe three clinical vignettes highlighting two distinct patterns of ibrutinib-to-venetoclax transition. While patients following the favorable pattern transited to venetoclax without experiencing disease flare, the one patient who took the unfavorable path showed rapid disease rebound, with large-cell transformation occurring one week after ibrutinib interruption. A high burden of

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Sulfonamides

Venetoclax (VEN), a highly selective BCL-2 inhibitor, is successfully used in the treatment of chronic lymphocytic leukemia (CLL). The purine analogue - cladribine (2-CdA) - is also administered to CLL patients, especially as a part of chemoimmunotherapy.. To compare the effects of the VEN+2-CdA regimen with that of the 2 drugs used alone on the apoptosis of CLL lymphocytes in vitro.. Mononuclear cells were collected from 103 previously untreated CLL patients. They were incubated with VEN (40 nM) or/and 2-CdA (16 μM) for 48 h. Cytotoxicity, overall apoptosis, mitochondrial transmembrane potential changes (ΔΨm), and expression of selected apoptosis-involved proteins were measured.. The cytotoxicity, overall apoptosis, caspase-3 or caspase-9 expression, and ΔΨm were significantly higher after VEN+2-CdA addition compared to both drugs used alone, with a very strong synergistic effect observed. The percentage of BCL-2-positive cells decreased after VEN and VEN+2-CdA addition compared to controls. The TP53-expressing cells increased under the influence of all tested regimens. The VEN+2-CdA increased the expression of BIM, BAX and NOXA compared to either controls or VEN or 2-CdA alone. Similar increases in PUMA expression were observed after VEN, 2-CdA and VEN+2-CdA addition. The FAS-associated death-domain protein (FADD) expression was significantly higher after 2-CdA and 2-CdA+VEN addition as compared to control.. Our results confirm the involvement of both VEN and 2-CdA in the intrinsic apoptotic pathway. They also demonstrate that these agents have a synergistic effect on CLL cells in vitro. Further studies are needed to assess the influence of VEN+2-CdA on the expression of apoptosis-involved genes.

Topics: Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Caspase 9; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Successes with anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) and enhanced activity of Fc-engineered vs unmodified antibody therapy suggest a potentially impactful role for natural killer (NK) cells and other innate immune cells in controlling this disease. Stimulated NK cells have shown promise as a cellular therapy, but their application has been constrained by limited expansion capacity and low cytotoxic activity against CLL cells. Here, we demonstrate that both healthy donor-derived and CLL patient-derived NK cells expand rapidly when stimulated with feeder cells expressing membrane-bound interleukin-21 (mbIL-21) and have potent cytotoxic activity against allogeneic or autologous CLL cells. Combination with anti-CD20 antibodies significantly enhances NK recognition and killing of CLL targets. As any CLL immune therapy would likely be given in combination, we assess commonly used treatments and demonstrate that ibrutinib has mixed suppressive and protective effects on expanded NK cells, whereas expanded NKs are highly resistant to venetoclax. We demonstrate efficacy in vivo in 2 xenograft mouse models of human CLL that support building upon a regimen of venetoclax and obinutuzumab with mbIL-21-expanded NK cells. Collectively, these data support development of mbIL-21-expanded NKs combined with the CD20 antibody obinutuzumab and venetoclax in the treatment of CLL.

Topics: Animals; Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Mice

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Sulfonamides

The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.

Topics: Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Epigenesis, Genetic; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2

Venetoclax (VEN) inhibits the prosurvival protein BCL2 to induce apoptosis and is a standard therapy for chronic lymphocytic leukemia (CLL), delivering high complete remission rates and prolonged progression-free survival in relapsed CLL but with eventual loss of efficacy. A spectrum of subclonal genetic changes associated with VEN resistance has now been described. To fully understand clinical resistance to VEN, we combined single-cell short- and long-read RNA-sequencing to reveal the previously unappreciated scale of genetic and epigenetic changes underpinning acquired VEN resistance. These appear to be multilayered. One layer comprises changes in the BCL2 family of apoptosis regulators, especially the prosurvival family members. This includes previously described mutations in BCL2 and amplification of the MCL1 gene but is heterogeneous across and within individual patient leukemias. Changes in the proapoptotic genes are notably uncommon, except for single cases with subclonal losses of BAX or NOXA. Much more prominent was universal MCL1 gene upregulation. This was driven by an overlying layer of emergent NF-κB (nuclear factor kappa B) activation, which persisted in circulating cells during VEN therapy. We discovered that MCL1 could be a direct transcriptional target of NF-κB. Both the switch to alternative prosurvival factors and NF-κB activation largely dissipate following VEN discontinuation. Our studies reveal the extent of plasticity of CLL cells in their ability to evade VEN-induced apoptosis. Importantly, these findings pinpoint new approaches to circumvent VEN resistance and provide a specific biological justification for the strategy of VEN discontinuation once a maximal response is achieved rather than maintaining long-term selective pressure with the drug.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Recurrence

Standard treatment regimens for the management of patients with refractory splenic marginal zone lymphoma (SMZL) are currently unavailable. Here, we report a case of SMZL, which, after failing multiple therapeutics, demonstrated an impressive clinical response to combined Venetoclax and Velcade (V

Topics: Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Splenic Neoplasms; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retreatment; Sulfonamides

Topics: Abnormal Karyotype; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Patients with chronic lymphocytic leukaemia (CLL) disease progression on ibrutinib or after sequential ibrutinib and venetoclax-based treatments (double-refractory) have poor outcomes. In this retrospective study, we analysed outcomes with combined ibrutinib and venetoclax treatment in these groups of patients. The median treatment-free and overall survival for 22 patients with prior progression on ibrutinib (venetoclax-naïve) were 23.7 and 47.1 months respectively. In 11 patients with double-refractory CLL, the median treatment-free and overall survival were 11.2 and 27.0 months respectively. The combination of ibrutinib and venetoclax may help bridge the current gap in options for patients with disease refractory to the most commonly used novel agents.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Retrospective Studies; Sulfonamides

B-cell prolymphocytic leukaemia (B-PLL) is an aggressive B-cell lymphoproliferative disease with few clinically proven targeted treatments. Due to the rarity of the condition, there is a paucity of clinical trial data and none that involve targeted inhibitors. We present a unique case of relapsed refractory B-PLL treated to a sustained minimal residual disease-negative remission with venetoclax monotherapy, to add to the current evidence base and rationale for future studies using BCL-2 inhibitors in B-PLL.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic, B-Cell; Neoplasm, Residual; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Suppressor Protein p53

Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10-4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Pyrazoles; Pyrimidines

The phase II CAPTIVATE study investigated first-line treatment with ibrutinib plus venetoclax for chronic lymphocytic leukemia in two cohorts: minimal residual disease (MRD)-guided randomized treatment discontinuation (MRD cohort) and fixed duration (FD cohort). We report tumor debulking and tumor lysis syndrome (TLS) risk category reduction with three cycles of single-agent ibrutinib lead-in before initiation of venetoclax using pooled data from the MRD and FD cohorts.. In both cohorts, patients initially received three cycles of ibrutinib 420 mg/day then 12 cycles of ibrutinib plus venetoclax (5-week ramp-up to 400 mg/day).. In the total population (N = 323), the following decreases from baseline to after ibrutinib lead-in were observed: percentage of patients with a lymph node diameter ≥5 cm decreased from 31% to 4%, with absolute lymphocyte count ≥25 × 109/L from 76% to 65%, with high tumor burden category for TLS risk from 23% to 2%, and with an indication for hospitalization (high TLS risk, or medium TLS risk and creatinine clearance <80 mL/minute) from 43% to 18%. Laboratory TLS per Howard criteria occurred in one patient; no clinical TLS was observed.. Three cycles of ibrutinib lead-in before venetoclax initiation provides effective tumor debulking, decreases the TLS risk category and reduces the need for hospitalization for intensive monitoring for TLS.

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Creatinine; Cytoreduction Surgical Procedures; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Sulfonamides; Tumor Lysis Syndrome

PI3K inhibitors (PI3Ki) are approved for relapsed chronic lymphocytic leukemia (CLL). Although patients may show an initial response to these therapies, development of treatment intolerance or resistance remain clinical challenges. To overcome these, prediction of individual treatment responses based on actionable biomarkers is needed. Here, we characterized the activity and cellular effects of 10 PI3Ki and investigated whether functional analyses can identify treatment vulnerabilities in PI3Ki-refractory/intolerant CLL and stratify responders to PI3Ki.. Peripheral blood mononuclear cell samples (n = 51 in total) from treatment-naïve and PI3Ki-treated patients with CLL were studied. Cells were profiled against 10 PI3Ki and the Bcl-2 antagonist venetoclax. Cell signaling and immune phenotypes were analyzed by flow cytometry. Cell viability was monitored by detection of cleaved caspase-3 and the CellTiter-Glo assay.. pan-PI3Kis were most effective at inhibiting PI3K signaling and cell viability, and showed activity in CLL cells from both treatment-naïve and idelalisib-refractory/intolerant patients. CLL cells from idelalisib-refractory/intolerant patients showed overall reduced protein phosphorylation levels. The pan-PI3Ki copanlisib, but not the p110δ inhibitor idelalisib, inhibited PI3K signaling in CD4+ and CD8+ T cells in addition to CD19+ B cells, but did not significantly affect T-cell numbers. Combination treatment with a PI3Ki and venetoclax resulted in synergistic induction of apoptosis. Analysis of drug sensitivities to 73 drug combinations and profiling of 31 proteins stratified responders to idelalisib and umbralisib, respectively.. Our findings suggest novel treatment vulnerabilities in idelalisib-refractory/intolerant CLL, and indicate that ex vivo functional profiling may stratify PI3Ki responders.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Quinazolinones; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local; Rituximab; Sulfonamides

The over-expression of the Bcl-2 protein is a common feature of many solid cancers and hematological malignancies, and it is typically associated with poor prognosis and resistance to chemotherapy. Bcl-2-specific inhibitors, such as venetoclax, have recently been approved for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma, and they are showing promise in clinical trials as a targeted therapy for patients with relapsed or refractory acute myeloid leukemia (AML). However, successful treatment of AML with Bcl-2-specific inhibitors is often followed by the rapid development of drug resistance. An emerging paradigm for overcoming drug resistance in cancer treatment is through the targeting of mitochondrial energetics and metabolism. In AML in particular, it was recently observed that inhibition of mitochondrial translation via administration of the antibiotic tedizolid significantly affects mitochondrial bioenergetics, activating the integrated stress response (ISR) and subsequently sensitizing drug-resistant AML cells to venetoclax. Here we develop an integrative systems biology approach to acquire a deeper understanding of the molecular mechanisms behind this process, and in particular, of the specific role of the ISR in the commitment of cells to apoptosis. Our multi-scale mathematical model couples the ISR to the intrinsic apoptosis pathway in venetoclax-resistant AML cells, includes the metabolic effects of treatment, and integrates RNA, protein level, and cellular viability data. Using the mathematical model, we identify the dominant mechanisms by which ISR activation helps to overcome venetoclax resistance, and we study the temporal sequencing of combination treatment to determine the most efficient and robust combination treatment protocol.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Systems Biology

Topics: Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Venetoclax in combination with obinutuzumab has significantly improved efficacy versus immunochemotherapy (progression-free survival) in patients with chronic lymphocytic leukaemia who have not  received prior treatment. The objective of this study was to evaluate its efficiency in Spain using a cost-utility analysis.. Using a partitioned-survival analysis model adapted to the Spanish  context and based on three health states (progression-free survival, survival  after progression, and death), a simulation of the evolution of patients who  were candidates for initiating first-line treatment was conducted for a lifetime  time horizon. Venetoclax in combination with obinutuzumab was compared to  the most commonly used therapeutic options for these patients at the time of  study design: chlorambucil in combination with obinutuzumab, ibrutinib,  fludarabine in combination with cyclophosphamide and rituximab, and  bendamustine in combination with rituximab. In order to estimate survival  curves, efficacy data were derived from the CLL14 trial and a network meta- analysis. The  analysis was conducted from the perspective of the Spanish  National Healthcare System and included direct healthcare costs (i.e.  pharmacological costs and their administration), and those associated with the management of the disease and adverse events. The resource use was validated by an expert group. Quality of life data were used to estimate the  quality-adjusted life years obtained for each alternative. A threshold of  €25,000/quality-adjusted life years was used. The robustness of the model was evaluated using deterministic and probabilistic sensitivity analyses.. Venetoclax in combination with obinutuzumab was shown to be a  dominant alternative compared to the rest of the treatment alternatives, with a  lower cost per patient (€-67,869 compared to chlorambucil in combination  with obinutuzumab, €-375,952 compared to ibrutinib, €-61,996 compared to  fludarabine in combination with cyclophosphamide and rituximab, and €- 77,398 compared to bendamustine in combination with rituximab). It also had  a greater gain in quality-adjusted life years (0.551 quality-adjusted life years  gained compared to chlorambucil in combination with obinutuzumab and  ibrutinib, 1.639 quality-adjusted life years gained compared to fludarabine in  combination with cyclophosphamide and rituximab, and 1.186 quality-adjusted  life years gained compared to bendamustine in combination with  rituximab). Between 68% and 85% of the simulations performed in the  sensitivity analysis showed that venetoclax in combination with obinutuzumab  had lower costs and more quality-adjusted life years gained.. Venetoclax in combination with obinutuzumab is an efficient and  dominant alternative for treating previously untreated patients with chronic lymphocytic leukaemia compared to the available  alternatives and from the perspective of the Spanish National Health System.. Venetoclax en combinación con obinutuzumab ha mostrado frente a  la inmunoquimioterapia mejoras significativas en términos de eficacia (supervivencia libre de progresión) en pacientes con leucemia  infocítica crónica que no han recibido tratamiento previo. El objetivo de este  estudio fue evaluar su eficiencia en España a partir de un análisis de coste- utilidad.Método: A partir de un modelo de análisis de la supervivencia adaptado al  contexto español y basado en tres estados de salud (supervivencia libre de  progresión, supervivencia tras progresión y muerte), se llevó a cabo una  simulación de la evolución de los pacientes candidatos a iniciar una primera  línea de tratamiento para un horizonte temporal de toda la vida. Venetoclax en  combinación con obinutuzumab se comparó frente a las opciones terapéuticas  más utilizadas para estos pacientes en el momento del diseño del estudio:  clorambucilo en combinación con obinutuzumab, ibrutinib, fludarabina en  combinación con ciclofosfamida y rituximab, y bendamustina en combinación  con rituximab. Los datos de eficacia para estimar las curvas de supervivencia  fueron derivados del estudio CLL14 y de un metaanálisis en red. El análisis  consideró la perspectiva del Sistema Nacional de Salud incluyendo los costes  sanitarios directos, en concreto los farmacológicos y su administración, y los  asociados al manejo de la enfermedad y acontecimientos adversos. El uso de  recursos fue validado por un grupo de expertos. Se emplearon datos de calidad  de vida para estimar los años de vida ajustados por calidad obtenidos  para cada alternativa. Se consideró un umbral de 25.000 €/años de vida  ajustados por calidad. La robustez del modelo se evaluó mediante análisis de  sensibilidad determinísticos y probabilísticos.. Venetoclax en combinación con obinutuzumab se mostró como  una alternativa dominante frente al resto de alternativas de tratamiento, con  un menor coste por paciente (–67.869 € frente a clorambucilo en combinación  con obinutuzumab, –375.952 € frente a ibrutinib, –61.996 € frente a  ludarabina en combinación con ciclofosfamida y rituximab, y –77.398 € frente  a bendamustina en combinación con rituximab) y una mayor ganancia en años  de vida ajustados por calidad (0,551 años de vida ajustados por calidad  ganados frente a clorambucilo en combinación con obinutuzumab e ibrutinib,  1,639 años de vida ajustados por calidad ganados frente a fludarabina en  combinación con ciclofosfamida y rituximab, y 1,186 años de vida ajustados  por calidad ganados frente a bendamustina en combinación con rituximab).  Entre el 68% y el 85% de las simulaciones realizadas en el análisis de  sensibilidad mostraban a venetoclax en combinación con obinutuzumab con un  menor coste y un mayor número de años de vida ajustados por calidad  ganados.. Venetoclax en combinación con obinutuzumab se muestra como una alternativa eficiente y dominante como tratamiento de  pacientes con leucemia linfocítica crónica no tratados previamente frente a las  alternativas disponibles y desde la perspectiva del Sistema Nacional de Salud.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Cost-Benefit Analysis; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Quality of Life; Rituximab; Spain; Sulfonamides

Chronic lymphocytic leukemia (CLL) is a hematological neoplasm of CD19-positive mature-appearing B lymphocytes. Despite the clinical success of targeted therapies in CLL, the development of resistance diminishes their therapeutic activity. This is also true for the Bcl-2 antagonist venetoclax. We investigated the molecular mechanisms that drive venetoclax resistance in CLL, with a clear focus to provide new strategies to successfully combat it. Activation of CLL cells with IFNγ, PMA/ionomycin, and sCD40L diminished the cytotoxicity of venetoclax. We demonstrated that the metabolic activity of cells treated with 1 nM venetoclax alone was 48% of untreated cells, and was higher for cells co-treated with IFNγ (110%), PMA/ionomycin (78%), and sCD40L (62%). As of molecular mechanism, we showed that PMA/ionomycin and sCD40L triggered translocation of NFκB in primary CLL cells, while IFNγ activated p38 MAPK, suppressed spontaneous and venetoclax-induced apoptosis and induced formation of the immunoproteasome. Inhibition of immunoproteasome with ONX-0914 suppressed activity of immunoproteasome and synergized with venetoclax against primary CLL cells. On the other hand, inhibition of p38 MAPK abolished cytoprotective effects of IFNγ. We demonstrated that venetoclax-resistant (MEC-1 VER) cells overexpressed p38 MAPK and p-Bcl-2 (Ser70), and underexpressed Mcl-1, Bax, and Bak. Inhibition of p38 MAPK or immunoproteasome triggered apoptosis in CLL cells and overcame the resistance to venetoclax of MEC-1 VER cells and venetoclax-insensitive primary CLL cells. In conclusion, the p38 MAPK pathway and immunoproteasome represent novel targets to combat venetoclax resistance in CLL.

Topics: Antineoplastic Agents; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Ionomycin; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax, a highly selective Bcl-2 inhibitor, is an orally bioavailable drug that has been approved as first-line therapy for chronic lymphocytic leukemia (CLL) in combination with obinutuzumab, as well as monotherapy in the setting of relapsed CLL. Although some of its life-threatening side effects are well known, including tumor lysis syndrome and cytopenias, others less known side effects include skin reactions. Skin rash is commonly reported in literature, which is often mild and not life-threatening. In this case report, the authors describe what is potentially the second case of venetoclax-induced vitiligo reported in literature. A 77-year-old man with CLL Rai stage II with cytogenetics showed 11 q23 deletion in 14% of cells, and 14q32 partial deletion in 9% of cells developed vitiligo in his extremities 2 years into treatment. A decision was made to continue venetoclax with close monitoring as the side effect was mild and not debilitating. The patient continued to do well. Although vitiligo is not associated with increased mortality risk, its development is associated with increased psychological stress. The mechanism by which vitiligo develops remains unclear. There may be an association between drug-induced vitiligo and improved cancer prognosis; however, larger studies need to be carried out to prove this hypothesis.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Vitiligo

Patients with chronic lymphocytic leukemia (CLL) show suboptimal responses to the vaccines against SARS-CoV-2; it has been shown though that a booster dose of the BNT162b2 vaccine may lead to a significant increase in the seroconversion rates of immunocompromised patients. We conducted a prospective, non-interventional study to evaluate the immunogenicity of a third dose of the BNT162b2 vaccine in adult patients with CLL. Sera were tested before the first, after the second, and before and after the third dose for anti-SARS-CoV-2 receptor binding domain (RBD) spike protein IgG (anti-RBD). Thirty-nine patients with CLL were included in the study. The seroconversion rate increased from 28.2% before the third dose to 64.1% after the third dose and was higher in treatment-naïve patients (72.7% versus 47.1% in actively treated patients, p = 0.042). All but one patient achieving a seroconversion after the second dose retained after the third, while eight patients not achieving a seroconversion after the second dose (38.1%), did so after the third. Moreover, patients actively treated with venetoclax had a higher seroconversion rate than those treated with ibrutinib (87.5% versus 14.3%, p = 0.001). This study confirms the beneficial effect of a third dose of the BNT162b2 vaccine on the seroconversion rate in patients with CLL. Our results also strongly suggest that the use of venetoclax is correlated with higher immunogenicity/seroconversion rates than that of ibrutinib, a finding that has been reported by another study. A treatment strategy change during the pandemic favoring the use of venetoclax may be suggested based on our results, although these results should be validated in larger studies.

Topics: Adult; Antibodies, Viral; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Humans; Immunoglobulin G; Leukemia, Lymphocytic, Chronic, B-Cell; Prospective Studies; SARS-CoV-2

Inhibitors of B cell receptor (BCR) signaling such as the Bruton's tyrosine kinase (BTK) inhibitors are effective therapeutics for chronic lymphocytic leukemia (CLL). The first-in-class covalent BTK inhibitor, ibrutinib, produces durable responses in most CLL patients; however, complete responses are only observed in a minority of patients. B cell lymphoma 2 (BCL2), an anti-apoptotic protein that contributes to CLL cell survival, has also been investigated as a therapeutic target. The BCL2 inhibitor venetoclax is effective in patients with CLL and can produce undetectable minimal residual disease, allowing discontinuation of therapy. In combination, ibrutinib and venetoclax have shown preclinical synergy and clinical efficacy. Nemtabrutinib is a next generation, reversible inhibitor of BTK that potently inhibits BCR signaling in treatment-naïve and ibrutinib-refractory CLL cells ex vivo. The clinical efficacy of combining BTK inhibitors with BCL2 inhibitors motivated us to evaluate the novel combination of nemtabrutinib and venetoclax. In vitro studies show that nemtabrutinib and venetoclax are not antagonistic to each other. In an adoptive transfer CLL mouse model, mice treated with nemtabrutinib and venetoclax had prolonged survival compared to mice treated with ibrutinib and venetoclax. Our preclinical studies further validate the combination of BTK inhibitors with venetoclax and justify further investigation of combining nemtabrutinib with venetoclax in CLL.

Topics: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Mice; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual

Patients with chronic lymphocytic leukemia (CLL) refractory to covalent BTK and BCL2 inhibitors have a new unmet clinical need. Standard treatment options are able to obtain only limited and short-lasting disease control associated with reduced overall survival, and thus these patients have become ideal candidates for enrollment in clinical trials. Favorable results have been obtained with the use of noncovalent BTK inhibitors (roughly 70% overall response rate regardless of the actual resistance or intolerance to previous covalent BTK inhibitors) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy (with complete responses in up to 45% of cases and an undetectable measurable residual disease rate of 65% in the bone marrow). These 2 approaches should be considered valid options in this setting, although not yet approved. For young fit patients achieving remissions with salvage treatments, the option of allogeneic stem cell transplantation should be discussed as the outcome appears to be unaffected by number and type of previous targeted agents. Novel treatment strategies interfering with different mechanisms of CLL cell survival and proliferation are warranted, including small molecules with novel targets (eg, CDK9, MCL1, ERK inhibitors), CAR T cells targeting different antigens, CAR natural killer cells, or bispecific antibodies.

Topics: Antigens, CD19; Antineoplastic Agents; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Remission Induction

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; p.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Retrospective Studies; Sulfonamides

The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting.. To determine the incidence of grade 3 and 4 neutropenia and identify risk factors for neutropenia among CLL patients treated with the VenG regimen.. We conducted a retrospective, single-center study of all adult patients with a diagnosis of CLL treated with VenG at the University of Colorado Hospital. Demographic information, laboratory data, clinical data, and medication prescriptions were collected from the patients' electronic medical record.. A total of 14 patients (73%) developed neutropenia during the course of therapy. The mean time to neutropenia from the start of treatment was 42 days (range 1-131). Our cohort harbored more high risk disease features and more comorbidities (CIRS score of 12). Four patients (28.6%) in the neutropenic group developed infectious complications during therapy and 6 (31%) patients were unable to be dose escalated to the final FDA approved dose of 400 mg.. Our study cohort had higher incidence of grade 3 and 4 neutropenia occurring in 73% of patients. This could be attributed to a higher rate of comorbidities, high risk features, concomitant interacting medications, and prior chemotherapy. Further studies are warranted to determine if growth factor support is efficacious to achieve dose escalation with this therapy.

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Retrospective Studies; Risk Factors; Sulfonamides

Richter syndrome (RS) represents the development of high-grade lymphoma in patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) and presents a diagnostic and therapeutic challenge with an adverse prognosis. The genetic background and morphology of RS in CLL patients treated with chemoimmunotherapy is extensively characterised; however, our knowledge about RS in patients treated with targeted oral therapies should be extended. To understand the morphologic and molecular changes leading to RS in CLL patients treated with the Bruton's tyrosine kinase inhibitor, ibrutinib, and the BCL2 inhibitor, venetoclax, sequential samples from six CLL/SLL patients undergoing RS were collected in both the CLL and RS phases. A detailed immunophenotypic analysis of formalin-fixed, paraffin-embedded tissue specimens of RS phase was performed, followed by extensive molecular characterisation of CLL and RS samples, including the immunoglobulin heavy chain gene (IGH) rearrangement, TP53 mutations, drug-induced resistance mutations in BTK and BCL2 genes and various copy number changes and point mutations detectable with multiplex ligation-dependent probe amplification (MLPA). Rare, non-diffuse large B-cell lymphoma phenotypes of RS were observed in 3/6 cases, including plasmablastic lymphoma and a transitory entity between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. The majority of cases were clonally related and harboured an unmutated variable region of the immunoglobulin heavy chain gene. Abnormalities affecting the TP53 gene occurred in all patients, and every patient carried at least one genetic abnormality conferring susceptibility to RS. In the background of RS, 2/5 patients treated with ibrutinib showed a BTK C481S resistance mutation. One patient developed a BCL2 G101V mutation leading to venetoclax resistance and RS. In conclusion, our findings contribute to better understanding of RS pathogenesis in the era of targeted oral therapies. Rare phenotypic variants of RS do occur under the treatment of ibrutinib or venetoclax, and genetic factors leading to RS are similar to those identified in patients treated with chemoimmunotherapy. To our best knowledge, we have reported the first BCL2 G101V mutation in an RS patient treated with venetoclax.

Topics: Adenine; Adult; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Genes, p53; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Mutation; Piperidines; Prognosis; Proto-Oncogene Proteins c-bcl-2; Risk Factors; Sulfonamides

The covalent inhibitor of Bruton's tyrosine kinase ibrutinib and the specific Bcl-2 inhibitor venetoclax are both highly efficacious single-agent drugs in the treatment of chronic lymphocytic leukemia (CLL). Based on their complementary modes of action, ibrutinib and venetoclax are hypothesized to act in a synergistic fashion. Currently, it is unclear whether combined treatment is indeed superior to continuous single-agent treatment and what mechanisms underlie the resistance to combination treatment. In addition, the effects of such treatment on the skewed T-cell compartment characteristic of CLL are as yet unknown. In the murine Eµ-TCL1 adoptive transfer model resembling aggressive CLL, we found that combined treatment resulted in the deepest responses, with the longest duration related to a combination of decreased proliferation and increased induction of apoptosis. In addition, alterations in T-cell subsets were most prominent after combination treatment, with increased naive cells and reduced effector memory cells. Remarkably, effects of single agents but also combination treatment were eventually interrupted by relapse, and we found downregulation of BIM expression as a plausible cause of acquired drug resistance. Nevertheless, in this murine model, the combination of venetoclax and ibrutinib has increased efficacy over single agents, accompanied by a restoration of the T-cell compartment.

Topics: Adenine; Animals; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Piperidines; Proto-Oncogene Proteins; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Sulfonamides

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cost-Benefit Analysis; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Quality-Adjusted Life Years; Sulfonamides; United States

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocyte Count; Sulfonamides; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Anti-CD20 monoclonal antibodies (mAbs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL) by improving survival of patients with CLL in conjunction with chemotherapy. However, the novel targeted agents such as Bruton tyrosine kinase inhibitors (BTKis) and venetoclax have now mostly replaced chemotherapy in frontline treatment of CLL. Several clinical trials have been conducted to examine the role of anti-CD20 mAbs in combination with BTK inhibitors and venetoclax. Addition of rituximab to ibrutinib does not improve progression-free survival (PFS) of treatment-naive patients with CLL, possibly related to ibrutinib's antagonistic effect on anti-CD20 antibodies. Alternatively, addition of a glycoengineered anti-CD20 mAb obinutuzumab to a more selective BTKi acalabrutinib may improve PFS but does not improve overall survival of patients with CLL in the frontline setting, pending long-term follow-up. Thus, we suggest that the addition of an anti-CD20 mAb to a BTKi is of most benefit to patients with autoimmune cytopenia or rapidly progressive disease. In contrast to BTKis, combination of fixed-duration venetoclax and anti-CD20 mAb can induce deep remission with high rates of undetectable minimal residual disease, correlating with improved survival of patients with CLL in both frontline and relapsed/refractory settings. In this review, we discuss clinical trials of BTKis and venetoclax that have investigated the role of anti-CD20 mAbs in frontline and relapsed settings of CLL treatment. We also provide an algorithm suggesting how anti-CD20 mAbs may be incorporated in the treatment of patients with CLL, including specific scenarios.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Humanized; Antigens, CD20; Antineoplastic Agents; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Protein Kinase Inhibitors; Pyrazines; Rituximab; Sulfonamides

Both BTKi and BCL2i are regarded as standards of care for frontline treatment of CLL. In this paper, I present the arguments for favoring BTKi as initial therapy. Venetoclax-based regimens have the advantage of being fixed in duration, but patients with select high-risk features may experience inferior PFS relative to those without high-risk features.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Protein Kinase Inhibitors; Sulfonamides

Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Protein Kinase Inhibitors; Rituximab; Sulfonamides

Topics: Adenine; Antibodies, Monoclonal, Humanized; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Network Meta-Analysis; Piperidines; Pyrazines; Sulfonamides; Survival Rate

Treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) has significantly improved more recently with the approval of several new agents, including ibrutinib, idelalisib, and venetoclax. Despite the outstanding efficacies observed with these agents, these treatments are sometimes discontinued due to toxicity, unresponsiveness, transformation of the disease and/or resistance. Constitutive NF-κB activation that protects CLL cells from apoptotic stimuli represents one of molecular mechanisms that underlie the emergence of drug resistance. As prostaglandin E (EP)4 receptor agonists have been shown to successfully inhibit the NF-κB pathway in B-cell lymphoma cells, we investigated the potential of the highly specific EP4 receptor agonist L-902688 for the potential treatment of patients with CLL. We show here that low micromolar concentrations of L-902688 can indeed induce selective cytotoxicity towards several B-cell malignancies, including CLL. Moreover, L-902688-mediated activation of the EP4 receptor in patient derived CLL cells resulted in inhibition of the NF-κB pathway, cell proliferation, and induction of apoptosis. Most importantly, we show for the first time that in combination with ibrutinib, idelalisib, or venetoclax, L-902688 induces synergistic cytotoxic activity against patient derived CLL cells. To conclude, the modulation of NF-κB activity by EP4 receptor agonists represents an innovative approach to improve the treatment of patients with CLL. In particular, EP4 receptor agonists appear to represent promising adjuncts to the already existing therapies for patients with CLL due to these promising synergistic activities.

Topics: Adenine; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug Synergism; Humans; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Piperidines; Purines; Pyrrolidinones; Quinazolinones; Receptors, Prostaglandin E, EP4 Subtype; Sulfonamides; Tetrazoles; U937 Cells

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Sulfonamides; Ultrasonography

Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ (

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The Bcl-2 inhibitor venetoclax has been recently introduced into the treatment of chronic lymphocytic leukemia. Venetoclax is a highly effective drug, however acquired resistance may make long-term treatment challenging. In our study, we present potential novel resistance mechanisms and prognostic markers that are potentially able to predict the early appearance of the resistance.. Repeated complete blood counts, flow cytometric measurements, and physical examinations were performed during the patient follow-up. Clinical and laboratory parameters showed that the patient developed clinical resistance to venetoclax on day 450 of therapy. Resistance mutation analysis (D103Y) and apoptosis arrays from samples at the time of resistance were done.. We were able to identify the resistance mutations just a very low variant allele frequency level from the resistant samples. Furthermore we detected increased Bcl-2 expression in peripheral blood (PB), and XIAP overexpression in bone marrow (BM) that could lead to venetoclax resistance. We examined the immunophenotype of CLL cells and recognized that while the expression of CD86 did not change until day 270 of the treatment, since then its expression steadily increased. Moreover, we compared the expression of CD86 in the resistant PB and BM samples and did not find a notable difference between the compartments.. Our results imply that CLL cells may try to avoid the apoptotic effect of venetoclax through increased CD86 expression by activating antiapoptotic mechanisms. Confirmatory experiments are still required to unequivocally prove that CD86 is a prognostic marker, however, its predictive property during the venetoclax treatment is promising.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

The BCL2 inhibitor venetoclax is transforming the management of patients with chronic lymphocytic leukemia (CLL), given its high efficacy in relapsed/refractory CLL as observed in both early-phase and randomized clinical trials. The present study aimed to determine whether venetoclax is effective and well tolerated in patients with CLL or Richter's syndrome (RS) in a real-world setting and to highlight factors impacting survival. Data from a venetoclax French compassionate use program were collected for 67 patients (60 with CLL and 7 with RS). Most patients presented adverse genetic features, such as TP53 disruption (74%) or complex karyotype (58%). Tumor lysis syndrome was observed in 14 (22%) patients, and 16 (24%) patients were hospitalized for grade III/IV infection. In the CLL cohort, ORR was 75 %, 1-year PFS was 61% (95% CI = 47-72%) and 1-year OS 70% (95% CI = 56-80%). No impact of TP53 disruption was noted while complex karyotype was identified as a predictor of both inferior PFS (HR = 3.46; 95% CI = 1-12; log-rank p = 0.03) and OS (HR = 3.2; 95% CI = 0.9-11.4, log-rank p = 0.047). Among the seven patients with RS, two achieved an objective response to venetoclax; however, the median OS was only 1.1 month. The well-balanced safety/efficacy profile of venetoclax is confirmed in this real-world setting. Complex karyotype should be evaluated as a predictive factor of survival for patients treated by venetoclax.

Topics: Abnormal Karyotype; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Compassionate Use Trials; Drug Evaluation; Female; France; Genes, p53; Hematopoietic Stem Cell Transplantation; Humans; Infections; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Progression-Free Survival; Retrospective Studies; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

The abnormal expression of B-cell lymphoma-2 (Bcl-2) family members is often associated with the progression of the disease. Bcl-2 inhibitors (eg, venetoclax) were first reported to inhibit the proliferation of malignant lymphocytes and have a significant effect on patients with chronic lymphoblastic leukemia, but research on myeloid tumors is relatively delayed. Venetoclax was approved in 2018 for the treatment of acute myeloid leukemia (AML) patients who were not suitable for high-dose chemotherapy. The approval of venetoclax is an advance in the treatment of hematological tumors.. Here we report a 64-year-old male with an increased white blood cell (WBC) count (39.0 × 109/L) and lymphocyte count (30.6 × 109/L) on physical examination in July 2014. The patients were diagnosed with chronic lymphocytic leukemia (CLL) through bone marrow (BM) smears and immunophenotyping without any cytogenetic or molecular abnormalities. Chlorambucil was prescribed, WBC was stable between 15 × 109/L and 25 × 109/L in the past 6 years. He came to the hospital again in May 2020 and complained of fatigue for 2 weeks. WBC (16.7 × 109/L) and lymphocyte (14.76 × 109/L) counts were increased, hemoglobin (HGB) and platelet (PLT) were decreased in peripheral blood, which indicated the progression of the disease.. The patient was diagnosed as secondary AML after CLL based on the clinical and laboratory findings.. He achieved a morphological complete remission in both AML and CLL without any adverse reactions after one course of venetoclax monotherapy.. He received standard daunorubicin and cytarabine combined with venetoclax as consolidation therapy and is now ready for allogeneic-hematopoietic stem cell transplantation.. Our case presents a challenge to traditional treatment. New drugs such as venetoclax have shown outstanding effects in this respect. High expression of Bcl-2 can identify the responders of venetoclax. These findings should be validated in future clinical trials. We fully believe that in the near future, the comprehensive use of targeted drugs with different mechanisms will not only improve the quality of life of patients, but also completely change the prognosis of patients with recurrent and refractory hematological malignancies.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cytarabine; Daunorubicin; Disease Progression; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Leukocyte Count; Lymphocyte Count; Male; Middle Aged; Remission Induction; Sulfonamides; Treatment Outcome

Ibrutinib inhibits Bruton tyrosine kinase while venetoclax is a specific inhibitor of the anti-apoptotic protein BCL2. Both drugs are highly effective as monotherapy against chronic lymphocytic leukemia (CLL), and clinical trials using the combination therapy have produced remarkable results in terms of rate of complete remission and frequency of undetectable minimal residual disease. However, the laboratory rationale behind the success of the drug combination is still lacking. A better understanding of how these two drugs synergize would eventually help develop other rational combination strategies. Using an ex vivo model that promotes CLL proliferation, we show that modeled ibrutinib proliferative responses, but not viability responses, correlate well with patients' actual clinical responses. Importantly, we demonstrate for the first time that ibrutinib and venetoclax act on distinct CLL subpopulations that have different proliferative capacities. While the dividing subpopulation of CLL responds to ibrutinib, the resting subpopulation preferentially responds to venetoclax. The combination of these targeted therapies effectively reduced both the resting and dividing subpopulations in most cases. Our laboratory findings help explain several clinical observations and contribute to the understanding of tumor dynamics. Additionally, our proliferation model may be used to identify novel drug combinations with the potential of eradicating residual disease.

Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Piperidines; Protein Kinase Inhibitors; Sulfonamides; Tumor Cells, Cultured

BACKGROUND Chronic lymphocytic leukemia (CLL) is a hematological disease characterized by the clonal proliferation and accumulation of neoplastic B lymphocytes in the blood, bone marrow, lymph nodes, and spleen. Autoimmune hemolytic anemia (AIHA) is an acquired hemolytic anemia in which the destruction of erythrocytes is helped by anti-erythrocyte auto-antibodies. This has a controversial effect on the clinical outcome and survival of patients with CLL. Venetoclax, a second-generation BH3 mimetic compound, is one of the new therapies that has been approved for the treatment of CLL. Venetoclax disrupts the antiapoptotic signaling through BCL2. Common adverse events associated with venetoclax include neutropenia, thrombocytopenia, and diarrhea. This case report describes a patient with CLL who developed AIHA when treated with venetoclax. CASE REPORT A patient of 62-year-old woman, who was treated with multiple lines of therapy, presented autoimmune hemolytic anemia after treatment with venetoclax. The anemia was resolved after holding venetoclax and being treated with rituximab. In January 2019, there were reports of 7 patients developing AIHA related to venetoclax therapy in Europe, according to the EudraVigilance database. How venetoclax can cause AIHA is not completely clear. This complication can happen when the erythrocyte antigen is altered by the drug that can produce antibodies. The other described mechanism is the binding of the drug with erythrocytes, which leads to production of an immune response. CONCLUSIONS Although AIHA can be a complication of CLL, it may be caused by treatment with venetoclax. That may be confirmed after eliminating other causes.

Topics: Anemia, Hemolytic, Autoimmune; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Sulfonamides

Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; CRISPR-Cas Systems; DNA Damage; Genes, p53; Humans; Indolizines; Interleukin-2 Receptor alpha Subunit; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Morpholines; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Oxidative Phosphorylation; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pelger-Huet Anomaly; Sulfonamides

Topics: Antigens, CD20; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

This study aimed to describe treatment sequencing and healthcare costs among chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients treated with venetoclax in a US managed care population.. CLL/SLL patients initiating venetoclax between 04/11/2016 and 06/30/2019 were selected from Optum's de-identified Clinformatics Data Mart Database. Costs per-patient-per-month were described during the first 60 days of venetoclax-based treatment (initiation phase) and subsequent post-initiation phase. Based on venetoclax prescribing information, clinical event-related costs were identified through claims for tumor lysis syndrome (TLS) diagnosis, monitoring, prophylaxis, immunoglobulin treatment, neutropenia, thrombocytopenia, infection, renal impairment, hypertension, or cardiac arrhythmia. Statistical testing was not conducted due to small sample size.. Twenty-five, 30, and 66 patients initiated venetoclax as their first observed regimen (1L), second observed regimen (2L), and third or later observed regimen (3L+), respectively. Most 2L (56.7%) and 3L+ (74.2%) venetoclax recipients previously received ibrutinib. Mean monthly all-cause costs during the initiation phase were $26,429 (1L cohort), $19,580 (2L cohort), and $23,918 (3L + cohort). Among the 2L cohort, mean monthly all-cause [clinical event-related] (including TLS) costs during initiation and post-initiation phases of venetoclax treatment were $15,506 [$6368] (initiation phase) and $14,318 [$5273] (post-initiation phase; median duration: 3.7 months) for patients receiving 1L ibrutinib, and $24,908 [$12,198] (initiation phase) and $16,905 [$7066] (post-initiation phase; median duration: 3.0 months) for patients not receiving 1L ibrutinib.. In this descriptive study, highest mean costs were observed during venetoclax initiation phase. Venetoclax patients previously receiving ibrutinib had lower mean total all-cause and clinical event-related (including TLS) costs during their venetoclax line of therapy than those previously receiving non-ibrutinib therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Health Care Costs; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Anemia, Hemolytic, Autoimmune; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Hypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

Topics: Apoptosis; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins, Intravenous; Immunomodulation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Lymphocytes; Receptors, Antigen, T-Cell; Sulfonamides

Topics: Acute Kidney Injury; Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Recently, several small molecule drugs were approved for treatment of chronic lymphocytic leukemia (CLL), significantly improving patient management. However, knowledge about how to combine these therapies for optimal effects and what patients will best benefit from them is lacking. Here, we show that drug synergies can be identified by single cell signaling analyses. We investigated the effects of idelalisib, ibrutinib, and venetoclax on 35 protein epitopes by phospho flow in CLL cells. The activity of proteins in the B-cell receptor signalosome and the phosphatidylinositol 3-kinase pathway were altered upon drug exposure. Combined treatment with ibrutinib and venetoclax give promising results in clinical studies and we show that this combination exerted synergistic inhibitory effects on cell signaling and cell viability. Cell viability was monitored by flow cytometry and with independent drug sensitivity screens. Our analyses indicate that the standard dosages of ibrutinib and venetoclax can be lowered without loss of efficacy, potentially reducing drug costs, and toxicities. Observed correlation between signaling and viability indicates that signaling molecules could serve as biomarkers to predict response to therapy. We suggest that phospho flow should be considered as a novel approach for dose and synergy prediction in a precision medicine setting for CLL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Purines; Quinazolinones; Signal Transduction; Sulfonamides

Elderly chronic lymphocytic leukaemia (CLL) patients treated outside of trials have notably greater toxicity with the Bruton's tyrosine kinase inhibitor ibrutinib compared to younger patients. It is not known whether the same holds true for the B-cell lymphoma 2 inhibitor venetoclax. We provide a comprehensive analysis of key safety measures and efficacy in 342 patients comparing age categories ≥75 and <75 years treated in the relapsed, refractory non-trial setting. We demonstrate that venetoclax has equivalent efficacy and safety in relapsed/refractory CLL patients who are elderly, the majority of whom are previous ibrutinib-exposed and therefore may otherwise have few clear therapeutic options.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Sulfonamides

Topics: Adenine; Aged; Aged, 80 and over; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate

The development of drugs able to target BTK, PI3k-delta and BCL2 has dramatically improved chronic lymphocytic leukaemia (CLL) therapies. However, drug resistance to these therapies has already been reported due to non-recurrent changes in oncogenic pathways and genes expression signatures. In this study, we investigated the cooperative role of the BCL2 inhibitor venetoclax and the BRD4 inhibitor JQ1. In particular, we found that JQ1 shows additional activity with venetoclax, in CLL cell lines and in ex vivo isolated primary CD19

Topics: Azepines; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Transcription Factors; Triazoles

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Goals; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Retrospective Studies; Sulfonamides

Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematologic malignancies; however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells.. Using samples from patients (. AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1, but not Bcl-2 protein levels, in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nmol/L) were additive or synergistic with AMG-176.. AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low-dose venetoclax was additive or synergistic.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Male; Middle Aged; Myeloid Cell Leukemia Sequence 1 Protein; Naphthalenes; Primary Cell Culture; Proto-Oncogene Proteins c-bcl-2; Spiro Compounds; Sulfonamides

Topics: Amino Acid Substitution; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Disease Progression; DNA Mutational Analysis; Drug Resistance, Neoplasm; Gene Frequency; Glycine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Molecular; Mutation; Mutation Rate; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Cells, Cultured; Valine

Topics: Abnormal Karyotype; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Sulfonamides; Treatment Outcome

Progression of chronic lymphocytic leukemia (CLL) and resistance to therapy are affected by tumor microenvironmental factors. One such factor is B-cell activating factor (BAFF), a cytokine that is produced mainly by nurse-like cells (NLC) and enhances CLL cells survival and modulates response to therapy. In CLL cells, BAFF activates NF-κB signaling, but how NF-κB supports CLL survival is not entirely clear. In this study we show that BAFF induces accumulation of the signaling and autophagy adaptor p62/SQSTM1 in a manner dependent on NF-κB activation. p62 potentiates mTORC1 signaling and activates NRF2, the master regulator of the anti-oxidant response. We found that expression of NRF2 target genes, such as NAD(P)H quinone oxidoreductase 1 (NQO1), is particularly enriched in CLL cells with high ROR1 surface expression (ROR1

Topics: Antibodies, Monoclonal, Humanized; B-Cell Activating Factor; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Cytoprotection; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mechanistic Target of Rapamycin Complex 1; Neoplasm Proteins; NF-E2-Related Factor 2; NF-kappa B; Prodrugs; Reactive Oxygen Species; Receptor Tyrosine Kinase-like Orphan Receptors; RNA, Messenger; Sequestosome-1 Protein; Signal Transduction; Sulfonamides

Chronic lymphocytic leukemia (CLL) is one of the most common hematological neoplasms and is the most common leukemia in western industrial nations. According to the World Health Organization classification, CLL is an indolent B‑cell non-Hodgkin's lymphoma (NHL). Diagnosis requires an increase of B‑lymphocytes to more than 5.0 G/l as well as detection of CD5- and CD19-positive B‑lymphocytes. Symptoms can be B symptoms, fatigue or frequent infections. Therapy is only required if there are pronounced symptoms or changes in the blood count, such as a relevant drop in hemoglobin and/or platelets. The prognosis strongly depends on the individual molecular and cytogenetic risk factors. For a long time, the first-line treatment was characterized by chemotherapy in combination with CD20 antibodies. In recent years, the approval of new targeted drugs has changed the treatment landscape significantly and has led to a shift towards chemotherapy-free regimens.. Die chronische lymphatische Leukämie (CLL) zählt zu den häufigsten hämatologischen Neoplasien und ist die häufigste Leukämie in den westlichen Industrienationen. Nach Klassifikation der Weltgesundheitsorganisation wird die CLL zu den indolenten B‑Zell-Non-Hodgkin-Lymphomen gezählt. Für die Diagnose sind ein Anstieg der B‑Lymphozyten auf >5000/µl sowie der Nachweis von CD5- und CD19-positiven B‑Lymphozyten erforderlich. Symptome können B‑Symptome, Fatigue oder gehäufte Infektionen sein. Eine Therapie ist erst bei ausgeprägten Symptomen oder Blutbildveränderungen wie einem relevanten Abfall von Hämoglobin und/oder Thrombozyten erforderlich. Die Prognose hängt stark von den individuellen molekular- und zytogenetischen Risikofaktoren ab. Lange war die Erstlinientherapie durch Chemotherapien in Kombination mit CD20-Antikörpern geprägt; zuletzt haben neue zielgerichtete Wirkstoffe die Therapielandschaft jedoch stark verändert, zunehmend hin zu chemotherapiefreien Regimen.

Topics: Adenine; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Risk Factors; Sulfonamides

Targeted therapies for chronic lymphocytic leukemia (CLL) include venetoclax, the oral inhibitor of B-cell lymphoma-2, and inhibitors of kinases in the B-cell receptor signaling pathway, like Bruton tyrosine kinase and phosphatidylinositol 3 kinase. Randomized clinical trials clearly demonstrated improved progression-free survival with targeted therapy over chemoimmunotherapy in first-line and treatment of relapsed/refractory CLL. Comparative trials of venetoclax-based vs other targeted therapies have not been conducted. Differentiating features and considerations with targeted therapies include goals of treatment and therapeutic approach as well as side effect and toxicity profiles. With targeted therapy options for first-line and relapsed CLL, it is ever more important to develop sound rationale and strategy for selecting first-line and treatment of relapsed disease and for long-term management of the disease, including therapeutic sequencing. Fixed-duration therapy with a treatment-free remission is a particularly appealing prospect, since it avoids continuous exposure to treatment and potential for toxicity. We discuss rationale and practical application of venetoclax in first-line and treatment of relapsed and refractory CLL. Venetoclax is highly active at achieving deep remission for most treated patients with CLL, including those with high-risk disease such as del(17p) CLL.

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Karyotype; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Biopsy; Bridged Bicyclo Compounds, Heterocyclic; Eosinophils; Female; Humans; In Situ Hybridization; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Skin; Skin Diseases; Sulfonamides; Treatment Outcome

Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.. To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].. We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (. For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Sulfonamides

Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds. We assessed immunoglobulin heavy variable chain (IGHV) mutation status, common genomic aberrations, and gene mutations in 421 untreated patients within the CLL14 trial (NCT02242942), comparing obinutuzumab+chlorambucil (GClb) vs obinutuzumab+venetoclax (VenG). The incidences of genomic aberrations considering the hierarchical model were del(17p) 7%, del(11q) 18%, +12 18%, and del(13q) 35%, whereas IGHV was unmutated in 60% of patients. NOTCH1 mutations were most common (23%), followed by SF3B1 (16%), ATM (13%), and TP53 (10%). Although the overall response rate (ORR) for GClb was lower in patients with del(17p), del(11q), mutated TP53, ATM, and BIRC3, none of these parameters reduced complete remission (CR) rate and ORR with VenG. At a median follow-up of 28 months, del(17p) and mutated TP53 were the only abnormalities with an effect on progression-free survival (PFS) for both treatment groups: GClb (hazard ratio [HR], 4.6 [P < .01]; HR, 2.7 [P < .01], respectively) and VenG (HR, 4.4 [P < .01]; HR, 3.1 [P < .01], respectively). No other factors affected outcome with VenG, whereas for GClb del(11q), BIRC3, NOTCH1, and unmutated IGHV were associated with shorter PFS. Multivariable analysis identified del(17p), del(11q), unmutated IGHV, and mutated TP53, BIRC3, and SF3B1 as independent prognostic factors for PFS with GClb, whereas for VenG, only del(17p) was significant. VenG was superior to GClb across most genetic subgroups. Patients with adverse genetic markers had the strongest benefit from VenG, particularly subjects with unmutated IGHV, which was identified as a predictive factor in a multivariable treatment-interaction analysis.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Chromosome Aberrations; Clinical Trials, Phase III as Topic; Follow-Up Studies; Genes, Neoplasm; Genetic Markers; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Multicenter Studies as Topic; Mutation; Neoplasm, Residual; Prognosis; Progression-Free Survival; Remission Induction; Sulfonamides

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Mutation; Phospholipase C gamma; Piperidines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Highly active BTK inhibitors (BTKis) and the BCL2 inhibitor venetoclax have transformed the therapeutic landscape for chronic lymphocytic leukemia (CLL). Results of prospective clinical trials demonstrate the efficacy of venetoclax to salvage patients with disease progression on BTKis, but data on BTKi therapy after disease progression on venetoclax are limited, especially regarding durability of benefit. We retrospectively evaluated the records of 23 consecutive patients with relapsed/refractory CLL who received a BTKi (ibrutinib, n = 21; zanubrutinib, n = 2) after stopping venetoclax because of progressive disease. Median progression-free survival (PFS) and median overall survival after BTKi initiation were 34 months (range, <1 to 49) and 42 months (range, 2-49), respectively. Prior remission duration ≥24 months and attainment of complete remission or undetectable measurable residual disease on venetoclax were associated with longer PFS after BTKi salvage (P = .044 and P = .029, respectively). BTKi therapy achieved durable benefit for patients with the BCL2 Gly101Val venetoclax resistance mutation (estimated 24-month PFS, 69%). At a median survivor follow-up of 33 months (range, 2-53), 11 patients remained on BTKi and 12 had stopped therapy because of disease progression (n = 8) or toxicity (n = 4). Our findings indicate that BTKi therapy can provide durable CLL control after disease progression on venetoclax.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Disease Progression; Drug Evaluation; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Proteins; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Remission Induction; Retrospective Studies; Salvage Therapy; Sulfonamides; Treatment Outcome

Whether BTK inhibitors are effective when used after venetoclax in patients with chronic lymphocytic leukemia is an important unanswered question. In a large retrospective cohort study examining outcomes for next line treatment after venetoclax, BTK inhibitors were found to result in durable responses in patients who were not previously BTK inhibitor resistant.

Topics: Agammaglobulinaemia Tyrosine Kinase; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pyrazoles; Pyrimidines; Retrospective Studies; Sulfonamides

This study aimed to assess the total cost of care (TCC) and budget impact of introducing 12-month fixed duration venetoclax + obinutuzumab (VEN+G) as first-line treatment for chronic lymphocytic leukemia (CLL) from the perspective of a US health plan with 1,000,000 (1M) members.. The 3-year model included the following comparators: fludarabine + cyclophosphamide + rituximab (FCR), bendamustine + rituximab (BR), obinutuzumab + chlorambucil (GClb), ibrutinib (Ibr), and Ibr+Rituximab/obinutuzumab [Ibr+R/Ibr+G]). TCC included US-specific costs associated with treatment (i.e., drug, administration, and wastage), adverse events, routine care, and monitoring. Dosing and safety data were drawn from clinical trials and US package inserts. Budget impact outcomes were presented on an absolute and per-member per-month (PMPM) basis. Sensitivity analyses explored uncertainty in influential parameters, including scenarios testing the duration of treat-to-progression agents.. Over the 3-year time horizon, introducing VEN+G in a 1M-member health plan resulted in total cost savings of $1,550,663 (PMPM - $0.04), compared to a scenario without VEN+G. The fixed 12-month duration of VEN+G contributed to this cost saving by reducing cumulative treatment costs compared with Ibr-based regimens. By year 3, the cumulative difference in TCC of VEN+G compared with Ibr, Ibr+G, and Ibr+R amounted to - $300,942, - $367,001, and - $369,784, respectively. Extensive sensitivity analyses supported the base case findings.. Introducing VEN+G among first-line CLL treatments to a US health plan resulted in cost savings compared to a plan with chemoimmunotherapies and Ibr-based therapies only. Economic benefits of VEN+G, a novel agent with fixed treatment duration, coupled with proven clinical benefits should help inform formulary adoption decisions and treatment recommendations.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Duration of Therapy; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; United States

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Lysis Syndrome

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukoencephalopathy, Progressive Multifocal; Purpura, Thrombocytopenic, Idiopathic; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Bispecific antibodies are promising new therapeutics in B cell malignancies. Whether they lead to potent T cell activation despite described T cell dysfunction in chronic lymphocytic leukemia (CLL), and are able to effectively target high-risk or venetoclax-resistant samples, is currently unknown.. CD19. These data show that CD3xCD19 DART in CLL leads to robust T cell activation and lysis of high-risk venetoclax resistant CLL cells through a non-apoptotic mechanism.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Bispecific; Antigens, CD19; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Case-Control Studies; CD3 Complex; CD8-Positive T-Lymphocytes; Cytotoxicity, Immunologic; Female; Follow-Up Studies; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Male; Middle Aged; Mutation; Prognosis; Sulfonamides; T-Lymphocytes; Tumor Suppressor Protein p53

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Genetic Markers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Prognosis; Sulfonamides

Topics: Baculoviral IAP Repeat-Containing 3 Protein; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Rituximab; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Patients; Sulfonamides; Tumor Lysis Syndrome

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Gene Deletion; Genes, p53; Humans; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lipoprotein Lipase; Male; Middle Aged; Neoplasm Proteins; Piperidines; Proportional Hazards Models; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Assessment; Rituximab; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53; ZAP-70 Protein-Tyrosine Kinase

Bleeding is a common adverse event following ibrutinib monotherapy. However, it remains unclear how hemostasis is affected by venetoclax in combination with ibrutinib. Here we investigated hemostasis in patients with chronic lymphocytic leukemia (CLL) at baseline, during ibrutinib monotherapy, and during venetoclax and ibrutinib combination therapy or venetoclax monotherapy. Primary hemostasis, assessed by Multiplate using adenosine diphosphate (ADP), arachidonic acid (AA), and thrombin receptor agonist peptide (TRAP-6), was impaired in all CLL patients at baseline, remained unchanged upon ibrutinib monotherapy, and improved significantly following venetoclax added to ibrutinib or as monotherapy. Secondary hemostasis assessed by thromboelastography (TEG) was normal and unchanged throughout treatment. The frequency of clinical bleeding events was the highest during ibrutinib monotherapy, in line with the demonstrated improved primary hemostasis upon addition of venetoclax, thus pointing toward a treatment option for CLL patients with increased bleeding risk.

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Hemostasis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Sulfonamides

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

B-cell chronic lymphocytic leukemia (CLL) results from accumulation of leukemic cells that are subject to iterative re-activation cycles and clonal expansion in lymphoid tissues. The effects of the well-tolerated alkaloid Berberine (BRB), used for treating metabolic disorders, were studied on ex-vivo leukemic cells activated in vitro by microenvironment stimuli. BRB decreased expression of survival/proliferation-associated molecules (e.g. Mcl-1/Bcl-xL) and inhibited stimulation-induced cell cycle entry, irrespective of TP53 alterations or chromosomal abnormalities. CLL cells rely on oxidative phosphorylation for their bioenergetics, particularly during the activation process. In this context, BRB triggered mitochondrial dysfunction and aberrant cellular energetic metabolism. Decreased ATP production and NADH recycling, associated with mitochondrial uncoupling, were not compensated by increased lactic fermentation. Antioxidant defenses were affected and could not correct the altered intracellular redox homeostasis. The data thus indicated that the cytotoxic/cytostatic action of BRB at 10-30 μM might be mediated, at least in part, by BRB-induced impairment of oxidative phosphorylation and the associated increment of oxidative damage, with consequent inhibition of cell activation and eventual cell death. Bioenergetics and cell survival were instead unaffected in normal B lymphocytes at the same BRB concentrations. Interestingly, BRB lowered the apoptotic threshold of ABT-199/Venetoclax, a promising BH3-mimetic whose cytotoxic activity is counteracted by high Mcl-1/Bcl-xL expression and increased mitochondrial oxidative phosphorylation. Our results indicate that, while CLL cells are in the process of building their survival and cycling armamentarium, the presence of BRB affects this process.

Topics: Antineoplastic Agents; Apoptosis; B-Lymphocytes; Berberine; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mitochondria; Oxidative Phosphorylation; Patients; Primary Cell Culture; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis); however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose. Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. This limitation can potentially be overcome with rapid dose escalation (RDE). We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. Median time to target dose was 9 days. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. TLS was seen in more patients with a higher initial tumor burden. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre-venetoclax dose to 24 hours post-venetoclax dose of 10 × 103/μL was associated with an increased risk of TLS (hazard ratio, 1.32; P = .02), after controlling for venetoclax dose level. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Receptors, Antigen, B-Cell; Sulfonamides

The B-cell receptor signaling pathway and dysregulation of the Bcl-2 family of proteins play crucial roles in the pathogenesis of chronic lymphocytic leukemia (CLL). Despite significant advances in the treatment of the disease, relapse and drug resistance are not uncommon. In the current study, we investigated the dual PI3/PIM kinase inhibitor IBL-202 in combination with venetoclax as a treatment option for CLL using both primary CLL cells and TP53-deficient OSU-CLL cells generated using the CRISPR-Cas9 system. IBL-202 and venetoclax were highly synergistic against primary CLL cells cocultured with CD40L fibroblasts (combination index [CI], 0.4, at a fractional effect of 0.9) and TP53-knockout (KO) OSU-CLL cells (CI, 0.5, at a fractional effect of 0.9). Synergy between the drugs was consistent, with a significant (P < .05) reduction in the 50% inhibitory concentration for both drugs. IBL-202 and venetoclax in combination induced cell-cycle arrest and slowed the proliferation of both wild-type and TP53-KO cell lines. The drug combination inhibited AKT phosphorylation, reduced expression of Bcl-xL and NF-κB, and increased the Noxa/Mcl-1 ratio. Downregulation of CXCR4 was consistent with inhibition of the SDF-1α-induced migratory capacity of CLL cells. Synergy between IBL-202 and venetoclax against primary CLL cells cultured under conditions that mimic the tumor microenvironment suggests this drug combination may be effective against CLL cells within the lymph nodes and bone marrow. Furthermore, the efficacy of the combination against the TP53-KO OSU-CLL cell line suggests the combination may be a highly effective treatment strategy for high-risk CLL.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Tumor Microenvironment

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Recent developments in the management of chronic lymphocytic leukemia (CLL) have moved the standard of care away from chemoimmunotherapy to targeted agents such as oral kinase inhibitors or BCL-2 antagonists, alone or in combination with anti-CD20 antibodies. Two different treatment approaches have evolved: continuous, indefinite treatment and, more recently, fixed-duration combination treatment. With venetoclax-based treatment, there is a requirement to follow the established guidelines for close monitoring during initiation and ramp up, to reduce the risk of tumor lysis syndrome. The patient's risk should be assessed before the initiation of venetoclax. Appropriate management strategies should be used, including uricosuric agents, hydration, and routine laboratory monitoring, per guidelines. With early identification, immediate management, and dose adjustments, we suggest that tumor lysis syndrome and other toxicities, such as neutropenia and infections, with venetoclax-based treatment can be dealt with successfully.

Topics: Agammaglobulinaemia Tyrosine Kinase; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Sulfonamides; Tumor Lysis Syndrome

Topics: Aged; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 13; Chromosomes, Human, Pair 17; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Recurrence; Rituximab; Smith-Magenis Syndrome; Sulfonamides; Tumor Suppressor Protein p53

Chronic lymphocytic leukemia (CLL) accounts for 10% of hematologic malignancies. CLL is a malignancy of CD5+ B cells and it is characterized by the accumulation of small, mature-appearing neoplastic lymphocytes in the blood, bone marrow, and secondary lymphoid tissues. In the present case, a middle-aged female patient with poor prognosis unmutated IGHV CLL achieved cytogenetic and molecular remission with minimal adverse events following six cycles of low dose recombinant human IL-2 (rIL-2) in combination with low dose targeted venetoclax. Personalized low dose rIL-2 in combination with either lenalidomide or venetoclax mediates natural killer stimulation and is an effective non-toxic immunotherapy administered in the outpatient setting for poor prognosis CLL.

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunologic Factors; Immunotherapy; Interleukin-2; Killer Cells, Natural; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Piperidines; Precision Medicine; Prognosis; Remission Induction; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Aged; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Cyclophosphamide; Doxorubicin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Methylprednisolone; Piperidines; Prednisone; Pyrazoles; Pyrimidines; Recurrence; Rituximab; Salvage Therapy; Sulfonamides; Vincristine

Topics: Acyclovir; Aged; Antineoplastic Agents; Antiviral Agents; Bridged Bicyclo Compounds, Heterocyclic; Exanthema; Female; Hepatitis; Herpesvirus 3, Human; Humans; Immunocompromised Host; Leukemia, Lymphocytic, Chronic, B-Cell; Opportunistic Infections; Pancreatitis; Recurrence; Sulfonamides; Treatment Outcome; Varicella Zoster Virus Infection

Venetoclax in combination with obinutuzumab is an efficacious and tolerable combination that provides a fixed-duration, chemotherapy-free option for patients with previously untreated chronic lymphocytic leukemia (CLL). With the expanding number of therapeutic alternatives available for CLL, discussion of efficacy and potential adverse effects is paramount to formulating the optimal treatment regimen for each individual patient. Many ongoing studies will further define the ideal combination and long-term efficacy of these novel therapies in a prospective manner.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Precision Medicine; Sulfonamides

Morbidity and mortality due to immunosuppression remain among the foremost clinical challenges in chronic lymphocytic leukemia (CLL). Although immunosuppression is considered to originate within the lymph node (LN) microenvironment, alterations in T and natural killer (NK) cells have almost exclusively been studied in peripheral blood (PB). Whereas chemoimmunotherapy further deteriorates immune function, novel targeted agents like the B-cell lymphoma 2 inhibitor venetoclax potentially spare nonmalignant lymphocytes; however, the effects of venetoclax on nonleukemic cells have not been explored. We address these unresolved issues using a comprehensive analysis of nonmalignant lymphocytes in paired LN and PB samples from untreated CLL patients, and by analyzing the effects of venetoclax-based treatment regimens on the immune system in PB samples from previously untreated and relapsed/refractory patients. CLL-derived LNs contained twice the amount of suppressive regulatory T cells (T

Topics: Adult; Aged; Antineoplastic Agents; Blood; Bridged Bicyclo Compounds, Heterocyclic; CD8-Positive T-Lymphocytes; Female; Humans; Immune System; Immunosuppression Therapy; Killer Cells, Natural; Leukemia, Lymphocytic, Chronic, B-Cell; Lymph Nodes; Lymphocytes; Male; Middle Aged; Sulfonamides; T-Lymphocytes, Regulatory

Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Clonal Evolution; Disease Progression; Drug Resistance, Neoplasm; Energy Metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice; Middle Aged; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Oxidative Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Treatment Outcome; Xenograft Model Antitumor Assays

In this issue of Cancer Cell, Guièza et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Adenine; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Clinical Trials, Phase III as Topic; Frail Elderly; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Survival Rate; Treatment Outcome

Continuous treatment vs fixed duration of monotherapies and combinations of targeted agents are treatment options in relapsed chronic lymphocytic leukemia. The optimal choice of relapse treatment is dependent on the prior frontline therapy, duration of remission after frontline, genetic markers, and patients' condition, including age and comorbidities. Combination therapies may result in deep responses with undetectable minimal residual disease (uMRD). Although uMRD is an excellent predictive marker for disease progression, it is rarely used in clinical practice and needs additional evaluation in clinical trials before discontinuation of therapy should be guided according to uMRD.

Topics: Adenine; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Piperidines; Pyrazoles; Pyrimidines; Recurrence; Rituximab; Sulfonamides

TP53-disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long-term response to ibrutinib. We hereby report that ibrutinib-induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53-mutated (TP53-M) CLL cells compared to TP53 wild-type cells. Contrariwise, venetoclax effectively killed TP53-M cells. Gene expression profile analysis of TP53-M cells revealed a downmodulation of B-cell receptor (BCR)-related genes and an upmodulation of genes with anti-apoptotic/pro-survival activity, suggesting that the survival and proliferation of TP53-M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53-M CLL patients.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Cell Survival; Down-Regulation; Female; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Mutation; Piperidines; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Sulfonamides; Tumor Suppressor Protein p53

BH3 mimetics are novel targeted drugs with remarkable specificity, potency and enormous potential to improve cancer therapy. However, acquired resistance is an emerging problem. We report the rapid development of resistance in chronic lymphocytic leukemia cells isolated from patients exposed to increasing doses of navitoclax (ABT-263), a BH3 mimetic. To mimic such rapid development of chemoresistance, we developed simple resistance models to three different BH3 mimetics, targeting BCL-2 (ABT-199), BCL-X

Topics: Antineoplastic Agents; bcl-X Protein; Benzothiazoles; Biomimetics; Bridged Bicyclo Compounds, Heterocyclic; Cholesterol; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Glutamine; Humans; Indoles; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Lipogenesis; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Recurrence, Local; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Receptors, Antigen, B-Cell; Sulfonamides

Chronic lymphocytic leukemia (CLL) pathophysiology is characterized by a complex crosstalk of tumor cells with the microenvironment. In this regard, NF-κB signaling is considered as important signaling axis, with a variety of key molecules aberrantly expressed or genetically altered in patients with CLL. One of these molecules is BIRC3 (cIAP2), a central regulator of noncanonical NF-κB signaling that serves as pathway brake in the absence of microenvironmental signals. However, the contribution of BIRC3 expression to CLL progression and potential therapeutic implications is unknown.. We demonstrate that patients with CLL with low BIRC3 expression experience a more rapid disease progression, which coincides with an enhanced activation of canonical NF-κB target genes evidenced by an increased p65/Rel-B nuclear translocation ratio. As a consequence of enhanced canonical NF-κB target gene activation, both anti- and proapoptotic Bcl-2 family members were upregulated in BIRC3. Here we show the impact of BIRC3 expression in CLL disease progression in the absence of BIRC3 mutations and show altered canonical NF-κB target gene activation with therapeutic implications.

Topics: Adult; Aged; Aged, 80 and over; Animals; Apoptosis; Baculoviral IAP Repeat-Containing 3 Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Nucleus; Cell Survival; Coculture Techniques; Datasets as Topic; Disease Progression; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice; Middle Aged; NF-kappa B; NIH 3T3 Cells; Proof of Concept Study; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Treatment Outcome; Up-Regulation

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. SIGNIFICANCE: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Resistance, Neoplasm; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Models, Molecular; Mutation; Neoplasm Recurrence, Local; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Cells, Cultured

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome

Topics: Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Progression-Free Survival; Randomized Controlled Trials as Topic; Rituximab; Standard of Care; Sulfonamides; Treatment Outcome

The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.

Topics: Aged; Aged, 80 and over; Apoptosis; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Drug Therapy, Combination; Epoxy Compounds; Eukaryotic Initiation Factor-4A; Female; Follow-Up Studies; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Macrolides; Male; Middle Aged; Models, Molecular; Myeloid Cell Leukemia Sequence 1 Protein; Prognosis; Protein Biosynthesis; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Sulfonamides; Thiazoles; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Central Nervous System Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Sulfonamides; Tissue Distribution

Venetoclax is a BCL2 inhibitor with activity in relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). We conducted a multi-centre retrospective analysis of 105 R/R CLL patients who received venetoclax pre-National Health Service commissioning. The median age was 67 years and median prior lines was 3 (range: 1-15). 48% had TP53 disruption. At ≥2 lines, 60% received a Bruton Tyrosine Kinase inhibitor (BTKi) and no prior phosphoinositide 3-kinase inhibitor (Pi3Ki), 25% received a Pi3Ki and no prior BTKi, and 10% received both. Patients discontinued B cell receptor inhibitor (BCRi) because of toxicity in 44% and progression in 54%. Tumour lysis syndrome risk was low, intermediate or high in 27%, 25%, and 48% respectively. Overall response was 88% (30% complete response [CR]). The overall response rate was 85% (CR 23%) in BTKi-exposed patients, 92% (CR 38%) in Pi3Ki-exposed patients and 80% (CR 20%) in both (P = 0·59). With a median follow-up of 15·6 months, 1-year progression-free survival was 65·0% and 1-year overall survival was 75·1%. Dose reduction or temporary interruption did not result in an inferior progression-free or discontinuation-free survival. Risk of progression or death after stopping a prior BCRi for progression was double compared to those stopping for other reasons (predominantly toxicity) (Hazard Ratio 2·01 P = 0·05). Venetoclax is active and well tolerated in R/R CLL post ≥1 BCRi. Reason(s) for stopping BCRi influences venetoclax outcomes.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Retrospective Studies; Sulfonamides; Treatment Outcome; United Kingdom

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Rituximab; Sulfonamides

In this issue, Blombery and colleagues show that the chronic lymphocytic leukemia (CLL) cells bearing Gly101Val mutation confer resistance to venetoclax by reducing the affinity of BCL2 for venetoclax by 180-fold in cell lines and in patient cells. Detection of this mutation provides a potential biomarker for impending disease progression and an opportunity for targeted and combinational therapy to treat CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Patients; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms, Multiple Primary; Remission Induction; Sulfonamides

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Potent MCL1 inhibitors are showing strong anticancer activity in preclinical models of hematologic cancers, especially when given in combination with other therapies. The drugs are now in phase I testing, with initial clinical results expected soon.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Mice; Molecular Targeted Therapy; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Xenograft Model Antitumor Assays

Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice.. This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected.. These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Patient Safety; Practice Patterns, Physicians'; Proto-Oncogene Proteins c-bcl-2; Retrospective Studies; Sulfonamides; Treatment Outcome; Tumor Lysis Syndrome

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase II as Topic; Disease Progression; Drug Resistance, Neoplasm; Female; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Recurrence, Local; Neoplasm, Residual; Proto-Oncogene Proteins c-bcl-2; Risk; Sulfonamides

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8;

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Progression-Free Survival; Retrospective Studies; Sulfonamides

Topics: Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Remission Induction; Sulfonamides; Treatment Outcome; von Willebrand Diseases

Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies.. In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0-1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination.. We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need.. Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.

Topics: Adenine; Antineoplastic Agents; beta 2-Microglobulin; Bridged Bicyclo Compounds, Heterocyclic; Databases, Factual; Female; Hemoglobins; Humans; Immunotherapy; L-Lactate Dehydrogenase; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Prognosis; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Sulfonamides; Survival Rate

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Venetoclax is a first-in-class cancer therapy that interacts with the cellular apoptotic machinery promoting apoptosis. Treatment of patients suffering chronic lymphocytic leukaemia with this BCL-2 antagonist has revealed emergence of a drug-selected BCL-2 mutation (G101V) in some patients failing therapy. To understand the molecular basis of this acquired resistance we describe the crystal structures of venetoclax bound to both BCL-2 and the G101V mutant. The pose of venetoclax in its binding site on BCL-2 reveals small but unexpected differences as compared to published structures of complexes with venetoclax analogues. The G101V mutant complex structure and mutant binding assays reveal that resistance is acquired by a knock-on effect of V101 on an adjacent residue, E152, with venetoclax binding restored by a E152A mutation. This provides a framework for considering analogues of venetoclax that might be effective in combating this mutation.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Crystallization; Crystallography, X-Ray; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Surface Plasmon Resonance

The BCL2 inhibitor venetoclax has shown activity in patients with chronic lymphocytic leukemia (CLL), but its efficacy in combination with other agents in patients with CLL and coexisting conditions is not known.. In this open-label, phase 3 trial, we investigated fixed-duration treatment with venetoclax and obinutuzumab in patients with previously untreated CLL and coexisting conditions. Patients with a score of greater than 6 on the Cumulative Illness Rating Scale (scores range from 0 to 56, with higher scores indicating more impaired function of organ systems) or a calculated creatinine clearance of less than 70 ml per minute were randomly assigned to receive venetoclax-obinutuzumab or chlorambucil-obinutuzumab. The primary end point was investigator-assessed progression-free survival. The safety of each regimen was also evaluated.. In total, 432 patients (median age, 72 years; median Cumulative Illness Rating Scale score, 8; median creatinine clearance, 66.4 ml per minute) underwent randomization, with 216 assigned to each group. After a median follow-up of 28.1 months, 30 primary end-point events (disease progression or death) had occurred in the venetoclax-obinutuzumab group and 77 had occurred in the chlorambucil-obinutuzumab group (hazard ratio, 0.35; 95% confidence interval [CI], 0.23 to 0.53; P<0.001). The Kaplan-Meier estimate of the percentage of patients with progression-free survival at 24 months was significantly higher in the venetoclax-obinutuzumab group than in the chlorambucil-obinutuzumab group: 88.2% (95% CI, 83.7 to 92.6) as compared with 64.1% (95% CI, 57.4 to 70.8). This benefit was also observed in patients with. Among patients with untreated CLL and coexisting conditions, venetoclax-obinutuzumab was associated with longer progression-free survival than chlorambucil-obinutuzumab. (Funded by F. Hoffmann-La Roche and AbbVie; ClinicalTrials.gov number, NCT02242942.).

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil; Comorbidity; Female; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Progression-Free Survival; Sulfonamides

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Proteins; Patient Selection; Piperidines; Progression-Free Survival; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Rituximab; Sulfonamides; Treatment Outcome; Vidarabine

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Down-Regulation; Drug Synergism; Enhancer of Zeste Homolog 2 Protein; Enzyme Inhibitors; Histones; Humans; Indazoles; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyridones; Pyrimidines; Quinazolinones; Signal Transduction; Sulfonamides; Tumor Microenvironment

Topics: Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Herpesvirus 1, Human; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Venetoclax is an approved drug for the treatment of some hematological malignancies. Venetoclax can cause reduction in B-lymphocyte counts as an on-target effect. The purpose of this analysis is to quantify the relationship between venetoclax exposure and B-lymphocyte levels to inform dosing of venetoclax in healthy subjects. Data were pooled from 10 studies in healthy subjects with venetoclax doses ranging from 10 mg to 400 mg and food ranging from fasting to high-fat meals. Venetoclax pharmacokinetics (PK) was characterized in 203 subjects using a population approach, as implemented in NONMEM version 7.3 (Icon Development Solutions, Ellicott City, MD, USA). A semimechanistic pharmacodynamic (PD) model with a linear drug effect was fit to the B-lymphocyte data to determine the exposure-response relationship. The population PK and PD model described the observed data adequately. The 200 and 400 mg doses were shown to reduce the B-lymphocyte levels by 24% (15-35%) and 38% (25-54%), respectively. B-lymphocytes recovered to normal levels within an average of 48 (21-64) days and 59 (30-66) days, respectively, with 200 and 400 mg doses. Venetoclax can be safely administered in healthy subjects. The PK-PD model characterized the relationship between venetoclax exposure and reduction in B-lymphocytes and will help design future venetoclax studies in healthy subjects.

Topics: Adult; Aged; Antineoplastic Agents; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Drug Interactions; Female; Healthy Volunteers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Lymphocyte Count; Middle Aged; Models, Biological; Sulfonamides; Young Adult

Topics: Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Retrospective Studies; Sulfonamides

Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens. Peripheral blood samples from 21 patients with relapsed/refractory CLL in acalabrutinib phase I (100-400 mg/day) and II (100 mg BID) clinical trials were collected prior to and on days 8 and 28 after treatment initiation and evaluated for plasma chemokines, reverse phase protein array, immunoblotting and pseudoemperipolesis. The on-target pharmacodynamic profile of acalabrutinib in CLL lymphocytes was comparable to ibrutinib in measures of acalabrutinib-mediated changes in CCL3/CCL4 chemokine production, migration assays and changes in B-cell receptor signaling pathway proteins and other downstream survival proteins. Among several CLL-targeted agents, venetoclax, when combined with acalabrutinib, showed optimal complementary activity in vitro, ex vivo and in vivo in TCL-1 adoptive transfer mouse model system of CLL. These findings support selective targeting and combinatorial potential of acalabrutinib.

Topics: Adenine; Adoptive Transfer; Animals; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cell Movement; Chemokine CCL3; Chemokine CCL4; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Combined Modality Therapy; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proteomics; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease.

Topics: Adenine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Progression-Free Survival; Randomized Controlled Trials as Topic; Rituximab; Sulfonamides; Time Factors

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Purines; Quinazolinones; Sulfonamides

Topics: Adult; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; Male; Middle Aged; Neoplasm Proteins; Protein Kinase Inhibitors; Rituximab; Sulfonamides; Syk Kinase; T-Lymphocytes

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1α (SDF-1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT-199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Cycle; Cell Survival; Coculture Techniques; Drug Evaluation, Preclinical; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Nitrophenols; Piperazines; Sulfonamides; Tumor Cells, Cultured; Tumor Microenvironment

Topics: Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Sulfonamides

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease Management; Drug Resistance, Neoplasm; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recurrence; Sulfonamides; Survival Analysis; Treatment Outcome; Tumor Lysis Syndrome

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Neoplasms; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mice, Inbred C57BL; Retrospective Studies; Sulfonamides

Topics: Adenine; Antineoplastic Agents, Immunological; Bridged Bicyclo Compounds, Heterocyclic; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Remission Induction; Sulfonamides

Topics: Antibodies, Monoclonal, Humanized; Bendamustine Hydrochloride; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local; Sulfonamides

Topics: Adenine; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Hairy Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax.. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study.. Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported.. The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin.. AbbVie in collaboration with Genentech/Roche.

Topics: Adult; Anti-Bacterial Agents; Antineoplastic Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azithromycin; Bridged Bicyclo Compounds, Heterocyclic; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Female; Healthy Volunteers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.

Topics: Adult; Aged; Aged, 80 and over; Alternative Splicing; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Disease Models, Animal; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Epoxy Compounds; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Macrolides; Male; Mice; Mice, Transgenic; Middle Aged; Mitochondria; Mutation; Myeloid Cell Leukemia Sequence 1 Protein; Phosphoproteins; Primary Cell Culture; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; RNA Splicing Factors; Spliceosomes; Sulfonamides; Thiophenes

Topics: Adenine; Adult; Antibodies, Monoclonal, Humanized; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Pyrazoles; Pyrimidines; Sulfonamides

Early data on venetoclax-containing regimens for the treatment of chronic lymphocytic leukemia (CLL) show promising results with deep remissions, but are hampered by potential risk for tumor lysis syndrome (TLS). Whether optimal duration of venetoclax treatment can be guided by minimal residual disease (MRD) is currently unknown. To study whether TLS risk can be mitigated in an unfit population by introducing preinduction, and whether MRD-guided duration of venetoclax treatment is a feasible and efficacious approach, we performed the Dutch-Belgian Cooperative Trial Group for Hemato-oncology (HOVON) 139/GIVE trial. The study treatment consists of 4 treatment phases: preinduction (2 cycles obinutuzumab), induction I (6 cycles obinutuzumab and venetoclax), induction II (6 cycles venetoclax), and a randomization phase (group A: maintenance with 12 additional cycles of venetoclax irrespective of MRD; group B: MRD guided venetoclax maintenance with a maximum of 12 cycles). Here we report on a planned interim safety analysis as well as preliminary efficacy and MRD data of the first 30 patients enrolled. Downgrading of TLS risk after preinduction occurred in 25 patients: 3 from high to medium, 3 from high to low, and 19 from medium to low risk. No patient remained high risk. From these 30 patients, peripheral blood MRD data were obtained for 28 patients at the end of induction II (6 months after the last obinutuzumab dose), of whom 26 had undetectable MRD levels, and for 18 patients who reached the 3-month after-randomization point, of whom 16 had undetectable MRD levels. Obinutuzumab preinduction is tolerated well in these unfit patients and results in abrogating high TLS risk in all patients. Preliminary data indicate that efficacy is maintained with a high proportion of patients with undetectable MRD levels after combination treatment.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Remission Induction; Risk Factors; Sulfonamides; Tumor Lysis Syndrome

Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.. We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).. A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).. In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Topics: Adenine; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Drug Administration Schedule; Humans; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Piperidines; Proportional Hazards Models; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Retrospective Studies; Sulfonamides; Treatment Outcome; Young Adult

Venetoclax is a potent, selective inhibitor of BCL-2, a key regulator of the intrinsic pathway of apoptosis. In preclinical studies, venetoclax bound to BCL-2 with high affinity and rapidly induced apoptosis in chronic lymphocytic leukemia (CLL) cells. In early-phase clinical trials in CLL, venetoclax treatment led to tumor lysis syndrome in some patients with a large tumor burden, but this risk was subsequently mitigated by a revised study design that included lower initial dosing with intrapatient dose ramp up and close tumor lysis syndrome monitoring and prophylaxis. Other toxicities, such as neutropenia and gastrointestinal adverse events, were manageable. Venetoclax monotherapy resulted in durable and deep responses in patients with relapsed, refractory CLL, including for those with deletion 17p, leading to the approval of venetoclax by the US FDA for relapsed or refractory deletion 17p CLL, and recently to additional approvals in Europe and Canada. Trials also suggest that venetoclax induces deeper and more durable responses when used in combination with rituximab, and combination studies with other agents are ongoing. Phase III trials are also underway, and will provide data on the efficacy and safety of venetoclax in combination with monoclonal antibodies and targeted therapies in larger patient populations.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug-Related Side Effects and Adverse Reactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides; Tumor Lysis Syndrome

Topics: Alemtuzumab; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Cyclophosphamide; Humans; In Situ Hybridization, Fluorescence; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recurrence; Remission Induction; Rituximab; Sulfonamides; Vidarabine

Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia.

Topics: Adenine; Aminoimidazole Carboxamide; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prohibitins; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Repressor Proteins; Ribonucleosides; Sulfonamides; Thiazolidines; Tumor Cells, Cultured; Up-Regulation

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Genes, p53; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Medical Oncology; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Rituximab; Sequence Deletion; Sulfonamides; Tumor Suppressor Protein p53

Loss of

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Proto-Oncogene Proteins c-bcl-2; Receptor Tyrosine Kinase-like Orphan Receptors; Sulfonamides; Tumor Cells, Cultured

Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cohort Studies; Dietary Fats; Dose-Response Relationship, Drug; Female; Food-Drug Interactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Recurrence; Retreatment; Rituximab; Sulfonamides; Survival Analysis; Treatment Outcome

Although the BTK inhibitor ibrutinib has transformed the management of patients with chronic lymphocytic leukemia (CLL), it does not induce substantial apoptosis in vitro, and as such the mechanisms underlying its ability to kill CLL cells are not well understood. Acalabrutinib, a more specific BTK inhibitor now in development, also appears to be highly effective in CLL, but the connection of its mechanism with CLL cell death is also unclear. Using dynamic BH3 profiling, we analyzed alterations in the function of the mitochondrial apoptotic pathway induced by ibrutinib and acalabrutinib. We studied CLL patient samples treated ex vivo with both drugs, as well as primary samples from CLL patients on clinical trials of both drugs. We found that BTK inhibition enhances mitochondrial BCL-2 dependence without significantly altering overall mitochondrial priming. Enhancement of BCL-2 dependence was accompanied by an increase in the pro-apoptotic protein BIM. In contrast, treatment with the selective BCL-2 inhibitor venetoclax enhanced overall mitochondrial priming without increasing BCL-2 dependence. Pre-treatment of CLL cells with either BTK inhibitor, whether ex vivo or in vivo in patients, enhanced killing by venetoclax. Our data suggest that BTK inhibition enhances mitochondrial BCL-2 dependence, supporting the ongoing development of clinical trials combining BTK and BCL-2 inhibition.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bcl-2-Like Protein 11; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mitochondria; Molecular Targeted Therapy; Neoplasm Proteins; Peptide Fragments; Piperidines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides

The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax).. A group of experts from the Spanish Chronic Lymphocytic Leukemia Group reviewed all published literature from January 2010 to January 2016, in order to provide recommendations based on clinical evidence. For those areas without strong scientific evidence, the panel of experts established consensus criteria based on their clinical experience.. The project has resulted in several practical recommendations that will facilitate the diagnosis, treatment, and follow-up of patients with CLL.. There are many controversial issues in the management of CLL with no appropriate studies for making consensus recommendations.

Topics: Adenine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides

Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter's syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring.

Topics: Adenine; Aged; Aged, 80 and over; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Baculoviral IAP Repeat-Containing 3 Protein; Bridged Bicyclo Compounds, Heterocyclic; Circulating Tumor DNA; Clonal Evolution; Disease Progression; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Myeloid Differentiation Factor 88; Phosphoproteins; Piperidines; Proto-Oncogene Proteins p21(ras); Pyrazoles; Pyrimidines; Receptor, Notch1; RNA Splicing Factors; Sulfonamides; Treatment Outcome; Tumor Suppressor Protein p53

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Although the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.. The LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.. The ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2.. Our study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cell Survival; Cells, Cultured; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mitochondria; Nitrophenols; Peptide Fragments; Phosphorylation; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Results from an international phase II study show that the investigational BCL2 inhibitor venetoclax is effective in patients with chronic lymphocytic leukemia and the chromosome 17p deletion, whose prognosis is particularly poor. Venetoclax yielded high and durable responses in this population, including several complete remissions.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Chromosome Deletion; Chromosomes, Human, Pair 17; Clinical Trials, Phase II as Topic; Congresses as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Treatment Outcome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Alleles; Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Class I Phosphatidylinositol 3-Kinases; Gene Expression; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Piperidines; Prognosis; Protein-Tyrosine Kinases; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Sulfonamides; Tumor Suppressor Protein p53

BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Mice, Knockout; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Time Factors; Tumor Suppressor Protein p53

The Bcl-2 antagonist ABT-199 (venetoclax) has demonstrated promising clinical activity in patients with chronic lymphocytic leukemia (CLL). ABT-199 is strongly cytotoxic against unstimulated peripheral blood CLL cells in vitro but is much less effective against CLL cells that have received survival signals from the microenvironment. In particular, stimulation of CLL cells with CD40L results in substantial resistance mediated by induction of the antiapoptotic Bcl-2 family proteins Bcl-xL and Bfl-1. In this study, we investigated whether resistance to ABT-199 can be conferred by B-cell receptor (BCR) stimulation, which is another important survival signal from the leukemic microenvironment. We show that sustained BCR stimulation results in significant ABT-199 resistance, which correlates with induction of the antiapoptotic protein Mcl-1 and less consistently with downregulation of proapoptotic Bmf, Hrk, and BimEL A major role for Mcl-1 in conferring ABT-199 resistance is additionally supported by knockdown and enforced expression experiments with primary CLL cells. We further show that SYK, BTK, and phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitors significantly downregulate Mcl-1, but with different efficacy. Complete Mcl-1 downregulation was consistently achieved only with SYK inhibitors R406 and GS-9973 (entospletinib), whereas the BTK inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib in more than half of the cases had only a partial effect. The greater ability of SYK inhibitors to downregulate Mcl-1 correlated with their greater capacity to block BCR-mediated inactivation of GSK-3, a major negative regulator of Mcl-1. The finding that BCR signaling inhibitors differ in their ability to target Mcl-1 is relevant for the design of clinical trials combining these agents with ABT-199.

Topics: Adenine; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Gene Expression Regulation, Leukemic; Gene Knockdown Techniques; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Oxazines; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Sulfonamides

Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients. An in vitro microenvironment model was developed with primary CLL cells that could be incorporated into an automated high-content microscopy-based screen of kinase inhibitors (KIs) to identify agents that may improve venetoclax therapy in a personalized manner. Marked interpatient variability was noted for which KIs were effective; nevertheless, sunitinib was identified as the most common clinically available KI effective in overcoming venetoclax resistance. Examination of the underlying mechanisms indicated that venetoclax resistance may be induced by microenvironmental signals that upregulate antiapoptotic Bcl-xl, Mcl-1, and A1, which can be counteracted more efficiently by sunitinib than by ibrutinib or idelalisib. Although patient-specific drug responses are common, for many patients, combination therapy with sunitinib may significantly improve the therapeutic efficacy of venetoclax.

Topics: Adenine; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cellular Microenvironment; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; Humans; Imaging, Three-Dimensional; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Quinazolinones; Reproducibility of Results; Signal Transduction; Stromal Cells; Sulfonamides; Sunitinib; Up-Regulation

Venetoclax is a BH3 mimetic approved for treating chronic lymphocytic leukemia. Cancer cells are resistant to apoptosis but "primed for death" by elevated BCL-2, which binds to pro-apoptotic proteins and holds them in check. Venetoclax releases this antagonism and is the first approved drug to target a protein-protein interaction.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Administration Schedule; Drug Costs; Drug Interactions; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Treatment Outcome

Topics: Antineoplastic Agents; B-Lymphocytes; bcl-X Protein; Bendamustine Hydrochloride; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; CD40 Ligand; Cell Hypoxia; Cells, Cultured; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Nitrogen Mustard Compounds; Nitrophenols; Oxygen; p38 Mitogen-Activated Protein Kinases; Piperazines; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Vidarabine

Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes.. Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed.. The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2.. Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; B-Cell Activating Factor; bcl-X Protein; Bendamustine Hydrochloride; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Gene Expression Regulation, Leukemic; Humans; Isoquinolines; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Neoplastic Cells, Circulating; Nitrophenols; Piperazines; Piperidines; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyrimidines; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Rituximab; Sulfonamides; Tumor Microenvironment

Cyclin E/Cdk2 kinase activity is frequently deregulated in human cancers, resulting in impaired apoptosis. Here, we show that cyclin E/Cdk2 phosphorylates and stabilizes the pro-survival Bcl-2 family protein Mcl-1, a key cell death resistance determinant to the small molecule Bcl-2 family inhibitors ABT-199 and ABT-737, mimetics of the Bcl-2 homology domain 3 (BH3). Cyclin E levels were elevated and there was increased association of cyclin E/Cdk2 with Mcl-1 in ABT-737-resistant compared to parental cells. Cyclin E depletion in various human tumor cell-lines and cyclin E-/- mouse embryo fibroblasts showed decreased levels of Mcl-1 protein, with no change in Mcl-1 mRNA levels. In the absence of cyclin E, Mcl-1 ubiquitination was enhanced, leading to decreased protein stability. Studies with Mcl-1 phosphorylation mutants show that cyclin E/Cdk2-dependent phosphorylation of Mcl-1 residues on its PEST domain resulted in increased Mcl-1 stability (Thr92, and Thr163) and Bim binding (Ser64). Cyclin E knock-down restored ABT-737 sensitivity to acquired and inherently resistant Mcl-1-dependent tumor cells. CDK inhibition by dinaciclib resulted in Bim release from Mcl-1 in ABT-737-resistant cells. Dinaciclib in combination with ABT-737 and ABT-199 resulted in robust synergistic cell death in leukemic cells and primary chronic lymphocytic leukemia patient samples. Collectively, our findings identify a novel mechanism of cyclin E-mediated Mcl-1 regulation that provides a rationale for clinical use of Bcl-2 family and Cdk inhibitors for Mcl-1-dependent tumors.

Topics: Animals; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cyclin E; Cyclin-Dependent Kinase 2; Drug Resistance, Neoplasm; Humans; Immunoblotting; Immunoprecipitation; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Nitrophenols; Peptide Fragments; Phosphorylation; Piperazines; Protein Stability; Proto-Oncogene Proteins; Real-Time Polymerase Chain Reaction; Sulfonamides

Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction.

Topics: Aniline Compounds; Animals; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Calcium Signaling; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Immunohistochemistry; Inositol 1,4,5-Trisphosphate Receptors; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Mice; Mice, Nude; Multiple Myeloma; Neoplasm Transplantation; NIH 3T3 Cells; Peptides; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

BCL-xL is an anti-apoptotic BCL-2 family protein that inhibits apoptosis and is overexpressed in many cancers. We have reported that acquired resistance to the BCL-2 inhibitor ABT-199 (venetoclax) is associated with increased BCL-xL expression. Yet, how BCL-xL mediates chemoresistance in hematopoietic malignancies is not clear. This finding may help in design of new strategies for therapeutic intervention to overcome acquired chemoresistance mediated by BCL-xL.. We now show that the increased BCL-xL expression was inversely correlated with that of miR-377 in ABT-199-resistant cells. This finding was also extended to a panel of B-cell lymphoid lines and primary chronic lymphocytic leukemia (CLL) cells. miR-377 suppressed BCL-xL expression by recognizing two binding sites in the BCL-xL 3'-UTR. Mutation of these two miR-377 consensus-binding sites completely abolished its regulatory effect. Expression of a miR-377 mimic downregulated BCL-xL protein expression and significantly increased apoptotic cell death. Expression of a miR-377 inhibitor restored BCL-xL protein expression and limited cell death caused by the hypomethylating agent 5-azacytidine. Thus, miR-377-dependent BCL-xL regulation drives acquired therapeutic resistance to ABT-199. We further show that CLL patients who received a diverse array of chemotherapy regimens also had significantly higher BCL-xL and lower miR377 expression, indicating that exposure to chemotherapy might trigger transcriptional silencing of miR-377, which results in high levels of BCL-xL. Importantly, CLL patients with high BCL-xL/low miR-377 expression had an advanced tumor stage. Moreover, the high BCL-xL expression correlated with short treatment-free survival in 76 CLL patients. miR-377 is located at 14q32 in the DLK1-DIO3 region, which encodes the largest tumor suppressor miRNA cluster in humans. Examination of five additional 14q32 miRNAs revealed that the majority were significantly down-regulated in most CLL patients as well as in ABT-199-resistant cell lines. Remarkably, four of these miRNAs had significantly decreased expression in chemotherapy-treated CLL patients as compared to those untreated. These findings indicate a reduced expression of multiple miRNAs that may reflect a global silencing of this miRNA cluster in therapy-resistant lymphoid cells.. These findings reveal a novel mechanism by which down-regulation of miR-377 increases BCL-xL expression, promoting chemotherapy resistance in B-cell lymphoid malignancies.

Topics: Antineoplastic Agents; B-Lymphocytes; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; MicroRNAs; Mutation; Sulfonamides

Overexpression of the prosurvival protein Bcl-2 marks many B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. The first effective BH3 mimetic inhibitors of Bcl-2, ABT-737 and navitoclax, also target Bcl-xL, causing dose-limiting thrombocytopenia. This prompted the development of the Bcl-2-selective antagonist, ABT-199. Here we show that in lymphoid cells, ABT-199 specifically causes Bax/Bak-mediated apoptosis that is triggered principally by the initiator BH3-only protein Bim. As expected, malignant cells isolated from patients with chronic lymphocytic leukaemia are highly sensitive to ABT-199. However, we found that normal, untransformed mature B cells are also highly sensitive to ABT-199, both in vitro and in vivo. By contrast, the B-cell precursors are largely spared, as are cells of myeloid origin. These results pinpoint the probable impact of the pharmacological inhibition of Bcl-2 by ABT-199 on the normal mature haemopoietic cell lineages in patients, and have implications for monitoring during ABT-199 therapy as well as for the clinical utility of this very promising targeted agent.

Topics: Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Apoptosis Regulatory Proteins; B-Lymphocytes; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Resistance, Neoplasm; Flow Cytometry; Healthy Volunteers; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Membrane Proteins; Mice; Mice, Knockout; Myeloid Cells; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Cells, Cultured; Tumor Suppressor Proteins; Xenograft Model Antitumor Assays

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials, Phase III as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Protein Kinase Inhibitors; Purines; Quinazolinones; Sulfonamides

A phase I trial found that drug ABT-199 controls chronic lymphocytic leukemia in patients whose previous treatments failed. In about a quarter of patients, the drug, which blocks Bcl-2 and triggers cancer cell apoptosis, restored indicators of illness to normal.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Sulfonamides; Treatment Outcome

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world and affects mainly elderly patients. In current phase III trials, standard treatment options were established that differ mainly based on the fitness and age of the patient. The combination of fludarabine, cyclophosphamide, and the CD20 antibody rituximab (FCR) is recommended for young patients without relevant comorbidity, while bendamustine and rituximab (BR) should be favored for elderly (ca. >65 years) fit individuals. Bendamustine plus ofatumumab is another option in this situation. Patients with major comorbidities should receive chlorambucil combined with CD20 antibody (obinutuzumab or ofatumumab). In 2014, several new compounds were approved for patients with ultrahigh risk genetic factors (17p-, TP53mut) and for relapsed/refractory CLL: both idelalisib and ibrutinib are orally bioavailable kinase inhibitors that block key regulators of central pathways. For both agents, very impressive data are available with regard to tolerability and efficacy that will change the treatment paradigm in CLL. With ABT-199, a direct apoptosis inducer is being developed that in early clinical trials produced high remission rates combined with good tolerability. Combinations and sequences of the "novel" compounds obinutuzumab, ofatumumab, idelalisib, ibrutinib, and ABT-199 will be studied in coming years in clinical trials in order to prolong remission duration and reduce side effects with the eventual aim of curing CLL.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Evidence-Based Medicine; Germany; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Medical Oncology; Practice Guidelines as Topic; Sulfonamides; Treatment Outcome

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Discovery; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides; Treatment Outcome

Topics: Apoptosis; bcl-X Protein; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proto-Oncogene Proteins c-bcl-2; Sulfonamides