abt-199 and idelalisib

Over the last decade, there have been important developments in the treatment of lymphoproliferative disorders. Apart from conventional chemotherapy, a wide array of therapies has been developed, with different indications. The aim of this review is to evaluate the risk of infection associated with these therapies, as well as establishing prevention recommendations. In all cases, the patient's underlying disease as well as concomitant or previous therapies have an impact on the risk of infection. Anti-CD20 antibodies (rituximab, ofatumumab and obinutuzumab) have been associated with a higher risk of bacterial and viral infection, as well as reactivation of latent infections and opportunistic infections. Alemtuzumab is associated with severe, protracted immunosuppression. Ibrutinib and acalabrutinib have been linked to bacterial infections (especially respiratory infections), invasive fungal infections and opportunistic infections. Idelalisib carries a higher risk of Pneumocystis jirovecii and infection and cytomegalovirus reactivation. Venetoclax is associated with respiratory infections and neutropenia. Immune checkpoint inhibitors are not directly associated with a higher risk of infection; nevertheless, the use of corticosteroids and immunosuppressants to control immune-related adverse events results in an increase of the risk of infection. Brentuximab, lenalidomide and histone deacetylase inhibitors do not seem to be associated with a higher risk of infections. Although data are scarce, a higher number of infections have been observed with cellular therapies, mostly in patients with more than 3 previous antineoplastic treatments or those receiving tocilizumab or corticosteroids for managing the cytokine release syndrome. In all patients, we recommend appropriate vaccination, screening for latent infections, and individualized prophylaxis recommendations.

Topics: Adenine; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Communicable Disease Control; Humans; Immune Checkpoint Inhibitors; Infections; Lymphoproliferative Disorders; Piperidines; Purines; Pyrazines; Quinazolinones; Risk; Rituximab; Sulfonamides; Syndrome

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

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

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

B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management.. Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications. Patients on idelalisib require close clinical and frequent laboratory monitoring, particularly of liver function tests to ensure there are no serious adverse events. Monitoring for infections is important in patients on both idelalisib and ibrutinib. Venetoclax requires close clinical and laboratory monitoring to prevent significant tumor lysis. Targeted B cell receptor therapies each have unique side effect profiles which require careful clinical monitoring. As we continue to use these therapies, optimal management strategies will continue to be elucidated.

Topics: Adenine; Antineoplastic Agents; Atrial Fibrillation; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Hemorrhage; Humans; Lymphoma, Non-Hodgkin; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; 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

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

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

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

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

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

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

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

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

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

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

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

Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax).. Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020.. Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed.. A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.

Topics: Adenine; Adolescent; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Immunocompromised Host; Infections; Lymphopenia; Lymphoproliferative Disorders; Male; Middle Aged; Piperidines; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazines; Quinazolinones; Retrospective Studies; Risk Factors; Sulfonamides; Young Adult

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

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

Topics: Adenine; Aged; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Substitution; Humans; Leukemia, Prolymphocytic, B-Cell; Male; Piperidines; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, Antigen, B-Cell; Retreatment; Rituximab; Signal Transduction; Sulfonamides; Treatment Outcome

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; 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: 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

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

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

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

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

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

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

Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Humans; Membrane Proteins; Piperidines; Proto-Oncogene Proteins; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Receptors, CXCR4; Sulfonamides; Waldenstrom Macroglobulinemia

Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.

Topics: Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Lymphoma; Membrane Proteins; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Stability; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Purines; Quinazolinones; Quinolines; RNA, Messenger; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation

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