abt-199 and Hematologic-Neoplasms

Myelodysplasic syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real-life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS.

Topics: Aged; Azacitidine; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2

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

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the

Topics: Animals; Apoptosis; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; DNA Damage; Hematologic Neoplasms; Humans; Sulfonamides; Tumor Suppressor Protein p53

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy that originates from plasmacytoid dendritic cells. It can involve skin, bone marrow, and/or lymph nodes. There is no consensus recommendation regarding treatment especially in the relapsed setting. Tagraxofusp, a CD123 directed agent, was recently approved by the Food and Drug Administration to treat BPDCN. We report a case of an elderly patient with diagnosis of BPDCN who was treated initially with tagraxofusp followed by azacitidine and venetoclax combination on relapse.. Tagraxofusp is a novel therapy that needs more real-world experience. This case describes the clinical course of an elderly patient on tagraxofusp. We also review the literature of azacytidine/venetoclax combination as a potential yet tolerable treatment option for this rare disease entity. This is the fourth case in literature to be treated with this combination.

Topics: Acute Disease; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Hematologic Neoplasms; Humans; Male; Recombinant Fusion Proteins; Skin Neoplasms; Sulfonamides

Targeting anti-apoptotic pathways involving the BCL2 family proteins represents a novel treatment strategy in hematologic malignancies. Venetoclax, a selective BCL2 inhibitor, represents the first approved agent of this class, and is currently used in CLL and AML. However, monotherapy is rarely sufficient for sustained responses due to the development of drug resistance and loss of dependence upon the targeted protein. Numerous pre-clinical studies have shown that combining venetoclax with other agents may represent a more effective therapeutic strategy by circumventing resistance mechanisms. In this review, we summarize pre-clinical data providing a foundation for rational combination strategies involving venetoclax.. Novel combination strategies in hematologic malignancies involving venetoclax, primarily at the pre-clinical level, will be reviewed. We emphasize novel agents that interrupt complementary or compensatory pro-survival pathways, and particularly mechanistic insights underlying synergism. PubMed, Cochrane, EMBASE, and Google scholar were searched from 2000.. Although venetoclax has proven to be an effective therapeutic in hematologic malignancies, monotherapy may be insufficient for maximal effectiveness due to the development of resistance and/or loss of BCL2 addiction. Further pre-clinical and clinical development of combination therapies may be necessary for optimal outcomes in patients with diverse blood cancers.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; 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

B-cell lymphoma 2 (BCL2) is a key protein regulator of apoptosis. It is variably highly expressed in many hematological malignancies, providing protection from cell death induced by oncogenic and external stresses. Venetoclax is the first selective BCL2 inhibitor, and the first of a new class of anticancer drug (BH3-mimetics) to be approved for routine clinical practice, currently in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). To help understand the potential and limitations of this therapy, this brief review will touch on the history of development of venetoclax, dissect its mechanism of action, and summarize critical evidence for its approved use in the management of patients with CLL and AML. It will also consider recent data on mechanisms of resistance and explore concepts pertinent to its future development based on key lessons learned to date.

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopsy; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Hematologic Neoplasms; Humans; Male; Phenotype; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

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

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

Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways. Many of these strategies involve downregulation of Mcl-1, a pro-survival Bcl-2 family member that is not targeted by venetoclax, and which often confers resistance to this agent. Given encouraging clinical results involving venetoclax in both lymphoid and myeloid malignancies, it is likely that such combination approaches will be incorporated into the therapeutic armamentarium for multiple hematologic malignancies in the near future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Hematologic Neoplasms; Humans; Interleukin-3 Receptor alpha Subunit; NF-kappa B; Proteins; Proto-Oncogene Proteins c-bcl-2; Recombinant Fusion Proteins; Sulfonamides

Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Evaluation; Female; Hematologic Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Despite significant improvements in treatment, cure rates for many cancers remain suboptimal. The rise of cytotoxic chemotherapy has led to curative therapy for a subset of cancers, though intrinsic treatment resistance is difficult to predict for individual patients. The recent wave of molecularly targeted therapies has focused on druggable-activating mutations, and is thus limited to specific subsets of patients. The lessons learned from these two disparate approaches suggest the need for therapies that borrow aspects of both, targeting biologic properties of cancer that are at once distinct from normal cells and yet common enough to make the drugs widely applicable across a range of cancer subtypes. The intrinsic mitochondrial pathway of apoptosis represents one such promising target for new therapies, and successfully targeting this pathway has the potential to alter the therapeutic landscape of therapy for a variety of cancers. Here, we discuss the biology of the intrinsic pathway of apoptosis, an assay known as BH3 profiling that can interrogate this pathway, early attempts to target BCL-2 clinically, and the recent promising results with the BCL-2 antagonist venetoclax (ABT-199) in clinical trials in hematologic malignancies. See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."

Topics: Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Mitochondria; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; 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 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: Aged; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasms, Second Primary; Retrospective Studies; Sulfonamides; Survival Rate

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive subtype of myeloid malignancy characterized by skin, lymph node and central nervous system (CNS) involvement. Although various regimens are used, a standard therapeutic strategy for BPDCN has not been established. Recent studies revealed that BPDCN patients frequently have a mutation in ZRSR2, which is a minor spliceosome component. However, the association between the clinical features of BPDCN and ZRSR2 mutational status remains unknown. A 70-year-old man was referred to our hospital with skin rash and enlarged lymph nodes, as well as blasts in the peripheral blood. BPDCN was diagnosed based on the immunophenotype of the blasts derived from bone marrow. Whole exome sequencing revealed that BPDCN cells collected at diagnosis had mutations in ZRSR2, ZBTB33, CUL3, TET2 and NRAS. RNA sequencing analysis indicated that U12-type intron retention occurred in LZTR1, caused by ZRSR2 loss. After seven cycles of venetoclax combined with azacitidine therapy, BPDCN cells appeared in the peripheral blood and infiltrated the CNS. Two KRAS mutated clones appeared at BPDCN recurrence. These findings are important for understanding the pathogenesis of BPDCN, which will inform development of novel therapeutic strategies.

Topics: Aged; Clonal Evolution; Cullin Proteins; Dendritic Cells; Hematologic Neoplasms; Humans; Male; Ribonucleoproteins; Signal Transduction; Skin Neoplasms; Transcription Factors

Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population.. We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022.. We identified 13 patients (acute myeloid leukemia, n = 8; B-acute lymphoblastic leukemia, n = 3; myelodysplastic syndrome, n = 2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2 weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses.. Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Child; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Prospective Studies; Retrospective Studies; Young Adult

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy, especially in pediatrics, that can involve the bone marrow, skin, lymph nodes, and central nervous system (CNS). Given its variable clinical presentation, coupled with an immunohistochemistry pattern (CD4, CD56, TCF4, TCL-1, and CD123 positivity) that differs from other myeloid neoplasms, the diagnosis of BPDCN can be missed. Limited data are available to guide the treatment of pediatric BPDCN. Herein, we report a case of a pediatric patient who had BPDCN with central nervous system, orbital, and skin involvement. This patient achieved complete remission after receiving modified hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with venetoclax and intrathecal chemotherapy. He remains disease-free 200 days after receiving a stem cell transplant. This represents the first known published pediatric case using a modified hyper-CVAD plus venetoclax regimen for treating a pediatric BPDCN patient in the frontline setting.

Topics: Bridged Bicyclo Compounds, Heterocyclic; Child; Dendritic Cells; Hematologic Neoplasms; Humans; Male; Myeloproliferative Disorders; Skin; Skin Neoplasms

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; 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

The overexpression of antiapoptotic members (BCL-2, BCL-xL, MCL-1, etc.) of the BCL-2 family contributes to tumor development and resistance to chemotherapy or radiotherapy. Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax). However, acquired resistance to venetoclax or chemotherapy drugs due to an upregulation of MCL-1 has been observed, rendering MCL-1 an attractive new target for treatment. Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically. There is, therefore, still a need for alternative molecules. We previously described two drimane derivatives as the first covalent BH3 mimetics targeting MCL-1. Here, we described the characterization and biological efficacy of one of these compounds (NA1-115-7), isolated from Zygogynum pancheri, a plant belonging to the Winteraceae family. NA1-115-7 specifically induced the apoptosis of MCL-1-dependent tumor cells, with two hours of treatment sufficient to trigger cell death. The treatment of lymphoma cells with NA1-115-7 stabilized MCL-1, disrupted its interactions with BAK, and rapidly induced apoptosis through a BAK- and BAX-mediated process. Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment.

Topics: Antineoplastic Agents; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Hematologic Neoplasms; Humans; Leukocytes, Mononuclear; Myeloid Cell Leukemia Sequence 1 Protein; Myocytes, Cardiac; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Winteraceae

Topics: Bridged Bicyclo Compounds, Heterocyclic; Epigenesis, Genetic; Hematologic Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2

Topics: Antibodies, Monoclonal; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Female; Hematologic Neoplasms; Humans; Skin Neoplasms; Sulfonamides

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Cyclin-Dependent Kinase 9; Drug Synergism; Hematologic Neoplasms; Humans; Mice; Protein Kinase Inhibitors; Sulfonamides; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The selective inhibitor of nuclear export (SINE) compounds selinexor (KPT-330) and eltanexor (KPT-8602) are from a novel class of small molecules that target exportin-1 (XPO1 [CRM1]), an essential nucleo-cytoplasmic transport protein responsible for the nuclear export of major tumor suppressor proteins and growth regulators such as p53, p21, and p27. XPO1 also affects the translation of messenger RNAs for critical oncogenes, including MYC, BCL2, MCL1, and BCL6, by blocking the export of the translation initiation factor eIF4E. Early trials with venetoclax (ABT-199), a potent, selective inhibitor of BCL2, have revealed responses across a variety of hematologic malignancies. However, many tumors are not responsive to venetoclax. We used models of acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) to determine in vitro and in vivo responses to treatment with venetoclax and SINE compounds combined. Cotreatment with venetoclax and SINE compounds demonstrated loss of viability in multiple cell lines. Further in vitro analyses showed that this enhanced cell death was the result of an increase in apoptosis that led to a loss of clonogenicity in methylcellulose assays, coinciding with activation of p53 and loss of MCL1. Treatment with SINE compounds and venetoclax combined led to a reduction in tumor growth in both AML and DLBCL xenografts. Immunohistochemical analysis of tissue sections revealed that the reduction in tumor cells was partly the result of an induction of apoptosis. The enhanced effects of this combination were validated in primary AML and DLBCL patient cells. Our studies reveal synergy with SINE compounds and venetoclax in aggressive hematologic malignancies and provide a rationale for pursuing this approach in a clinical trial.

Topics: Active Transport, Cell Nucleus; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Hematologic Neoplasms; Humans; Sulfonamides

Topics: Adoptive Transfer; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Lymphoproliferative Disorders; Male; Middle Aged; Sulfonamides

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blast Crisis; Bridged Bicyclo Compounds, Heterocyclic; Disease-Free Survival; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Myeloproliferative Disorders; Retrospective Studies; Sulfonamides; Survival Rate

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and

Topics: Antineoplastic Agents; Biomarkers, Tumor; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Immunotherapy; Internet; Leukemia, Myeloid, Acute; Lymphoma, B-Cell; Phenotype; Proto-Oncogene Proteins c-bcl-2; Small Molecule Libraries; Sulfonamides; Transcriptome

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

Duvelisib is an orally active dual inhibitor of PI3K-δ and PI3K-γ in clinical development in hematologic malignancies (HM). To identify novel pairings for duvelisib in HM, it was evaluated alone and in combination with 35 compounds comprising a diverse panel of standard-of-care agents and emerging drugs in development for HM. These compounds were tested in 20 cell lines including diffuse large B-cell, follicular, T-cell, and mantle cell lymphomas, and multiple myeloma. Single agent activity was seen in fourteen cell lines, with a median GI50 of 0.59 μM. A scalar measure of the strength of synergistic drug interactions revealed a synergy hit rate of 19.3% across the matrix of drug combinations and cell lines. Synergy with duvelisib was prominent in lymphoma lines with approved and emerging drugs used to treat HM, including dexamethasone, ibrutinib, and the BCL-2 inhibitor venetoclax. Western blotting revealed that certain duvelisib-treated cell lines showed inhibition of phosphorylated (p) AKT at serine 473 only out to 12 hours, with mTORC2 dependent re-phosphorylation of pAKT evident at 24 hours. Combination with dexamethasone or ibrutinib, however, prevented this reactivation leading to durable inhibition of pAKT. The combination treatments also inhibited downstream signaling effectors pPRAS40 and pS6. The combination of duvelisib with dexamethasone also significantly reduced p-4EBP1, which controls cap dependent translation initiation, leading to decreased levels of c-MYC 6 hours after treatment. In support of the in vitro studies, in vivo xenograft studies revealed that duvelisib in combination with the mTOR inhibitor everolimus led to greater tumor growth inhibition compared to single agent administration. These data provide a rationale for exploring multiple combinations in the clinic and suggest that suppression of mTOR-driven survival signaling may be one important mechanism for combination synergy.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Synergism; Everolimus; Female; Hematologic Neoplasms; Humans; Isoquinolines; Mice; Mice, SCID; NF-kappa B; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Purines; Sulfonamides; TOR Serine-Threonine Kinases; Transplantation, Heterologous

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Bridged Bicyclo Compounds, Heterocyclic; Dendritic Cells; Female; Hematologic Neoplasms; Humans; Middle Aged; Positron Emission Tomography Computed Tomography; Simvastatin; Skin Neoplasms; Sulfonamides

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.. Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dendritic Cells; Hematologic Neoplasms; Humans; Male; Mice; Precision Medicine; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Survival Analysis; Treatment Outcome; Xenograft Model Antitumor Assays

The regulation of Mcl-1 expression is necessary for the induction of cancer cell apoptosis by ABTs such as ABT-737, ABT-263 and ABT-199. However, the reduction in Mcl-1 expression is not sufficient for initiating cell death in hematopoietic cancer cells with high Bcl-xL expression. Here, we demonstrate that 2-deoxyglucose (2-DG) enhanced the effect of ABT-199 to induce cell apoptosis in hematologic malignancies with up-regulated Bcl-xL expression. Our study revealed that 2-DG could decrease glucose-dependent and Akt-independent Mcl-1 expression, which is mediated by the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Moreover, the combination of 2-DG and ABT-199 triggered c-Jun NH2-terminal kinase (JNK) phosphorylation and subsequent Bcl-xL degradation, whereas 2-DG and ABT-199 alone had little effect on JNK activation. Therefore, the combination of 2-DG and ABT-199 initiated cell death through the reduction of Mcl-1 expression and JNK activation. Our study could provide a clinical theoretical basis for the use of ABT-199 in hematologic malignancies with excessive Bcl-xL expression.

Topics: Antimetabolites; Antineoplastic Agents; Apoptosis; bcl-X Protein; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Deoxyglucose; Drug Synergism; Enzyme Activation; Hematologic Neoplasms; HL-60 Cells; Humans; Mitogen-Activated Protein Kinase 8; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; RNA Interference; Sulfonamides

The concept of using BH3 mimetics as anticancer agents has been substantiated by the efficacy of selective drugs, such as Navitoclax and Venetoclax, in treating BCL-2-dependent haematological malignancies. However, most solid tumours depend on MCL-1 for survival, which is highly amplified in multiple cancers and a major factor determining chemoresistance. Most MCL-1 inhibitors that have been generated so far, while demonstrating early promise in vitro, fail to exhibit specificity and potency in a cellular context. To address the lack of standardised assays for benchmarking the in vitro binding of putative inhibitors before analysis of their cellular effects, we developed a rapid differential scanning fluorimetry (DSF)-based assay, and used it to screen a panel of BH3 mimetics. We next contrasted their binding signatures with their ability to induce apoptosis in a MCL-1 dependent cell line. Of all the MCL-1 inhibitors tested, only A-1210477 induced rapid, concentration-dependent apoptosis, which strongly correlated with a thermal protective effect on MCL-1 in the DSF assay. In cells that depend on both MCL-1 and BCL-X

Topics: Antineoplastic Agents; Apoptosis; Benzothiazoles; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Death-Associated Protein Kinases; Drug Resistance, Neoplasm; Hematologic Neoplasms; Humans; Indoles; Isoquinolines; Mitochondria; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.. The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements.. The mean and upper bound of the 2-sided 90 % confidence interval (CI) QTc change from baseline were <5 and <10 ms, respectively, at all time points and doses (<400, 400, and >400 mg). Three subjects had single QTc values >500 ms and/or ΔQTc > 60 ms. The effect of venetoclax concentration on both ΔQTc and QTc was not statistically significant (P > 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QTc were 0.137 (90 % CI [-1.01 to 1.28]) and 0.263 (90 % CI [-1.92 to 2.45]) ms, respectively.. Venetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Rate; Hematologic Neoplasms; Humans; Long QT Syndrome; Male; Middle Aged; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Dogs; Female; HeLa Cells; Hematologic Neoplasms; Humans; Mice; Mice, SCID; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Female; Hematologic Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; Sulfonamides