Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure.
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ABSTRACT:
SUBMITTER: Ball BJ
PROVIDER: S-EPMC7362378 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Venetoclax and hypomethylating agents (HMAs) induce high response rates in MDS, including patients after HMA therapy failure.
Ball Brian J BJ Famulare Christopher A CA Stein Eytan M EM Tallman Martin S MS Derkach Andriy A Roshal Mikhail M Gill Saar I SI Manning Benjamin M BM Koprivnikar Jamie J McCloskey James J Testi Rebecca R Prebet Thomas T Al Ali Najla H NH Padron Eric E Sallman David A DA Komrokji Rami S RS Goldberg Aaron D AD
Blood advances 20200701 13
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Project description:The efficacy and tolerability of the combination of hypomethylating agents with venetoclax (HMA-VEN) in patients with newly diagnosed acute myeloid leukemia has been a practice-changing milestone in the field. However, treatment failure and relapse remain major barriers to prolonged survival. TP53 mutation is a predictor of primary induction failure and portends especially poor outcomes. Prelinical data suggest that VEN resistance stems from these genetic changes, which lead to increases in antiapoptotic proteins such as MCL-1 and BCLXL. For patients who discontinue HMA-VEN for reasons other than disease progression, such as post allotransplantation, infection, and personal preference, rechallenge with HMA-VEN at the time of relapse may be considered. For those who progress on HMA-VEN, clinical trials with novel agents or rational drug combinations are preferred if available. If no trial option is available, fit patients may benefit from intensive chemotherapy. Emerging therapies aim to overcome venetoclax resistance, target interactions that promote leukemogenesis, and harness the immune system to irradicate leukemic blasts and stem cells.
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Project description:BackgroundPevonedistat is a first-in-class, small molecular inhibitor of NEDD8-activating enzyme that has clinical activity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Preclinical data suggest synergy of pevonedistat with azacitidine and venetoclax.MethodsThis single-center, phase 1/2 study evaluated the combination of azacitidine, venetoclax and pevonedistat in older adults with newly diagnosed secondary AML or with MDS or chronic myelomonocytic leukemia (CMML) after failure of hypomethylating agents. Patients received azacitidine 75 mg/m2 IV on days 1-7, venetoclax at maximum dose of 200-400 mg orally on days 1-21 (AML cohort) or days 1-14 (MDS/CMML cohort) and pevonedistat 20 mg/m2 IV on days 1, 3 and 5 for up to 24 cycles. The primary endpoints for the phase 2 portion of the study were the CR/CRi rate in the AML cohort and the overall response rate (CR + mCR + PR + HI) in the MDS/CMML cohort.FindingsForty patients were enrolled (32 with AML and 8 with MDS/CMML). In the AML cohort, the median age was 74 years (range 61-86 years), and 27 patients (84%) had at least one adverse risk cyto-molecular feature, including 15 (47%) with a TP53 mutation or MECOM rearrangement; seventeen patients (53%) had received prior therapy for a preceding myeloid disorder. The CR/CRi rate was 66% (CR 50%; CRi 16%), and the median overall survival (OS) was 8.1 months. In the MDS/CMML cohort, 7 patients (87%) were high or very high risk by the IPSS-R. The overall response rate was 75% (CR 13%; mCR with or without HI 50%; HI 13%). The most common grade 3-4 adverse events were infection in 16 patients (35%), febrile neutropenia in 10 patients (25%) and hypophosphatemia in 9 patients (23%). In an exploratory analysis, early upregulation of NOXA expression was observed, with subsequent decrease in MCL-1 and FLIP, findings consistent with preclinical mechanistic studies of pevonedistat. Upregulation of CD36 was observed, which may have contributed to therapeutic resistance.ConclusionsThe triplet combination of azacitidine, venetoclax and pevonedistat shows encouraging activity in this very poor-risk population of patients with AML, MDS or CMML. Trial registration ClinicalTrials.gov (NCT03862157).
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Project description:IntroductionHypomethylating agents (HMA) have played a pivotal role for treating myelodysplastic syndromes (MDS) over the past decade, inducing sustained hematological responses and delaying progression to leukemia. However, a vast majority of patients will experience treatment failure within 2 years, with poor prognoses and limited options, and management of this growing patient population remains unclear. Areas covered: With the introduction of new agents in the MDS field, a better understanding of the biology of MDS, and updated information on standard of care options (including allogeneic transplantation), we re-evaluate the global treatment strategy in MDS via novel agents, focusing in particular on investigational approaches for patients who fail to respond to HMA when applicable. This review aims to address two questions: what are reasonable alternatives to HMA in MDS, and what strategies can be used for patients experiencing HMA failure. Expert opinion/commentary: HMA therapy remains a mainstay of treatment, even if additional research is still warranted to maximize its benefits for the different groups of patients. The outcome of patients experiencing HMA failure remains grim, without standard of care, but several new approaches seem promising, as there is an increasing focus on studying treatments for patients refractory to HMA treatment.
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Project description:Aberrant DNA methylation plays a pivotal role in tumor development and progression. DNA hypomethylating agents (HMA) constitute a class of drugs which are able to reverse DNA methylation, thereby triggering the re-programming of tumor cells. The first-generation HMA azacitidine and decitabine have now been in standard clinical use for some time, offering a valuable alternative to previous treatments in acute myeloid leukemia and myelodysplastic syndromes, so far particularly in older, medically non-fit patients. However, the longer we use these drugs, the more we are confronted with the (almost inevitable) development of resistance. This review provides insights into the mode of action of HMA, mechanisms of resistance to this treatment, and strategies to overcome HMA resistance including next-generation HMA and HMA-based combination therapies.
| S-EPMC8257497 | biostudies-literature
Project description:We established acquired venetoclax resistant OCI-LY1R cell line by treating venetoclax sensitive parental OCI-Ly1 cell line with increasing doses of venetoclax up till 1µM. Parental OCI-Ly1 and venetoiclax-resistant OCI-Ly1R cells were treated with vehicle control or decitabine at 1uM for 3 days. We found that decitabine differantially regulated gene expression in venetoclax sensitive and resistant cells. With gene set enrichment analysis, we identified two pathways that were deregulated by decitabine in both cell lines.
2023-07-25 | GSE223598 | GEO
Project description:In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanucleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients who relapse after, or do not respond to, hypomethylating agent therapy, the outcome is dismal, and new agents and approaches that have the potential to alter the natural history of these diseases are desperately needed. Allogeneic stem cell transplant is the only known potentially curative approach in MDS, but its applicability has been limited by the advanced age of patients and attendant comorbidities. There is now an increasing array of new agents under clinical investigation in MDS that aim to exploit our expanding understanding of molecular pathways that are important in the pathogenesis of MDS. This review focuses on a critical appraisal of novel agents being evaluated in higher-risk MDS that go beyond the conventional hypomethylating agent therapies approved by the US Food and Drug Administration.
| S-EPMC6142530 | biostudies-literature
Project description:BackgroundThe identifying of B-cell lymphoma 2 (Bcl-2) as a therapeutic target has led to a paradigm shift in acute myeloid leukemia (AML) treatment. Pyroptosis is a novel antitumor therapeutic mechanism due to its cytotoxic and immunogenic effects. The combination of venetoclax and hypomethylating agents (HMAs) has been shown to lead to durable responses and significantly improve prognosis in patients with AML. However, our understanding of the mechanisms underlying this combinatorial activity is evolving.MethodsWe investigated whether the Bcl-2 inhibitor venetoclax induces AML cell pyroptosis and identified pyroptosis effector proteins. Via using western blotting, immunoprecipitation, RNA interference, CCK8 assays, and LDH assays, we explored the mechanism underlying the pyroptotic effect. The relationship between the expression of the pyroptosis effector protein GSDME and AML prognosis was investigated. The effect of GSDME demethylation combined with venetoclax treatment on pyroptosis was investigated and confirmed in mouse models and clinical samples.ResultsVenetoclax induces pyroptosis that is mediated by caspase-3-dependent GSDME cleavage. Mechanistically, venetoclax upregulates caspase-3 and GSDME cleavage by activating the intrinsic apoptotic pathway. GSDME is downregulated in AML by promoter methylation, and low GSDME expression is significantly associated with poor prognosis, based on public databases and patient sample analysis. In vivo and in vitro experiments showed that GSDME overexpression or HMAs-mediated restoration of GSDME expression significantly increased venetoclax-induced pyroptosis in AML.ConclusionGSDME-mediated pyroptosis may be a novel aspect of the antileukemic effect of Bcl-2 inhibitors. This finding offers new insights into potential biomarkers and therapeutic strategies, identifying an important mechanism explaining the clinical activity of venetoclax and HMAs in AML.
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Project description:APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients' T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.
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