Venetoclax and hypomethylating agents in TP53‐mutated acute myeloid leukaemia
Ibrahim AldossJianying ZhangRaju PillaiGeoffrey ShouseJames F. SanchezMatthew MeiRyotaro NakamuraAnthony S. SteinStephen J. FormanGuido MarcucciVinod Pullarkat
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The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.Keywords:
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The preclinical efficacy of the novel hypomethylating agent NTX-301 as a monotherapy and in combination with venetoclax in acute myeloid leukemia
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Abstract Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug–drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.
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"Retreatment with venetoclax and hypomethylating agents among AML patients who have relapsed after initial response and subsequent interruption of therapy." Leukemia & Lymphoma, 61(14), pp. 3532–3533
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A retrospective study of a large cohort of patients with acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) revealed a rare subset of patients with mutations in DDX41 where 11 of 12 patients achieving a negative measurable residual disease state after treatment with venetoclax in combination with hypomethylating agents. This study indicates the importance of identifying DDX41-mutated patients at diagnosis so as to achieve higher cure rates following venetoclax plus hypomethylating treatment. Acute myeloid leukaemia (AML) and high-risk myelodysplastic syndrome (MDS) is the most frequent aggressive blood cancer in adults with its 5-year overall survival below 25%,1 where state-of-the-art diagnostics include advanced genomics for prognostication and therapy planning.2 Venetoclax, the inhibitor of the anti-apoptotic Bcl-2 protein, has rapidly emerged as standard of care in unfit AML, combined with hypomethylating agents (HMAs). Due to its efficiency, the paradigm of front-line intensive chemotherapy is challenged adverse risk AML.3 In this issue, Nanaa et al. present a real-world analysis of more than 4500 patient with AML and high-risk MDS, analysing DDX41 mutations and sensitivity to venetoclax and HMA.4 Of the 12 patients identified with DDX41 mutation, all responded and 11/12 turned negative for measurable residual disease (MRD). Furthermore, there was observed a haematological response before a bone marrow response. This suggests an extraordinary response to venetoclax and HMA in AML/MDS with DDX41 mutation that should be confirmed in other patient cohorts and trials. Venetoclax and HMA seem not to have a companion diagnostic that predict long-term response. Interestingly, the efficiency of venetoclax has not been strongly correlated to Bcl-2 family protein expression, even if good antibodies are available for flow cytometry and immunohistochemistry. BH3 ratios seem to predict therapy response but is not available in standard diagnostics.5 However, certain mutations in the AML cells seem to identify venetoclax responders. Specifically, the somatic mutations in splicing factor genes, NPM1 and IDH1/2 likely predict response to venetoclax.6, 7 Since 11 of 12 of the DDX41-mutated patients in the study of Nanaa et al. responded with MRD negativity, the predictive power of a DDX41 mutation may be much stronger than other reported biomarkers of response. This strong therapeutic effect may mimic a type of genetic interaction where the combination of two genetic events results in cell death: synthetic lethality. Synthetic lethality is previously described for Bcl-2 inhibition combined with p53 activation in AML.8 In the model organisms Caenorhabditis elegans, its DDX41 ortholog has been identified as a component of the spliceosome, and genetic analyses revealed synthetic lethal interactions with spliceosomal components.9 Interestingly, venetoclax may be more effective in AML with mutations in genes associated with the spliceosome.7 Future studies are needed to understand the mechanisms behind the therapeutic effect of venetoclax and HMA in DDX41-mutated patients. Patients with the DDX41 mutation presented by Nanaa et al. seems to be exceptional responders. Identifying genetic biomarkers for extraordinary responders will help us to provide more precise therapy.10 However, next-generation sequencing of AML is usually targeted sequencing of 40–50 genes, and other mutations predicting response may be lost. However, identifying DDX41-mutated patients as exceptional responders to venetoclax plus HMA will help us to bring more AML patients to allogeneic transplant and cure. This should bring unfit patient into a long-term disease control. And inspire the research to identify more biomarkers for precision therapy with available drugs in AML and MDS.
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Outcomes of relapsed or refractory acute myeloid leukemia after front-line hypomethylating agent and venetoclax regimensAcute myeloid leukemia (AML) is the most common acute leukemia in adults.][6] Consequently, VEN+HMA regimens have emerged as a reasonable new standard of care for older patients. 7However, little is known about outcomes of patients after failure of front-line venetoclax-based regimens.We found that patients failing front-line VEN+HMA have high-risk biology, dismal overall survival (OS) despite salvage therapy, and new putative mechanisms of resistance.This knowledge may help guide physicians' expectations, inform discussion with patients, and design clinical trials in patients after venetoclax failure.This was a retrospective study to determine the outcomes of patients after failure of front-line VEN+HMA therapy.Patients with newly diagnosed (ND) AML enrolled on two clinical trials of VEN and HMA at our institute, either with primary refractory disease or relapse (R/R) after initial response were included (Online Supplementary Figure S1).In one trial, patients with ND AML aged 65 years or older received venetoclax 400-1,200 mg daily with decitabine 20 mg/m 2 for 5 days or azacitidine 75 mg/m 2 for 7 days every 4 weeks (clinicaltrials.govidentifier: NCT02203773). 4The other trial enrolled patients with ND AML aged 60 years or older, and patients received venetoclax 400 mg daily or equivalent with decitabine 20 mg/m 2 for 10 days every 4 weeks until response, followed by 5-day decitabine with venetoclax cycles (clinicaltrials.govidentifier: NCT03404193). 5None of the patients included in these analyses received any third agents such as targeted therapies.Responses included complete remission (CR), CR with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) according to the European LeukemiaNet 2017 criteria. 8Primary refractory disease was defined as lack of reduction of bone marrow (BM) blasts to 5% or less by up to cycle 4 of VEN+HMA, as originally defined in these two protocols designed in 2014 and 2017.Relapse was defined as clinically significant progressive disease with increase in BM blasts to more than 5% after achievement of CR/CRi/MLFS.OS was measured from the date of establishment of primary refractory disease or relapse after VEN+HMA therapy, until death or censored at last follow-up.The data cut-off date for this report was July 8 th , 2019.To provide context for this analysis, we compared outcomes, both from initial therapy, and from time of R/R disease, with front-line IC using a historical cohort.We found 278 patients treated with IC who matched for both age and European LeukemiaNet (ELN) 2017 cytogenetic risk status with 88 out of 95 patients treated with VEN+HMA.There were no patients in our historical IC cohort who matched for both age and cytogenetic risk status of seven patients who received VEN+HMA, and hence the comparison was limited to those 88 patients.Two out of those seven unmatched patients had R/R disease after VEN+HMA.The patients in the IC cohort were diagnosed between 2000 and 2018, and received treatment with IC containing at least 1 g/m 2 /day of cytarabine
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Background: Acute myeloid leukemia (AML) remains a highly fatal disease. Based on the available evidence of deregulated pathways of proliferation and apoptosis in AML, we hypothesize that pharmacological modulation of AML blasts by inhibitors of BCL-2 (Venetoclax) and novel CDK7 inhibitor (CRI-256) will be potently synergistic for the treatment of AML.
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