Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients

Abstract

Venetoclax + hypomethylating agent (Ven‐HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND‐AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND‐AML was to identify molecular predictors of treatment response to Ven‐HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, “favorable” predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and “unfavorable” TP53 (40% vs. 67%), FLT3‐ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy‐related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow‐up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5–4.8), adverse karyotype (1.6, 1.1–2.6), TP53 mutation (1.6, 1.0–2.4), and absence of IDH2 mutation (2.2, 1.0–4.7); these risk factors were subsequently applied to construct an HR‐weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3‐tiered, CR/CRi‐based, and genetics‐enhanced survival model for AML patients receiving upfront therapy with Ven‐HMA.

CEBPA bZIP in-frame mutations in acute myeloid leukemia: prognostic and therapeutic implications

“…Meanwhile, venetoclax plus hypomethylating agents (VEN + HMA) were efficient in AML patients with specific molecular profiles (such as NPM1 , IDH2 , etc.) [ 6 , 7 ]. However, relevant data related to the role of VEN + HMA regimens in CEBPA bZIP-inf AML patients is limited.…”

Age-specific survival in acute myeloid leukemia in the Nordic countries through a half century

“…Intensive chemotherapy is complemented with inhibitors targeting specific mutations, such as FLT3, IDH1 and IDH2 , and the mutational profile is now a key component in risk classification [ 3 ]. For old, unfit and relapsing patients the BCL2 -inhibitor venetoclax has recently increased the treatment options [ 3 , 4 , 9 ]. For AML it was approved in Europe in 2021 in combination with a hypomethylating agent.…”

“…For AML it was approved in Europe in 2021 in combination with a hypomethylating agent. In USA this treatment has shown improved survival in the elderly patients [ 9 ]. How the novel molecular medicine will translate to population-level survival figures for AML will be seen in the near future.…”

Comparing venetoclax in combination with hypomethylating agents to hypomethylating agent-based therapies for treatment naive TP53-mutated acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND)

“…Responses to venetoclax and their durability are linked to specific molecular profiles, these associations are particularly notable with mutations in DDX41, RUNX1, SRSF2, NPM1, IDH1 or IDH2 [ 7 – 11 ]. Resistance to venetoclax-based combinations is frequently associated with the emergence of clones that impart resistance and is often linked to specific molecular signatures or pathways ( TP53 , FLT3 , DNMT3A or RAS ) [ 2 , 8 , 9 ].…”

“…The majority of trials and retrospective reports in the literature on HMA + VEN outcomes in treatment naïve TP53 m AML, have reported CR rates of approximately 20–40% and median OS range of (6.0–11.0 months) [ 5 , 9 ]. In recently conducted real-world study on 301 AML patients, who were treated with HMA + VEN, TP53 m was deemed unfavorable with inferior CR rates and overall survival [ 8 ]. The data suggest desperate need for novel and effective treatment combinations for patients with TP53 m AML.…”