P544: MOLECULAR PREDICTORS OF RESPONSE AND SURVIVAL IN TREATMENT-NAÏVE PATIENTS WITH ACUTE MYELOID LEUKEMIA FOLLOWING VENETOCLAX AND HYPOMETHYLATING AGENTS

Abstract

Background: Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA-approved for elderly/unfit AML patients. Limited data exists on molecular predictors of response and survival. In a prior study, response was superior (CR/CRi >80%) with NPM1, IDH1/2, DNMT3A mutations, inferior with TP53, RUNX1, FLT3/ITD, RAS and prolonged survival with NPM1 and IDH2 mutations (2 yr OS 71.8%/79.5%) (DiNardo, Blood, 2020). Aims: Our objective was to determine the impact of mutations on response and survival in treatment-naïve AML patients receiving Ven+HMA. Methods: Treatment-naïve AML patients receiving Ven+HMA outside a clinical trial at the Mayo Clinic were included. Molecular studies were performed by next-generation sequencing. Response was assessed according to the 2017 European LeukemiaNet (ELN) criteria. Standard statistical analyses were performed using JMP Pro (Version 16.0.0). Results: i) Patient characteristics 103 AML patients (median age 74 years, 67% male, 62% de novo) received upfront Ven+HMA. ELN cytogenetic risk included favorable (6%, n=6), intermediate (50%, n=52) or adverse (44%, n=45). Mutations involved TP53 in 25 patients (25%), TET2 in 24 (23%), IDH1/IDH2 in 20 (19%), RUNX1 in 19 (19%), ASXL1 in 18 (18%),), SRSF2 in 18 (18%), K/NRAS in 15 (15%), NPM1 in 13 (13%), DNMT3A in 13 (13%), FLT3-ITD in 10 (10%) patients. ii) Predictors of response 40 (39%) patients achieved complete remission (CR), 20 (19%) CR with incomplete hematological recovery (CRi), resulting in CR/CRi in 60 (58%) patients. In univariate analysis, presence of ASXL1 mutation was associated with favorable response (CR/CRi 83% vs 53%, p=0.01), secondary AML (CR/CRi 49% vs 65%, p=0.09), adverse karyotype (49% vs 67%, p=0.11), presence of TP53 (32% vs 67%, p=0.002) and FLT3-ITD mutations (30% vs 61%; p=0.06) predicted inferior response. In multivariable analysis, including the aforementioned variables, presence of ASXL1 mutation (83% vs 53%; OR 4.5) and absence of TP53 (67% vs 32%; OR 3.3) and FLT3-ITD mutations predicted favorable response (61% vs 30%; OR 6.4). Moreover, in ASXL1 mutated patients, CR/CRi was not impacted by presence of TP53 mutation (100% vs 81%) whereas in ASXL1 unmutated patients, presence of TP53 mutation predicted inferior response (26% vs 63%; p=0.001). Presence of NPM1 (CR/CRi; 69% vs 57%, p=0.41), IDH1/2 (70% vs 55%; p=0.23), DNMT3A (54% vs 59%; p=0.73), RUNX1 (58% vs 58%; p=0.1), RAS (60% vs 58%, p=0.88) did not impact response. iii) Predictors of survival After a median follow up of 6.6 months, 68 patients died and 9 underwent allogeneic stem cell transplant. Median overall survival (mOS) was 8.5 months and longer in transplanted patients (not reached vs 8.4 months, p=0.08). Age-adjusted analysis in 94 patients not transplanted, identified CR/CRi (p<0.0001), NPM1 (p=0.009), IDH1/2 mutations (p=0.02) as favorable, and TP53 (p=0.01), ASXL1 mutations (p=0.17) adverse karyotype (p=0.05) unfavorable risk factors for survival. Despite higher CR/CRi, ASXL1 mutated patients had shortened mOS due to higher relapse. Multivariable analysis confirmed the negative survival impact of not achieving CR/CRi, ASXL1 mutation and adverse karyotype. Accordingly, a three-tiered model was generated by using the three variables (Figure 1). Image:Summary/Conclusion: Our observations differ from those of DiNardo, et al. (Blood, 2020). The current study identifies presence of ASXL1 mutation and absence of TP53 and FLT3-ITD mutations as predictors of favorable response. Additionally, we propose a novel three-tiered survival model based on response, ASXL1 mutation and karyotype.