Intensive Induction Chemotherapy Vs Hypomethylating Agents + Venetoclax (HMA/VEN) in NPM1-Mutant Newly Diagnosed Acute Myeloid Leukemia (AML) - a Multicenter Cohort Study
Authors: Bewersdorf Jan Philipp , Shimony Shai , Shallis Rory M. , Liu Yiwen , Schaefer Eva Johanna , Zeidan Amer M. , Goldberg Aaron D. , Stein Eytan M. , Marcucci Guido , Lindsley R. Coleman , Chen Evan C. , Ramos Jorge , Stein Anthony Selwyn , DeAngelo Daniel J. , Neuberg Donna S. , Stone Richard M , Ball Brian J. , Stahl Maximilian 
Published: December 2023

Introduction:
Intensive induction chemotherapy (IC) with cytarabine + anthracycline remains the standard of care for younger and fit patients (pts) with acute myeloid leukemia (AML). Post-hoc analyses from clinical trials evaluating venetoclax (VEN)-based therapies in AML have identified mutations in NPM1 as being associated with high rates of durable responses. However, these trials were conducted in pts age ≥75 years or unfit for IC. Thus, it is unknown whether IC or hypomethylating agent (HMA)+VEN is the optimal frontline treatment for pts with NPM1-mutant AML. We performed a large multicenter retrospective cohort study dedicated to pts with newly diagnosed AML with NPM1 mutations, comparing treatment modalities and assessing the impact of clinical and molecular characteristics on response and survival.
Methods:
We included pts with newly diagnosed, NPM1-mutant AML who were treated at 4 large academic centers with IC (either conventional 7+3 or liposomal cytarabine/daunorubicin [CPX-351]) or HMA+VEN. Detection of NPM1 mutations was performed at the participating sites either by polymerase chain reaction (PCR) or next-generation sequencing (NGS) per local standards. Composite complete response (cCR) was defined as complete response (CR) + CRi (CR with incomplete count recovery) per European LeukemiaNet 2017 criteria. Overall survival (OS) was compared between groups by log-rank test. Cox regression multivariable model for OS was fitted using a stepwise backward selection to evaluate the effect of treatment, allogeneic stem cell transplantation (allo-SCT) as a time-varying covariate and additional covariates with a p&lt;0.1 in the univariate model.
Results:
We reviewed 1132 pts with AML and included 225 pts with NPM1-mutant AML in the final analysis ( Table 1). Among these pts, 71% (n=160) and 29% (n=65) received IC and HMA+VEN, respectively. Some pts (22%) in the IC group also received midostaurin compared to 0% in the HMA+VEN group. Pts who received IC for NPM1-mutant AML were younger (median age 61 years [Range: 22 -76] vs 74 years [33 -89]; p&lt;0.001) when compared to HMA+VEN and less likely to have prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN; 10% vs 20%, p=0.042), and SF3B1 mutations (3.1% vs 15%; p=0.002). There was no difference in the rate of FLT3-ITD mutations between groups (36% vs 29%; p=0.36).
Rates of cCR and CR were higher for IC than HMA+VEN-treated pts (cCR: 87% vs 74%; p=0.018; CR: 83% vs 52%; p&lt;0.001), as well as rates of allo-SCT (56% vs 23%; p&lt;0.001). Median OS was 31 months (95% CI: 24 months [mo] - not reached [NR]) for the total cohort of pts with NPM1-mutant AML and was better in pts treated with IC vs HMA+VEN (IC: 24 mo OS 65% [95% CI: 57 - 74%] vs HMA+VEN: 24 mo OS 38% [95% CI: 26 - 55%]; p&lt;0.001).
While the median OS remained favorable for IC among pts age &gt; 60 years with NPM1-mutant AML (34 mo [95% CI: 24 mo - NR] vs 15 mo [13 mo - 28 mo]; p=0.015), there was no difference in OS by treatment type among the pts undergoing allo-SCT (IC: median OS not reached; 24 mo OS: 72% [95% CI: 63-83%] vs HMA+VEN: median OS 29 mo; 24 mo OS 69% [95% CI: 48-100%]; p=0.55).
In the univariate analysis, treatment (HMA+VEN vs IC), age, prior chemotherapy exposure, abnormal cytogenetics, SF3B1, TET2 and RNA splicing mutations were associated with worse outcomes ( Table 2). Of note, neither the presence of concurrent FLT3 or IDH1/2 mutations nor allo-SCT as a time-varying covariate had a statistically significant impact on OS. In the multivariable analysis, treatment with HMA+VEN vs. IC retained its predictive value (hazard ratio: 2.00; 95% CI: 0.92 - 3.03; p=0.006), as well as prior chemotherapy and abnormal cytogenetics ( Table 2).
Conclusion:
In pts with newly diagnosed NPM1-mutant AML, treatment with IC was associated with higher cCR rates and favorable OS when compared with HMA+VEN in multivariable regression analysis. However, as residual confounding cannot be excluded given the significant differences in baseline patient and disease characteristics between the two groups, a randomized clinical trial is needed to definitively verify the potential superiority of IC vs HMA+VEN in pts with newly diagnosed NPM1-mutant AML.