A Retrospective Analysis of Intensive Chemotherapy Vs. Venetoclax/Hypomethylating Agents for Patients Aged 60-75 with Favorable-Risk, NPM1-Mutated AML

Introduction: Patients with NPM1-mutated (NPM1m) acute myeloid leukemia (AML) in the absence of a FLT3-internal tandem duplication (ITD) mutation are considered to have favorable risk disease that may be cured with intensive chemotherapy (IC) alone. Yet as patients age, the potential for cure without transplant is counterbalanced by the increased risk of IC-related morbidity and mortality. The combination of venetoclax and a hypomethylating agent (Ven/HMA), which is also quite effective in NPM1m AML, is an appealing standard of care alternative for patients age 75 or older or who are deemed ineligible for IC; however, the curative potential of Ven/HMA alone in NPM1m AML is less well-established. Thus, for patients aged 60-75 in whom fitness can often be difficult to accurately assess, there is equipoise regarding the choice of an IC vs. Ven/HMA approach given these tradeoffs.

Methods: We performed a retrospective analysis of patients aged 60-75 with favorable risk, NPM1m AML and compared overall survival (OS) between those treated with IC to those who received Ven/HMA. Kaplan-Meier curve and the log-rank test were used for survival probabilities. Cox proportional hazard models were used for univariate and multivariate analyses. For the multivariate analysis, clinically-relevant variables and those associated with survival at a p-value of < 0.10 were included as covariates.

Results: 245 patients with NPM1m AML were identified in the Johns Hopkins institutional database, of which, 135 had favorable risk disease per ELN 2022 risk stratification guidelines. 55 of these patients were between the ages of 60 and 75. 36 (63.6%%) of these patients received IC and 19 (34.5%) received Ven/HMA as initial therapy. There were no differences between treatment groups in the distribution of patient sex, race, or baseline characteristics including performance status (PS), white blood cell count (WBC), platelet count, concomitant mutations, diagnostic modifiers, or extramedullary disease. Patients that received IC were significantly younger (mean (SD), 66.1 (3.9) vs. 69.6 (4.2), p=0.005), were more likely to have been treated before FDA approval of venetoclax (treatment era 1, 81% vs. 37%, p = 0.001), and to have undergone transplant in first remission (69% vs. 37%, p = 0.020). Response rates were similar between groups. The median OS for patients treated with IC was 6.2 years (95% CI 3.26-not reached [NR]) vs. 4.9 years (95% CI 1.1-NR) for patients that received Ven/HMA. In a univariate model of OS, there was no difference between the two groups (p = 0.523). Sex, race, age at diagnosis, treatment era, concomitant mutations, diagnostic modifiers, extramedullary disease, and performance status were not significantly associated with OS. Higher baseline WBC was associated with worse OS (p = 0.05), whereas transplant in first remission was associated with improved OS (p = 0.01). In a multivariate analysis including age and baseline WBC, the hazard ratio for Ven/HMA and OS was 2.1 (95% CI 0.73-5.9), but this was not statistically significant. Although a lower proportion (n = 7, 37%) of patients treated with Ven/HMA underwent alloHCT in first remission, the OS for those who did was excellent; none of the 7 patients relapsed and only 1 died of non-relapse mortality. The median OS was not reached after a median follow up of 2.4 years (range 1.2 to 7.3 years).

Conclusion: In the case of a patient aged 60-75 with favorable risk NPM1m AML, there is a tension between the desire to do no harm and the fear of compromising treatment efficacy. The resolution of this tension often relies on the subjective and inexact assessment of fitness. This analysis, limited as it is by its retrospective nature, suggests that outcomes are comparable between patients who are initially treated with IC orVen/HMA. Unlike similar analyses in the past, this one did not include patients with FLT3-ITD patients and used ELN 2022 guidelines to define disease risk. These findings are immediately relevant at the bedside as a guide to treatment choice for older patients with NPM1m, favorable risk disease. They also provide an important benchmark as the care for patients with NPM1m AML is transformed by the increasing use of gemtuzumab ozogamicin, next generation sequencing-based measurable residual disease testing, and the advent and the incorporation of Menin inhibitors into standard of care regimens.

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