Effect of NPM1 mutation Subtype and Co-Mutation Patterns on the Outcomes of Patients with Acute Myeloid Leukemia; A Referral Center Experience

Introduction

AML driven by NPM1 mutation (NPM1^mut) in the absence of FLT3-ITD mutation has been categorized by the ELN 2022 criteria in the “favorable” group. However, our center's experience noted some patients with “unfavorable” outcomes prompting us to search for potential distinguishing factors that may help stratify patients with adverse risk NPM1^mut.

Methods

We reviewed records of NPM1^mut AML patients from 2015 to 2024 and factors associated with relapse-free survival (RFS) and overall survival (OS) were evaluated using Cox regression.

Results

We identified 141 patients with NPM1^mut AML, subtype A was the most common (N=98), followed by subtype D (N=10), subtype B (N=6), and other subtypes (N=27) respectively. Ninety patients received chemotherapy (chemo), 41 received hypomethylating agent +/- venetoclax (HMA/ven) and 10 did not receive specific anti-AML therapy. We did not find statistically significant differences in RFS and OS among the different NPM1^mut subtypes.

Fifty patients underwent allogeneic stem cell transplants (HSCT); 33 in CR1 (indicated by adverse cytogenetics or co-mutations) and 17 in CR2+ (4 with MRD+ disease pre-HSCT). Median RFS was 70.7 months after HSCT. On multivariable analysis, increased WBC at diagnosis and treatment with HMA/ven compared to chemo were associated with inferior RFS and OS. Co-mutation with KRAS and TET2 was associated with worse RFS. Co-mutation with IDH1/IDH2 was associated with better OS, while KRAS and SRSF2 were associated with worse OS.

Conclusion

We did not find a statistically significant difference in RFS and OS between subtype A vs other subtypes of NPM1^mut. However, our results showed that prognoses of NPM1^mut AML patients can be influenced by co-mutations other than FLT3-ITD. We noticed inferior RFS among TET2 co-mutated patients, which has not been previously reported, but, whether this is related to underlying clonal hematopoiesis vs true clinical significance remains to be explored. Our results agree with prior reports of favorable outcomes from co-occurring IDH mutations and adverse outcomes when SRSF2 and RAS pathways are altered. The inferior RFS and OS outcomes in the HMA/ven cohort warrant further investigation in a larger randomized trial.

No relevant conflicts of interest to declare.