Effect of NPM1 Mutation Subtype and Co‐Mutation Patterns on the Outcomes of Acute Myeloid Leukemia

Introduction NPM1 mutated AML without FLT3‐ITD is considered “favorable” per the recent ELN 2022 criteria. However, our center has been challenged with treatment‐refractory patients, prompting a search for additional prognostic factors. Methods We reviewed records of NPM1 AML patients from 2015 to 2024. Factors associated with event‐free survival (EFS) and overall survival (OS) were evaluated using Cox regression. Results Among 141 patients with NPM1 AML, subtype A was the most common ( N = 99), followed by subtype D ( N = 10), subtype B ( N = 6), subtype G/I/J/K/R ( N = 3/5/3/2/1) and other subtypes ( N = 12). Ninety patients received chemotherapy (chemo), 41 received hypomethylating agent +/− venetoclax (HMA/ven) and 10 did not receive specific anti‐AML therapy. At 12 months, EFS for subtypes A, D, B, G/I/J/K/R, and other subtypes were 49%, 58%, 50%, 49%, and 31%, and OS were 71%, 79%, 50%, 44%, and 56%, respectively. Fifty patients had allogeneic stem cell transplants: 33 in CR1 and 17 in CR2+. EFS at 12 months post‐HSCT was 72%. On multivariable analysis, co‐mutation with KRAS (HR: 2.69, 95% CI: 1.20–6.00) or TET2 (HR: 1.99, 95% CI: 1.22–3.26) was associated with worse EFS. For each 50 k/mm 3 increase in WBC at diagnosis, the risk of relapse or death increased by 21%. For OS, co‐mutation with IDH1/IDH2 (HR: 0.40, 95% CI: 0.21–0.74) was associated with better OS, whereas co‐mutation with SRSF2 (HR: 2.70, 95% CI: 1.35–5.40) was associated with worse OS. Conclusion We did not find a statistically significant difference in EFS and OS among the NPM1 subtypes. However, our results showed that the prognoses of NPM1 AML can be influenced by other co‐occurring mutations. A larger study is needed to confirm our findings.