Introduction: NPM1-mutated acute myeloid leukemia (NPM1mut) is a common entity, usually associated with a favorable prognosis. The European LeukemiaNet (ELN) classification, updated in 2022, classifies patients with NPM1mut AML and ITD-FLT3mut as having an intermediate prognosis, while the remaining patients are part of the favorable group. A study from the HARMONY Alliance database proposed a genetic stratification model for NPM1mut AML that identifies 4 groups based on mutations in TP53, FLT3-ITD, DNMT3A, IDH, N/K RAS, PTPN11 and RAD21 genes (Hernández Sánchez A, Blood 2022). Other studies have identified patterns of mutations with poor prognosis, although other factors, such as measurable residual disease (MRD) after induction, could influence this effect (Othman J, Blood. 2024 Aug 15). Furthermore, prognosis may have been improved by the addition of midostaurin (MIDO) to treatment in FLT3mut patients and gentuzumab ozogamizine (GO) in FLT3wt patients. Aims: To evaluate the prognostic impact of frequent co-mutations detected by NGS and the type of treatment received in patients with NPM1mut AML who were candidates to intensive chemotherapy (IC) included in the multicenter cohort of the CETLAM group.Methods: A retrospective review was made of 164 adult patients diagnosed with NPM1mut AML between January 2019 and December 2024, who received IC according to the CETLAM protocol. Since April 2019, MIDO was added to FLT3mut patients, and in 2022, GO was added to FLT3wt patients. Clinical and biological characteristics at diagnosis, response to treatment, survival and the interaction between co-mutations and genetic/molecular risk groups were analyzed. The statistical analysis was performed using SPSS v19 and RStudio v3.Results: The median age was 61 years (range 18–75), and 55.5% were females, 8.4% had ECOG ≥2 at diagnosis and 4.3% corresponded to secondary leukemia. The ABD subtype of NPM1 was identified in 91.4% of cases, the majority being type A in 72.5%. Most frequent co-mutations (>10%) were: DNMT3A (55.3%), FLT3-ITD (34.9%), TET2 (21.6%), IDH1 (16.6%) and IDH2 (14.2%). 73.1% and 68% of the patients were classified as a favorable group of ELN2017 and ELN2022, respectively. All patients received IC: 49.7% an anthracycline and cytarabine-based regimen (“3+7” treatment excepted three patients who received CPX-351), 31.8% with MIDO, and 3.7% with GO. Complete remission (CR) after induction was 81.8%, with negative MRD in 45.3%. 41.8% of patients underwent alloHSCT; 60.6% due to biological or morphological progression. During follow-up, 31% of patients died, mainly due to progression (48.9%) and infection (19.1%). With a median follow-up of 22.6 months, overall survival (OS) was 107.4 months (95% CI: 94.9–119.9); while event-free survival (DFS) was 33.2 months (95% CI: 11.8–54.5). No statistically significant differences were found in OS in patients according to the ELN2017 risk classification, ELN2022 or molecular classification proposed by Harmony. However, the favorable risk group according to the ELN2022 had a statistically higher DFS (p=0.036) than the intermediate group, with a median DFS of 43.5 months (95% CI: 3.5–83.5) vs. 13.3 months (6.1–20.6), respectively. The Intermediate-2 group of the Harmony classification (FLT3-ITDwt/IDHmut) tended to present a higher DFS (p=0.056). No differences were found in OS or DFS according to the mutational group of NPM1 (ABD type vs. non-ABD), nor according to the type of treatment administered (“3+7” treatment, addition of midostaurin vs. addition of GO). Multivariate OS analysis identified the following independent prognostic factors: age (HR 1.06; 95% CI: 1.027–1.10), ECOG at diagnosis (HR 1.87; 95% CI: 1.27–2.75) and having achieved a CR at induction 1 (HR 0.16; 95% CI: 0.08–0.35). None of the co-mutations analyzed or VAF were associated with significant differences in OS. The presence of DNMT3A and TET2 tended to be statistically significant in increasing the risk of not achieving CR after induction 1 (OR 3.5; p=0.067) after induction 2 (OR 15.8; p=0.08), respectively. Conclusion: In this study, in patients with NPM1mut AML treated with IC +/- MIDO or GO, the comutations analyzed were not associated with OS or DFS. However, mutations in DNMT3A and TET2 showed a tendency to be associated with a lower likelihood of CR. Age and functional status at diagnosis were confirmed as. The molecular classification of Harmony could help discriminate subgroups with different survivals

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2025
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