TOPLINE

Nucleophosmin 1-mutated (NPM1mt) acute myeloid leukemia (AML) showed favorable response rates, with complete remission exceeding 75%, in a retrospective analysis of about 400 patients. Survival varied significantly by treatment approach and patient age.

METHODOLOGY

• Prognosis in NPM1mt AML is dependent on comutations, with a clear impact of measurable residual disease (MRD) detection on long-term outcomes, though the full spectrum of prognostic factors and expected outcomes by therapy have not been fully elucidated.
• Researchers conducted a retrospective analysis of 396 patients (18% of 2,215 total) with newly diagnosed NPM1-mutated AML treated at The University of Texas MD Anderson Cancer Center in Houston between January 2012 and December 2023. 
• Patients received either high-intensity regimens — combinations of cytarabine and idarubicin with or without a second nucleoside analog, with or without venetoclax — or low-intensity regimens — hypomethylating agents or low-dose cytarabine with venetoclax, or cladribine plus low-dose cytarabine and venetoclax alternating with azacitidine and venetoclax. 
• MRD assessment was performed on bone marrow samples using multicolor flow cytometry with a predicted sensitivity of 10^-4, and targeted next-generation sequencing was performed using panels of genes recurrently mutated in leukemia. 
• Outcome measures included overall survival (OS) calculated from diagnosis to death or last follow-up, and event-free survival (EFS) defined as duration from treatment initiation until failure to achieve complete remission at day 56, disease relapse, or death from any cause. 

TAKEAWAY

• Patients with NPM1mt AML treated with high-intensity chemotherapy achieved a median OS of 84.7 months with a 5-year rate of 53%, whereas those treated with hypomethylating agent and venetoclax had a median OS of 23.3 months with a 5-year rate of 19%. 
• In multivariate analysis among patients receiving high-intensity chemotherapy, independent predictors of worse OS included older age (hazard ratio [HR] for OS, 1.03; P = .029), FLT3-ITD mutation (HR for OS, 2.1; P = .004), extramedullary disease (HR for OS, 8.9; P < .001), and performance status > 2 (HR for OS, 9.8; P < .001). 
• For patients treated with hypomethylating agent and venetoclax, only older age emerged as an independent adverse prognostic factor for OS in multivariate analysis (HR for OS, 1.1; P = .01), while complex karyotype, myelofibrosis, and TP53 mutations did not retain significance. 
• The combination of cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax yielded superior survival compared with hypomethylating agent and venetoclax in age-matched analysis, with 5-year OS rates of 74% (95% CI, 53%-87%) vs 24% (95% CI, 5%-49%; P = .048). 

IN PRACTICE

“Among patients with NPM1mt treated with high-intensity chemotherapy, older age, a poor performance status, and presence of a FLT3-ITD mutation or extramedullary disease predicted a worse overall survival. For patients treated with a hypomethylating agent and venetoclax, older age was the only predictor of worse long-term outcomes. These findings can be used for risk stratification of newly diagnosed NPM1mt AML and provide benchmarks of response and survival for this subtype,” the authors of the study wrote.

SOURCE

The study was led by Aziz Farhat, MD, and Ghayas C. Issa, MD, MS, The University of Texas MD Anderson Cancer Center. It was published online in Cancer.

LIMITATIONS

According to the authors, the main limitation relates to the retrospective, single-center design with a variety of treatments tested, requiring cautious interpretation of the results. The relatively low proportion of patients with NPM1mt AML in the cohort likely reflects referral patterns at the institution, which enriches for patients with adverse-risk disease, including TP53-mutated and therapy-related AML, potentially contributing to lower observed frequency of NPM1mt AML. Molecular MRD assessment and variant allele frequency data were not available, limiting the depth of residual disease evaluation. The number of patients in each treatment subgroup was relatively small, particularly for the cladribine, low-dose cytarabine, and venetoclax regimen, necessitating prospective studies to confirm observations. The heterogeneity of reported results regarding myelodysplasia-related mutations indicates that their prognostic significance is likely context- and therapy-dependent and should be interpreted with caution.

DISCLOSURES

Issa disclosed support from the Andrew Sabin Family Foundation Fellowship and the Faculty Scholar Award at the University of Texas MD Anderson Cancer Center. The research received partial funding from the National Institutes of Health, National Cancer Institute Cancer Center Support (P30 CA016672). Issa also reported receiving research funding from Celgene, Merck, Kura Oncology, Cullinan Oncology, Syndax, Astex, Novartis, Pupil Bio, Sumitomo, Daiichi Sankyo, and Crossbow; consultancy or advisory board fees from AbbVie, Novartis, Sanofi, AstraZeneca, Syndax, Kura Oncology, Biostate, and Crossbow; and serving on the scientific advisory boards of Pupil Bio and Biostate. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.