Prognostic Significance of Mutations in Maintenance Hypomethylation Therapy for AML Patients

Maintenance Therapy in AML Remission

Although 40–80% of patients with acute myeloid leukemia achieve complete remission (CR) after intensive chemotherapy, most of them relapse over time due to the re-expansion of either original or newly formed leukemic clones. The presence of measurable minimal residual disease after chemotherapy completion is a strong predictor of poorer overall survival (OS) and relapse-free survival (RFS) in patients in remission.

One therapeutic option to prevent the re-expansion of leukemic cells is hypomethylation therapy with oral azacitidine. It is indicated for adult patients with AML who have achieved CR or CR with incomplete blood count recovery after induction therapy with or without consolidation treatment and are ineligible for hematopoietic stem cell transplantation (HSCT). This treatment significantly improved OS and RFS compared to placebo in the phase III QUAZAR AML-001 clinical trial in older patients in first remission, regardless of the presence of MRD.

Study Methodology and Goals of the Post Hoc Analysis

A total of 472 AML patients who achieved first remission after intensive chemotherapy and were not candidates for HSCT were randomly assigned in a 1:1 ratio to receive 300 mg of oral azacitidine or placebo for 14 days in each 28-day cycle. MRD presence was centrally assessed using multiparametric flow cytometry. OS and RFS were evaluated in subgroups defined by the mutational status of NPM1 and FLT3 genes at AML diagnosis.

The presented post hoc data analysis aimed to explore the efficacy of treatment concerning the mutational status of NPM1 and FLT3 genes. Mutations in the NPM1 gene (NPM1^mut) generally occur in about one-third of younger adults with AML and decrease with age. AML in patients with NPM1^mut is particularly sensitive to intensive chemotherapy and has a good prognosis, especially in the absence of FLT3 mutations (or with low allelic ratio FLT3 mutations). Mutations in the FLT3 gene also occur in about 30% of AML patients, but their prognostic significance depends on other concurrent genomic changes.

Results

Mutational status data were available for 469 patients, of whom 29.2% had NPM1^mut mutations, 14.1% had FLT3 mutations (FLT3^mut – either internal tandem duplications [ITD] or tyrosine kinase domain mutations [TKD^mut], or both), and 6.4% had both NPM1^mut and FLT3-ITD mutations.

In patients with NPM1^mut, oral azacitidine treatment improved OS by 37% compared to placebo (hazard ratio [HR] 0.63; 95% confidence interval [CI] 0.41–0.98), and RFS improved by 45% (HR 0.55; 95% CI 0.35–0.84). Median OS increased compared to placebo irrespective of MRD presence: 48.6 vs. 31.4 months in MRD-negative patients and 46.1 vs. 10.0 months in MRD-positive patients.

For patients with FLT3^mut taking oral azacitidine, OS improved by 37% compared to placebo (HR 0.63; 95% CI 0.35–1.12), and RFS improved by 49% (HR 0.51; 95% CI 0.27–0.95). Median OS for MRD-negative individuals was 28.2 vs. 16.2 months, and for MRD-positive patients 24.0 vs. 8.0 months compared to placebo.

Conclusion

The cited multivariate analysis indicates that oral azacitidine therapy significantly improved survival in AML patients in first remission, regardless of the mutational status of NPM1 and FLT3 genes, cytogenetic risk, or the presence of measurable residual disease after the completion of intensive chemotherapy.

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Sources:
1. Döhner H., Wei A. H., Roboz G. J. et al. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine. Blood 2022; 140 (15): 1674–1685, doi: 10.1182/blood.2022016293.
2. SPC Onureg. Available at: www.ema.europa.eu/en/documents/product-information/onureg-epar-product-information_cs.pdf

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