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Clinical impact of NPM1-mutant molecular persistence after chemotherapy for acute myeloid leukemia
Ing S Tiong1,2, Richard Dillon3,4, Adam Ivey1,5
1Department of Haematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australia.
Abstract:
Monitoring of NPM1 mutant (NPM1mut) measurable residual disease (MRD) in acute myeloid leukemia (AML) has an established role in patients who are treated with intensive chemotherapy. The European LeukemiaNet has defined molecular persistence at low copy number (MP-LCN) as an MRD transcript level <1% to 2% with a <1-log change between any 2 positive samples collected after the end of treatment (EOT). Because the clinical impact of MP-LCN is unknown, we sought to characterize outcomes in patients with persistent NPM1mut MRD after EOT and identify factors associated with disease progression. Consecutive patients with newly diagnosed NPM1mut AML who received ≥2 cycles of intensive chemotherapy were included if bone marrow was NPM1mut MRD positive at the EOT, and they were not transplanted in first complete remission. One hundred patients were followed for a median of 23.5 months; 42% remained free of progression at 1 year, either spontaneously achieving complete molecular remission (CRMRD-; 30%) or retaining a low-level NPM1mut transcript (12% for ≥12 months and 9% at last follow-up). Forty percent met the criteria for MP-LCN. Preemptive salvage therapy significantly prolonged relapse-free survival. Risk factors associated with disease progression were concurrent FLT3-internal tandem duplication at diagnosis and suboptimal MRD response (NPM1mut reduction <4.4-log) at EOT.
Insights
Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) with NPM1 mutations is crucial. Persistent low-level NPM1 mutations after treatment impact outcomes, but preemptive therapy can improve survival.
Area of Science:
- Hematology
- Oncology
- Molecular Diagnostics
Background:
- Measurable residual disease (MRD) monitoring of NPM1 mutations (NPM1mut) is established in acute myeloid leukemia (AML) post-intensive chemotherapy.
- Molecular persistence at low copy number (MP-LCN) is defined by European LeukemiaNet, but its clinical significance remains unclear.
Purpose of the Study:
- To investigate outcomes in NPM1mut AML patients with persistent MRD after treatment.
- To identify factors associated with disease progression in this cohort.
Main Methods:
- Retrospective analysis of 100 newly diagnosed NPM1mut AML patients receiving intensive chemotherapy.
- Patients had NPM1mut MRD positive at end of treatment (EOT) and were not transplanted in first complete remission.
- Follow-up for a median of 23.5 months to assess progression-free survival and molecular remission.
Main Results:
- 42% of patients were progression-free at 1 year; 30% achieved complete molecular remission (CRMRD-).
- 40% met criteria for MP-LCN; 12% maintained low-level NPM1mut for ≥12 months.
- Preemptive salvage therapy improved relapse-free survival.
Conclusions:
- Persistent NPM1mut MRD after intensive chemotherapy in AML has variable outcomes, with a significant proportion achieving molecular remission or maintaining low-level disease.
- Concurrent FLT3-internal tandem duplication and suboptimal MRD reduction at EOT are risk factors for disease progression.
- Preemptive therapy is a viable strategy to improve outcomes in patients with persistent NPM1mut MRD.
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