Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia
Maximilian Stahl1,2, Andriy Derkach3, Noushin Farnoud3,4,5
1Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Abstract:
Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.
Insights
Pre-treatment mutations predict measurable residual disease (MRD) clearance in acute myeloid leukemia (AML). Certain mutations and clone numbers indicate poor response to chemotherapy, suggesting early clinical trial enrollment for these patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Measurable residual disease (MRD) is a critical prognostic indicator in acute myeloid leukemia (AML).
- Predictors of achieving MRD clearance before treatment in AML are not well understood.
- Immunophenotypic monitoring is key for assessing MRD status.
Purpose of the Study:
- To identify pre-treatment molecular predictors of immunophenotypic MRD clearance in AML patients.
- To analyze the impact of specific mutations and clone burden on MRD response to induction and subsequent chemotherapy.
- To inform treatment strategies and clinical trial design for AML patients based on molecular profiles.
Main Methods:
- Analysis of pre-treatment next-generation sequencing data from 211 AML patients.
- Serial immunophenotypic monitoring of MRD after induction chemotherapy, subsequent therapy, and allogeneic stem cell transplant (allo-SCT).
- Correlation of genetic mutations and karyotypic abnormalities with MRD remission rates.
Main Results:
- Induction chemotherapy achieved MRD- remission in 35% of patients.
- Subsequent therapy converted 34% of MRD+ and 26% of persistent disease patients to MRD-.
- Mutations in CEBPA, NRAS, KRAS, NPM1 predicted high MRD- remission rates, while TP53, SF3B1, ASXL1, RUNX1 mutations and specific karyotypic abnormalities predicted low rates.
- Fewer individual clones were associated with higher likelihood of MRD- remission.
- Early or later MRD- achieved before allo-SCT correlated with favorable outcomes.
Conclusions:
- Specific pre-treatment molecular alterations and higher clone numbers are associated with poor MRD clearance with standard chemotherapy.
- Patients with unfavorable molecular profiles may benefit from early enrollment in clinical trials evaluating novel therapeutic strategies.
- Understanding molecular predictors of MRD response can guide personalized treatment approaches in AML.
