Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical
Catia Simoes1,2,3, Bruno Paiva1,2,3, David Martínez-Cuadrón4
1Department of Hematology, Clínica Universidad de Navarra, Pamplona, Spain.
Abstract:
The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase 3 FLUGAZA clinical trial, which randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine (FLUGA) vs 5-azacitidine. After consolidation, patients continued treatment if MRD was ≥0.01% or stopped if MRD was <0.01%, as assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N = 72) was the only independent prognostic factor for relapse-free survival (RFS) (HR, 3.45; P = .002). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR, 0.32; P = .013). Longer overall survival was observed in patients with undetectable MRD after induction though not after consolidation. Although leukemic cells from most patients displayed phenotypic aberrancies vs their normal counterpart (N = 259 of 265), CD34 progenitors from cases with undetectable MRD by MFC carried extensive genetic abnormalities identified by whole-exome sequencing. Interestingly, the number of genetic alterations significantly increased from diagnosis to MRD stages in patients treated with FLUGA vs 5-azacitidine (2.2-fold vs 1.1-fold; P = .001). This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.
Insights
Measurable residual disease (MRD) is a key prognostic factor for relapse-free survival in elderly acute myeloid leukemia (AML) patients after semi-intensive therapy. Achieving undetectable MRD improves outcomes, especially for those with adverse genetics, but enhanced sensitivity is needed for personalized treatment.
Area of Science:
- Hematology
- Oncology
- Clinical Trials
Background:
- The prognostic value of measurable residual disease (MRD) in elderly acute myeloid leukemia (AML) patients varies with treatment type (intensive vs. hypomethylating agents) and is unclear after semi-intensive therapy.
- Elderly AML patients often receive less intensive treatments, making the role of MRD in predicting outcomes crucial.
Purpose of the Study:
- To investigate the prognostic role of MRD in refining complete remission (CR) and guiding treatment duration in elderly AML patients treated with semi-intensive therapy.
- To evaluate MRD's impact on relapse-free survival (RFS) and overall survival (OS) in the context of the FLUGAZA clinical trial.
Main Methods:
- Phase 3 FLUGAZA clinical trial randomized 283 elderly AML patients to fludarabine plus cytarabine (FLUGA) or 5-azacitidine.
- MRD levels were assessed by multidimensional flow cytometry (MFC) after consolidation; treatment continuation was based on MRD status (≥0.01% vs. <0.01%).
- Multivariate analysis, including genetic risk and treatment arm, was performed to identify independent prognostic factors for RFS.
Main Results:
- MRD status in CR patients (N=72) was the sole independent prognostic factor for RFS (HR, 3.45; P=.002).
- Undetectable MRD significantly improved RFS in patients with adverse genetics (HR, 0.32; P=.013).
- Longer OS was observed with undetectable MRD after induction but not consolidation; genetic alterations increased during treatment, particularly with FLUGA.
Conclusions:
- MRD assessment is valuable for refining CR and guiding treatment after semi-intensive therapy or hypomethylating agents in elderly AML.
- Improved MRD detection sensitivity is necessary to individualize treatment strategies and potentially prolong survival in elderly AML patients achieving undetectable MRD.
- Despite phenotypic normality, CD34+ progenitors in MRD-undetectable cases harbor significant genetic abnormalities, highlighting the complexity of minimal residual disease.
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