Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical trial

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Simoes, C; Paiva, B; Martinez-Cuadron, D; Bergua, JM; Vives, S; Algarra, L; Tormo, M; Martinez, P; Serrano, J; Herrera, P; Ramos, F; Salamero, O; Lavilla, E; Gil, C; Lopez, JL; Vidriales, MB; Labrador, J; Falantes, JF; Sayas, MJ; Ayala, R; Martinez-Lopez, J; Villar, S; Calasanz, MJ; Prosper, F; San-Miguel, JF; Sanz, MA; Montesinos, P
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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.