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ASH 2018 | Defining the role of MRD assessment in elderly patients with acute myeloid leukemia

By Cynthia Umukoro

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Bruno PaivaBruno Paiva

Dec 18, 2018


The significance of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) treated with low-intensive therapies is poorly understood. The phase III Pethema-Flugaza trial aims to help define the role of MRD assessment by multidimensional flow cytometry (MFC) and its impact on therapeutic decision making in older AML patients treated with semi-intensive chemotherapy compared to hypomethylating agents (HMA). The results of this study were presented at the 60th Annual Meeting of the American Society of Hematology (ASH) by Bruno Paiva from the University of Navarra, Pamplona, Spain.

In this phase III study, 285 patients aged over 65 years (median age = 75 years) with AML were randomized to receive either three induction cycles with fludarabine (40 mg/m2/d, days 2–6) and cytarabine (75 mg/m2 subcutaneously, days 2–6), and G-CSF (FLUGA) followed by six consolidation cycles with reduced intensity FLUGA (n = 141) or three induction cycles with 5-azacitidine (AZA, 75 mg/m2 subcutaneously, days 1–7) followed by six consolidation cycles with AZA (n = 144). After consolidation, patients continued with the same treatment if MRD ≥ 0.01% or stopped if MRD < 0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery.

Key findings:

  • Complete remission (CR) rate in the FLUGA and AZA arm: 27% (38/141) vs 22% (31/144), P = 0.33
  • Partial remission (PR) rate or better in the FLUGA and AZA arms: 4% vs 18%, P < 0.001
  • A trend for a higher MRD-negative rate was observed among patients in CR treated with FLUGA compared to those treated with AZA: 25% vs 15%, respectively, P = 0.38
  • 2-year cumulative incidence of relapse (CIR) rate in patients with detectable MRD+ ≥ 10-3, detectable MRD+ ≥10-4 & < 10-3 and MRD-negative patients: 95% vs 74% vs 45%, respectively, HR = 0.45 (95% CI, 0.3–0.7), P < 0.001
  • 2-year CIR rates showed a non-significant trend towards more frequent relapses in patients treated with FLUGA compared to AZA: 91% vs 77%, respectively, HR = 1.7, = 0.09
  • Median overall survival (OS) in in patients with undetectable MRD, CR with detectable MRD and PR, respectively, 21 vs 12 vs 13 months, HR = 0.7 (95% CI, 0.5–1.1), P = 0.12

In summary, MRD below 0.1% confers a significantly higher risk of relapse and inferior survival in elderly patients with AML. The speaker, Bruno Paiva, noted that findings of the phase III PETHEMA-FLUGAZA trial demonstrate that “sensitive MFC-MRD assessment supersedes CR and is an independent prognostic factor in older patients with AML, treated with semi-intensive chemotherapy or HMA.” He further added that the risk of relapse observed in patients with undetectable MRD remains high, hence, innovative approaches are required to maintain MRD-negative CR status.

Watch Bruno Paiva discuss the results of this study in English and Spanish here.

Expert Opinion

Bruno PaivaBruno Paiva

References