PF216 ROLE OF MEASURABLE RESIDUAL DISEASE (MRD) IN REDEFINING COMPLETE RESPONSE (CR) IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PETHEMA‐FLUGAZA PHASE III CLINICAL TRIAL
Authors: B. Paiva, D. Martínez‐Cuadrón, J.M. Bergua, S. Vives, L. Algarra, M. Tormo, P. Martinez, J. Serrano, P. Herrera, F. Ramos, O. Salamero, E. Lavilla, C. Gil, J.L. Lopez, M.B. Vidriales, J. Labrador, J.F. Falantes, M.J. Sayas, J. Merino, A. Alfonso, F. Prosper, J. San Miguel, M.A. Sanz, P. Montesinos
Journal: HemaSphere (2019)

Background: The general outcome of elderly patients with AML is poor, even for those achieving morphological CR. However, the role of MRD in redefining CR remains poorly investigated in elderly AML due to the reluctance of treating with intensive chemotherapy and the renewed interest in low‐intensity therapy such as hypomethylating agents (HMA). Aims: To help defining the role of MRD assessment by multidimensional flow cytometry (MFC) and therapeutic decision making in older AML patients treated with semi‐intensive chemotherapy vs HMA. Methods: 285 AML patients (median age, 75) were included in the phase 3 PETHEMA‐FLUGAZA trial and were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5‐azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD &lt;0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery. At diagnosis, the EuroFlow AML panel was used to identify leukemia‐associated immunophenotypes (LAIP). At CR, bone marrow samples were stained with 8‐color combinations based on previously identified maturation arrest, lineage commitment and LAIPs. MRD was assessed with an estimated sensitivity of 0.01%. Results: On intention‐to‐treat, 38/141 (27%) patients achieved CR after 3 cycles of FLUGA and 31/144 (21.5%) after 3 cycles of AZA (p = .33). Among patients in CR with previously identified LAIP, 14/69 (20%) achieved a negative MRD status whereas the remaining 55 (80%) had persisting MRD: 56% with ≥0.1% MRD and 24% with &lt;0.1% MRD. Regarding the effect of semi‐intensive chemotherapy vs HMA on depth of response, we observed a non‐significant trend toward higher MRD‐negative rates among patients in CR after FLUGA vs AZA (25% vs 15%, respectively; p = .38). The 2‐year rates of cumulative incidence of relapse (CIR) for MRD‐positive ≥0.1%, &lt;0.1% and MRD‐negative patients were 95%, 74% and 45%, respectively (HR, 0.45; p &lt; .001). Of note, the CIR of patients in CR but persistent MRD were similarly poor as compared to those in partial remission (HR, 1.2; p = .54). Furthermore, MRD‐positive patients with adverse cytogenetics displayed the poorest outcome with significantly higher 2‐year CIR rates than MRD‐positive cases with intermediate/favorable cytogenetics (HR, 2.0; p = .01). Among patients in CR and persistent MRD, 2‐year CIR rates showed a non‐significant trend towards slightly more frequent relapses in those treated with FLUGA vs AZA (91% vs 77%, respectively; HR, 1.6; p = .12). On multivariable analysis for CIR including MFC‐MRD and cytogenetics, both retained significant prognostic value. The median overall survival (OS) for MRD‐positive ≥0.1%, &lt;0.1% and MRD‐negative patients was 13, 12 and 21 months, respectively. On multivariable analyses for OS including age, WBC count, cytogenetic grouping and secondary disease, persistent MRD showed a trend for independent prognostic value (HR, 2.4; p = .08). Summary/Conclusion: This study reveals 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. Nevertheless, the risk of relapse among the few patients with no MRD (5%) remains high after stopping treatment, and warrants innovative approaches aimed at maintaining an MRD‐negative CR status. Updated follow‐up and molecular data will be presented at the meeting.