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
Author(s): ,
Bruno Paiva
Affiliations:
Hematology,University of Navarra,Pamplona,Spain
,
David Martínez-Cuadrón
Affiliations:
Hematology,Hospital Universitario y Politécnico La Fe,Valencia,Spain
,
Juan Miguel Bergua
Affiliations:
Hematology,Hospital San Pedro de Alcántara,Cáceres,Spain
,
Susana Vives
Affiliations:
Hematology,Hospital Germans Trias i Pujol,Badalona,Spain
,
Lorenzo Algarra
Affiliations:
Hematology,Hospital General de Albacete,Albacete,Spain
,
Mar Tormo
Affiliations:
Hematology,Hospital Clínico Universitario de Valencia,Valencia,Spain
,
Pilar Martinez
Affiliations:
Hematology,Hospital Universitario 12 de Octubre,Madrid,Spain
,
Josefina Serrano
Affiliations:
Hematology,Hospital Reina Sofía,Cordoba,Spain
,
Pilar Herrera
Affiliations:
Hematology,Hospital Universitario Ramón y Cajal,Madrid,Spain
,
Fernando Ramos
Affiliations:
Hematology,Hospital Universitario de León,Léon,Spain
,
Olga Salamero
Affiliations:
Hematology,Hospital Universitario Vall d'Hebrón,Barcelona,Spain
,
Esperanza Lavilla
Affiliations:
Hospital Lucus Augusti,Lugo,Spain
,
Cristina Gil
Affiliations:
Hospital General Universitario de Alicante,Alicante,Spain
,
Jose Luis Lopez
Affiliations:
Fundación Jiménez Díaz,Madrid,Spain
,
Maria Belen Vidriales
Affiliations:
Hospital Clínico Universitario de Salamanca,Salamanca,Spain
,
Jorge Labrador
Affiliations:
Hospital Universitario de Burgos,Burgos,Spain
,
Jose Francisco Falantes
Affiliations:
Complejo Hospitalario Virgen del Rocío,Sevilla,Spain
,
María José Sayas
Affiliations:
Hospital Dr. Peset,Valencia,Spain
,
Juana Merino
Affiliations:
Clinica Universidad de Navarra,Pamplona,Spain
,
Ana Alfonso
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
Felipe Prosper
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
Jesus San Miguel
Affiliations:
Clínica Universidad de Navarra,Pamplona,Spain
,
Miguel Angel Sanz
Affiliations:
Hospital Universitario y Politécnico La Fe,Valencia,Spain
Pau Montesinos
Affiliations:
Hospital Universitario y Politécnico La Fe,Valencia,Spain
EHA Library. Montesinos P. Jun 14, 2019; 266006; PF216
Pau Montesinos
Pau Montesinos
Contributions
Abstract

Abstract: PF216

Type: Poster Presentation

Presentation during EHA24: On Friday, June 14, 2019 from 17:30 - 19:00

Location: Poster area

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 <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 <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%, <0.1% and MRD-negative patients were 95%, 74% and 45%, respectively (HR, 0.45; p<.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%, <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).

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.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

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