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437 Minimal Residual Disease (MRD) at Time of Complete Remission Is Commonly Detected in Acute Myeloid Leukemia (AML) Patients Age ≥60 Years and Significantly Impacts Outcome Based on Post-Remission Treatment Strategies: Prospective Analysis of ECOG-ACRIN (E-A) E2906 Phase III Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Clinical Studies: Minimal Residual Disease and Genetic Characterization
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, Non-Biological, Elderly, chemotherapy, Technology and Procedures, Study Population, Clinically relevant, Myeloid Malignancies, flow cytometry
Sunday, December 2, 2018: 5:30 PM
Seaport Ballroom F (Manchester Grand Hyatt San Diego)

James M. Foran, MD1, Zhuoxin Sun, PhD2*, Elisabeth Paietta, PhD3, Janis Racevskis, PhD3*, David F. Claxton, MD4, Hillard M Lazarus, MD5, Daniel A. Arber, MD6, Jacob M. Rowe, MD7, Jessica K. Altman, MD8, Aref Al-Kali, MD9, Hong Zheng, MD, PhD10, Keith W. Pratz, MD11, Edward R. Broun, MD12, Bayard L. Powell, MD13, Kristen Marie O'Dwyer, MD14, John Godwin, MD15, Yanming Zhang, MD16, Martin S. Tallman, MD17, Selina Luger, MD18 and Mark R. Litzow, MD19

1Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic Florida, Jacksonville, FL
2ECOG-ACRIN statistical center, Boston
3Cancer Center, Montefiore Medical Center, Bronx, NY
4Penn State Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, PA
5Adult Hematologic Malignancies & Stem Cell Transplant Section, University Hospitals Seidman Cancer Center, Cleveland, OH
6University of Chicago, Chicago, IL
7The Ruth and Bruce Rappaport Faculty of Medicine, Shaare Zedek Medical Center, Jerusalem, Israel
8Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
9Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Rochester, MN
10Penn State Cancer Institute, Penn State Hershey Medical Center, Hershey, PA
11John Hopkins University, Baltimore, MD
12OHC, Inc., Cincinnati, OH
13Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC
14University of Rochester Medical Center, Rochester, NY
15Providence Portland Medical Center, Portland, OR
16Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
17Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY
18Division of Hematology-Oncology/Department of Medicine, University of Pennsylvania, Philadelphia, PA
19Division of Hematology, Mayo Clinic, Rochester, MN

Background:

The persistence of detectable MRD in complete remission (CR/CRi - CR with incomplete CBC recovery) has been reported to contribute to inferior outcome in younger AML patients (pts) in retrospective studies, however MRD has not been studied prospectively in older adults (age ≥60 yrs) receiving intensive therapy with curative intent. We performed a planned prospective study of MRD status after AML induction therapy in older adults, integrated into the large multicenter ECOG-ACRIN (E-A) E2906 Phase III trial.

Methods

Eligible patients age ≥60 yrs with AML were randomized 1:1 to receive either ‘Standard’ 7&3 (Dauno 60mg/m2) induction, with 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior overall survival (OS) with standard therapy despite similar CR/CRi rates using stringent criteria, and similar 30-day induction mortality rates. Submission of diagnostic & remission bone marrow or peripheral blood samples was protocol mandated for prospective MRD assessment, and analysis was performed in the central E-A Leukemia Translational Research Lab (LTL) using 6-color multiparameter flow cytometry. MRD-positive (MRD+) was defined as ≥0.1%. LTL flow cytometric analysis was done blinded to treatment arm and outcome of patients. Only pt samples collected within +/-6 days of CR/CRi confirmation were included in this analysis. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine the MRD effect on OS and disease-free survival (DFS, relapse or death).

Results

The median follow-up is 47.8 months, and 297 of 685 evaluable patients (43.4%) achieved CR/CRi (Standard 44.6%; CLO 42.0%, p=ns). Remission MRD samples were only available for 147 CR/CRi patients (49.5%), owing to variability in sample viability and AML involvement, collection practices and timing of sample collection at individual sites, and patient/physician decision. 58/147 evaluable CR/CRi patients achieved MRD-negative (MRD-) status (Standard 40.7%, CLO 47.9%, p=0.74). Women (56.9% vs. men 43.1%, p=0.003) were more likely to be MRD-, but there was no other significant difference in MRD status stratified by clinical or disease features. MRD+ status at CR/CRi was associated with significantly inferior OS (p=0.031, Figure 1) and also inferior overall DFS (p=0.02); this was most pronounced for DFS after CLO (Arm B, Figure 2) (p=0.005), but not Standard (Arm A) therapy (p=0.41).

The impact of MRD+ was confirmed on multivariate analysis using Cox Model Fitting, for OS: OS for All MRD+ pts, HR 1.64 (95% CI 1.00-2.68) (p=0.05); OS for Standard (Arm A) MRD+ pts, HR 1.06 (95% CI 0.51-2.21) (p=0.87); and OS for CLO (Arm B) MRD+ pts, HR 2.30 (95% CI 1.05-5.06) (p=0.04). There was a similar impact for DFS on multivariate analysis using Cox Model Fitting: DFS for All MRD+ pts, HR 1.86 (95% CI 1.16-2.98) (p=0.01); DFS for Standard (Arm A) MRD+ pts, HR 1.15 (95% CI 0.60-2.19) (p=0.67); and DFS for CLO (Arm B) MRD+ pts, HR 3.45 (95% CI 1.47-8.09) (p=0.004).

Post-remission therapy was not stratified by MRD in E2906, and 33% of MRD-evaluable pts underwent allogeneic transplantation (no difference in transplant rate for MRD+ vs. MRD-).

Conclusions

MRD+ ≥0.1% is common (60.5%) after induction therapy in older adults & is significantly associated with inferior OS and DFS in 1st CR/CRi. However we observed excellent outcomes for MRD- pts in first CR/CRi regardless of induction regimen or post-remission therapy used. MRD+ pts in CR/CRi who went on to receive CLO consolidation had significantly poorer outcomes than those who went on to receive intermediate dose Ara-C consolidation. This observation differs strikingly from younger AML, and suggests that intensified Ara-C may abrogate the adverse impact of MRD in older pts in CR. These results strongly support incorporation of centralized MRD at the time of remission into future studies to guide optimal post-remission strategies in older pts with AML.

Disclosures: Foran: Merck: Research Funding; Boston Biomedical: Research Funding; Trillium: Research Funding; Stemline Therapeutics: Honoraria; H3 Biomedicine: Research Funding; LLS: Research Funding; H3 Biomedicine: Research Funding; Takeda Millennium: Research Funding; Agios: Research Funding; Xencor, Inc.: Research Funding; AAMDS Foundation: Honoraria; Agios: Research Funding; Jazz Pharmaceuticals: Honoraria; Merck: Research Funding; Trillium: Research Funding; Astellas: Honoraria; Takeda Millennium: Research Funding; Nohla Therapeutics: Research Funding; Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Actinium: Research Funding; Nohla Therapeutics: Research Funding; Actinium: Research Funding; Boehringer-Ingelheim: Research Funding; Boehringer-Ingelheim: Research Funding; Xencor, Inc.: Research Funding; Stemline Therapeutics: Honoraria; Boston Biomedical: Research Funding; AAMDS Foundation: Honoraria; LLS: Research Funding. Lazarus: Pluristem Ltd.: Consultancy. Altman: Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Novartis: Membership on an entity's Board of Directors or advisory committees; GSK: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; Agios: Other: Payment to the institution to conduct the trial ; Incyte: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genetech: Other: Payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work. Al-Kali: Novartis: Research Funding. Pratz: Boston Scientific: Consultancy; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Astellas: Consultancy, Research Funding. Powell: Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tallman: AROG: Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board; Orsenix: Other: Advisory board; AbbVie: Research Funding.

*signifies non-member of ASH