Measurable residual disease and posttransplantation gilteritinib maintenance for patients with <i>FLT3-ITD</i>–mutated AML
Abstract
Abstract BMT CTN (Blood and Marrow Transplant Clinical Trials Network) 1506 (“MORPHO”) was a randomized study of gilteritinib compared with placebo as maintenance therapy after hematopoietic cell transplantation (HCT) for patients with FLT3-ITD–mutated acute myeloid leukemia (AML). A key secondary end point was to determine the impact on survival of before and/or after HCT measurable residual disease (MRD), as determined using a highly sensitive assay for FLT3-ITD mutations. Generally, gilteritinib maintenance therapy was associated with improved relapse-free survival (RFS) for participants with detectable peri-HCT MRD, whereas no benefit was evident for those lacking detectable MRD. We conducted a post hoc analysis of the data and found that the level of MRD detected with this approach correlated remarkably with RFS and relapse risk, and that MRD detectable at any level negatively affected RFS. In the placebo arm, 42.2% of participants with detectable FLT3-ITD MRD relapsed compared with 13.4% of those without detectable MRD. We found that 14.8% of participants had multiple FLT3-ITD clones detected as MRD and had worse survival irrespective of treatment arm. Finally, we examined the kinetics of FLT3-ITD clonal relapse or eradication and found that participants on the placebo arm with detectable MRD relapsed rapidly after HCT, often within a few weeks. MRD-positive participants on the gilteritinib arm relapsed either with FLT3 wild-type clones (assessed by capillary electrophoresis), after cessation of gilteritinib with persistent MRD, or on progression of multiclonal disease. These data demonstrate the potential of FLT3-ITD MRD to guide therapy with gilteritinib for this subtype of AML. This trial was registered at www.clinicaltrials.gov as #NCT02997202.
Article Details
Authors (37)
Mark J. Levis
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Mehdi Hamadani
12Blood and Marrow Transplant and Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, WI
Brent R. Logan
2Division of Hematology and Oncology, Department of Medicine, Center for International Blood and Marrow Transplant Research/Medical College of Wisconsin, Milwaukee, WI
Richard J. Jones
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine
Anurag K. Singh
3Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas, Kansas City, KS
Mark R. Litzow
Mayo Clinic
John R. Wingard
5Department of Medicine, University of Florida, Gainesville, FL
Esperanza B. Papadopoulos
6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Alexander E. Perl
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Robert J. Soiffer
Dana-Farber Cancer Institute
Celalettin Ustun
9Rush University, Chicago, United States
Masumi Ueda Oshima
10Fred Hutchinson Cancer Center, Seattle, United States
Geoffrey L. Uy
Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States
Edmund K. Waller
Sumithira Vasu
29Department of Internal Medicine, The Ohio State University, Columbus, OH
Melhem Solh
14Bone marrow Transplant Group of Georgia, Atlanta, United States
Asmita Mishra
H. Lee Moffitt Cancer Center and Research Institute, TAMPA, Florida, United States
Lori S. Muffly
Stanford University School of Medicine
Hee-Je Kim
17Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
Matthias Stelljes
16Department of Medicine A, University Hospital Münster, Münster, Germany
Yuho Najima
Masahiro Onozawa
20Hokkaido University Hospital, Sapporo, Japan
Kirsty Thomson
21University College Hospital, London, United Kingdom
Arnon Nagler
3Division of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel HaShomer, Ramat Gan, Israel
Andrew H. Wei
Guido Marcucci
Caroline Chen
Department of Chemistry, University of California 1 , Berkeley, California 94720,
Nahla Hasabou
22Astellas Pharma Global Development, Inc, Northbrook, United States
Matt Rosales
Oncology Global Development, Astellas Pharma, Northbrook, IL
Jason Hill
Dept. Bioproducts and Biosystems Engineering, University of Minnesota
Stanley C. Gill
Astellas Pharma, Northbrook, IL
Rishita Nuthethi
22Astellas Pharma Global Development, Inc, Northbrook, United States
Denise King
23The Emmes Company, Rockville, United States
Adam Mendizabal
23The Emmes Company, Rockville, United States
Steven M. Devine
27National Marrow Donor Program, Minneapolis, MN
Mary M. Horowitz
2Division of Hematology and Oncology, Department of Medicine, Center for International Blood and Marrow Transplant Research/Medical College of Wisconsin, Milwaukee, WI
Yi-Bin Chen
1Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA