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Clinical Trial
. 2025 May 8;145(19):2138-2148.
doi: 10.1182/blood.2024025154.

Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML

Mark J Levis  1 , Mehdi Hamadani  2 , Brent R Logan  2 , Richard J Jones  1 , Anurag K Singh  3 , Mark R Litzow  4 , John R Wingard  5 , Esperanza B Papadopoulos  6 , Alexander E Perl  7 , Robert J Soiffer  8 , Celalettin Ustun  9 , Masumi Ueda Oshima  10 , Geoffrey L Uy  11 , Edmund K Waller  12 , Sumithira Vasu  13 , Melhem Solh  14 , Asmita Mishra  15 , Lori S Muffly  16 , Hee-Je Kim  17 , Matthias Stelljes  18 , Yuho Najima  19 , Masahiro Onozawa  20 , Kirsty Thomson  21 , Arnon Nagler  22 , Andrew H Wei  23 , Guido Marcucci  24 , Caroline Chen  25 , Nahla Hasabou  25 , Matt Rosales  25 , Jason Hill  25 , Stanley C Gill  25 , Rishita Nuthethi  25 , Denise King  26 , Adam Mendizabal  26 , Steven M Devine  27 , Mary M Horowitz  2 , Yi-Bin Chen  28
Affiliations
Clinical Trial

Measurable residual disease and posttransplantation gilteritinib maintenance for patients with FLT3-ITD-mutated AML

Mark J Levis et al. Blood. .

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.

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Conflict of interest statement

Conflict-of-interest disclosure: M.J.L. reports a consulting or advisory role with Daiichi Sankyo, Amgen, Astellas Pharma, Bristol Myers Squibb (BMS), AbbVie/Genentech, GlaxoSmithKline, Syndax, Takeda; reports expert testimony with Novartis; reports research funding from Astellas Pharma (to institution); and received travel, accommodations, and expenses from Astellas Pharma. M.H. reports honoraria from Celgene; reports consulting or advisory role with Incyte, ADC Therapeutics, Puma Biotechnology, Verastem, Kite/Gilead, MorphoSys, Omeros, Novartis, Gamida Cell, Seagen, Genmab, Myeloid Therapeutics, BeiGene, AstraZeneca, Sanofi, BMS/Celgene, CRISPR Therapeutics, Caribou Biosciences, AbbVie, and Genentech; reports speakers bureau participation with Genzyme, AstraZeneca, BeiGene, ADC Therapeutics, and Kite/Gilead; and reports research funding from Takeda, Spectrum Pharmaceuticals, Otsuka, Astellas Pharma, and Genzyme. M.R.L. reports honoraria from BeiGene Shanghai and Amgen; reports speakers bureau participation with BeiGene Shanghai and Amgen; report research funding from Amgen, Astellas Pharma, Actinium Pharmaceuticals, Syndax; received travel, accommodations, and expenses from BeiGene Shanghai and Amgen; and reports other relationship with Biosight. J.R.W. reports consulting or advisory role with Shire, Celgene, Cidara Therapeutics, F2G, and ORCA Therapeutics. E.B.P. reports employment with Biogen, Exelixis, Regulus Therapeutics, Graviton Bioscience Corp, and EpiKast; reports leadership with Biogen, Exelixis, and Regulus Therapeutics; reports stock and other ownership interests with Biogen, Exelixis, Regulus Therapeutics, Apellis Pharmaceuticals, Leap Therapeutics, and Actio Biosciences Inc; reports consulting or advisory role with Actio Biosciences; received research funding from AbbVie; and received travel, accommodations, and expenses from Biogen, Exelixis, and Regulus Therapeutics. A.E.P. received honoraria from Astellas Pharma, and Daiichi Sankyo; served in a consulting or advisory role with Astellas Pharma, Actinium Pharmaceuticals, Daiichi Sankyo, AbbVie, Forma Therapeutics, Sumitomo Dainippon, Celgene/BMS, Syndax, Genentech, BerGenBio, Immunogen, Foghorn Therapeutics, Rigel, and Curis; received research funding from Astellas Pharma (to institution), Bayer (to institution), Daiichi Sankyo (to institution), Fujifilm (to institution), AbbVie (to institution), and Syndax (to institution); and received travel, accommodations, and expenses from Daiichi Sankyo. R.J.S. reports leadership role with Kiadis Pharma, Be The Match/National Marrow Donor Program; served in a consulting or advisory role with Juno Therapeutics, Gilead Sciences, Rheos Medicines, Cugene, Jazz Pharmaceuticals, Precision Biosciences, Takeda, Jasper Therapeutics, Alexion Pharmaceuticals, Neovii, Vor Biopharma, Smart Immune, BlueSphere Bio; provided expert testimony for Pfizer; and received travel, accommodations, and expenses from Gilead Sciences. C.U. reports employment with Takeda and Blueprint Medicines; received honoraria from Novartis and Blueprint Medicines; and reports speakers bureau participation with Novartis. G.L.U. served in a consulting or advisory role with Jazz Pharmaceuticals. E.K.W. reports leadership role with Cambium Medical Technologies and Cambium Oncology; reports stock and other ownership interests in Cambium Medical Technologies, Cambium Oncology, Cerus, and Chimerix; received honoraria from Novartis, Verastem, Kite (a Gilead company), Pharmacyclics, Karyopharm Therapeutics, Sanofi, and Janssen Oncology; served in a consulting or advisory role with Novartis, Verastem, Pharmacyclics, Karyopharm Therapeutics, Partners Healthcare, Kite (a Gilead company), Cambium Medical Technologies, Alimera Sciences, and Sanofi; received research funding from Novartis, Amgen, Juno Therapeutics, Verastem, Partners Healthcare, and Sanofi; receives royalties from patent on preparing platelet lysate that has been licensed to Cambium Medical Technologies; and received travel, accommodations, and expenses from Janssen Oncology. S.V. served in a consulting or advisory role with Omeros and Johnson and Johnson; and received research funding from Sanofi (to institution). M. Solh reports speakers bureau participation with BMS, Amgen, Seagen, and GlaxoSmithKline; and received research funding from Partner Therapeutics. A. Mishra received research funding from Novartis. L.S.M. reports stock and other ownership interests in Corvus Pharmaceuticals; received honoraria from UpToDate; served in a consulting or advisory role with Amgen, Medexus Pharmaceuticals, Astellas Pharma, Kite (a Gilead company), and CTI BioPharma Corp; and received research funding from Adaptive Biotechnologies, Astellas Pharma, Jasper Therapeutics, Kite (a Gilead company), and BMS. H.-J.K. received honoraria from AbbVie, AML Hub, BMS, Hando, Novartis, Aston Sci, Amgen, Takeda, Green Cross, AIM ImmunoTech, Astellas Pharma, Jazz Pharmaceuticals, Janssen, LG Chemical, Pfizer, ViGen Cell, Ingenium, Sanofi, Meiji Pharm, and Merck Sharp & Dohme (MSD); served in a consulting or advisory role with Jazz Pharmaceuticals, Novartis, AbbVie, Astellas Pharma, MSD, BMS, Takeda, Sanofi, Handok, and AML Hub; and reports speakers bureau participation with Jazz Pharmaceuticals, Takeda, and Novartis. M. Stelljes served in a consulting or advisory role with Pfizer, MSD, BMS, Incyte, Takeda, Astellas, and Amgen; reports speakers bureau participation with Pfizer, Medac, MSD, Astellas, Jazz Pharmaceuticals, Amgen, Novartis, Gilead, Celgene, BMS, AbbVie, and Incyte; received research funding from Pfizer; and received travel support from Medac and Pfizer. Y.N. served in a consulting or advisory role with Daiichi Sankyo/UCB Pharma Japan, and Astellas Pharma; and reports speakers bureau participation with Astellas Pharma, Daiichi Sankyo/UCB Pharma Japan, AbbVie, Amgen, BMS Japan, Chugai Pharma, CSL Behring, Janssen Pharma, Kyowa, Nippon Shinyaku, Novartis, Otsuka, Sumitomo Pharma Oncology, Takeda, MSD, and JCR Pharmaceuticals. M.O. received honoraria from Astellas Pharma; and reports speakers bureau participation with Astellas Pharma, Daiichi Sankyo, Otsuka, and Novartis. A.H.W. received honoraria from Amgen, Servier, Novartis, Celgene, AbbVie/Genentech, Pfizer, Janssen Oncology, Astellas Pharma, MacroGenics, AstraZeneca, Gilead/Forty Seven, Stemline Therapeutics, and BeiGene; served in a consulting or advisory role with Servier, Novartis, Amgen, AbbVie/Genentech, Celgene, MacroGenics, Pfizer, Astellas Pharma, AstraZeneca, Janssen, Stemline Therapeutics, and BeiGene; reports speakers bureau participation with AbbVie/Genentech, Novartis, Celgene/BMS, Astex Pharmaceuticals, and Servier; received research funding from Novartis (to institution), Celgene (to institution), AbbVie (to institution), AstraZeneca (to institution), Servier (to institution), Amgen (to institution), and Roche (to institution); is a current employee of the Walter and Eliza Hall Institute (WEHI) which receives milestone and royalty payments related to venetoclax, and is eligible for benefits related to these payments; and receives payments from WEHI related to venetoclax. G.M. reports stock and other ownership interests in Ostentus Therapeutics, Inc; reports honoraria from Novartis and AbbVie; and reports speakers bureau participation with Novartis and AbbVie. C.C., N.H., M.R., J.H., S.C.G., and R.N. report employment with Astellas Pharma. S.M.D. reports leadership role with National Marrow Donor Program. M.M.H. served in a consulting or advisory role with Medac (to institution); and received research funding from Jazz Pharmaceuticals (to institution), Novartis (to institution), Sanofi (to institution), Astellas Pharma (to institution), Xenikos (to institution), and Gamida Cell (to institution). Y.-B.C. reports leadership role with ImmunoFree; reports stock and other ownership interests in ImmunoFree; and served in a consulting or advisory role with Magenta Therapeutics, Incyte, Novo Nordisk, Editas Medicine, Alexion Pharmaceuticals, Astellas Pharma, Takeda, Pharmacosmos, and Vor Biopharma. The remaining authors declare no competing financial interests.

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