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Randomized Controlled Trial
. 2025 Oct 28;9(20):5123-5133.
doi: 10.1182/bloodadvances.2025016306.

Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia

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 , Caroline Chen  22 , Nahla Hasabou  22 , Matt Rosales  22 , Jason E Hill  22 , Stanley C Gill  22 , Rishita Nuthethi  22 , Denise King  23 , Adam Mendizabal  23 , Steven M Devine  24 , Mary M Horowitz  2 , Yi-Bin Chen  25
Affiliations
Randomized Controlled Trial

Impact of transplant conditioning, NPM1 mutations, and measurable residual disease in FLT3-ITD acute myeloid leukemia

Mark J Levis et al. Blood Adv. .

Abstract

We conducted a post hoc analysis of data from Blood and Marrow Transplant Clinical Trials Network 1506 (MORPHO), a randomized trial of gilteritinib vs placebo as posttransplantation maintenance for patients with FLT3-ITD-mutated acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT), focusing the interactions between conditioning regimen intensity, measurable residual disease (MRD), and NPM1 comutation status reported from diagnosis. Comparing FLT3-ITD MRD before and after conditioning, there was no difference between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in eradication or reduction of FLT3-ITD MRD. For participants who were FLT3-ITD MRD negative before HCT, there was no difference in the cumulative incidence of relapse during follow-up between those receiving MAC vs RIC. NPM1 comutation was associated with the largest magnitude of relapse-free survival benefit from post-HCT gilteritinib, and in these participants, post-HCT gilteritinib in the setting of RIC appeared to be as effective as MAC at preventing relapse. MAC appeared superior to RIC in preventing relapse only in participants who were NPM1 wild type at diagnosis and FLT3-ITD MRD positive before HCT. Our findings suggest that only a subset of patients with FLT3-ITD AML undergoing HCT may benefit from MAC and that, similar to AML therapy before HCT, the intensity of the HCT regimen should be adapted according to the molecular features of the disease. 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 consulting or advisory role fees from Daiichi-Sankyo, Amgen, Astellas Pharma, Bristol Myers Squibb (BMS), AbbVie/Genentech, GlaxoSmithKline, Syndax, and Takeda; expert testimony fees from Novartis; research funding from Astellas Pharma (to institution [Inst]); and travel, accommodation, and expenses from Astellas Pharma. M.H. received honoraria from Celgene; consulting or advisory role fees from 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; speakers' bureau fees from Genzyme, AstraZeneca, BeiGene, ADC Therapeutics, and Kite/Gilead; and research funding from Takeda, Spectrum Pharmaceuticals, Otsuka, Astellas Pharma, and Genzyme. M.R.L. received honoraria, speakers' bureau fees, and travel, accommodation, and expenses from BeiGene Shanghai and Amgen; received research funding from Amgen, Astellas Pharma, Actinium Pharmaceuticals, and Syndax; and reports other expenses with BioSight. J.R.W. reports consulting or advisory role fees from Shire, Celgene, Cidara Therapeutics, F2G, and ORCA Therapeutics. E.B.P. reports employment with Biogen, Exelixis, Regulus Therapeutics, Graviton Bioscience Corp, and EpiKast; leadership roles for Biogen, Exelixis, and Regulus Therapeutics; stock and other ownership interests with Biogen, Exelixis, Regulus Therapeutics, Apellis Pharmaceuticals, Leap Therapeutics, and Actio Biosciences Inc; consulting or advisory role fees from Actio Biosciences; research funding from AbbVie; and travel, accommodation, and expenses from Biogen, Exelixis, and Regulus Therapeutics. A.E.P. received honoraria from Astellas Pharma and Daiichi Sankyo; consulting or advisory role fees from Astellas Pharma, Actinium Pharmaceuticals, Daiichi Sankyo, AbbVie, FORMA Therapeutics, Sumitomo Dainippon, Celgene/BMS, Syndax, Genentech, BerGenBio, Immunogen, Foghorn Therapeutics, Rigel, and Curis; research funding from Astellas Pharma (Inst), Bayer (Inst), Daiichi Sankyo (Inst), Fujifilm (Inst), AbbVie (Inst), and Syndax (Inst); and travel, accommodation, and expenses from Daiichi Sankyo. R.J.S. reports leadership roles with Kiadis Pharma and Be the Match/National Marrow Donor Program; consulting or advisory role fees from Juno Therapeutics, Gilead Sciences, Rheos Medicines, Cugene, Jazz Pharmaceuticals, Precision Biosciences, Takeda, Jasper Therapeutics, Alexion Pharmaceuticals, Neovii, Vor Biopharma, Smart Immune, and Bluesphere Bio; expert testimony fees from Pfizer; and travel, accommodation, and expenses from Gilead Sciences. C.U. reports employment with Takeda and Blueprint Medicines; received honoraria from Novartis and Blueprint Medicines; and received speakers' bureau fees from Novartis. G.L.U. reports consulting or advisory role fees from Jazz Pharmaceuticals. E.K.W. reports leadership roles for Cambium Medical Technologies and Cambium Oncology; stock and other ownership interests with Cambium Medical Technologies, Cambium Oncology, Cerus, and Chimerix; honoraria from Novartis, Verastem, Kite (a Gilead Company), Pharmacyclics, Karyopharm Therapeutics, Sanofi, and Janssen Oncology; consulting or advisory role fees from Novartis, Verastem, Pharmacyclics, Karyopharm Therapeutics, Partners Healthcare, Kite (a Gilead Company), Cambium Medical Technologies, Alimera Sciences, and Sanofi; research funding from Novartis, Amgen, Juno Therapeutics, Verastem, Partners Healthcare, and Sanofi; royalties from patent on preparing platelet lysate that has been licensed to Cambium Medical Technologies; and travel, accommodation, and expenses from Janssen Oncology. S.V. reports consulting or advisory role fees from Omeros and Johnson & Johnson; and research funding from Sanofi (Inst). M. Stelljes received speakers' bureau fees from BMS, Amgen, Seagen, and GlaxoSmithKline; and research funding from Partner Therapeutics. A. Mendizabal received research funding from Novartis. L.S.M. reports stock and other ownership interests with Corvus Pharmaceuticals; honoraria from UpToDate; consulting or advisory role fees from Amgen, Medexus Pharmaceuticals, Astellas Pharma, Kite (a Gilead Company), and CTI BioPharma Corp; and 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, Handok, Novartis, Aston Sci, Amgen, Takeda, Green Cross, AIM BioSciences, Astellas Pharma, Jazz Pharmaceuticals, Janssen, LG Chem, Pfizer, ViGen Cell, Ingenium, Sanofi, Meiji Seika Pharma, and MSD; consulting or advisory role fees from Jazz Pharmaceuticals, Novartis, AbbVie, Astellas Pharma, MSD, BMS, Takeda, Sanofi, Handok, and AML-Hub; and speakers' bureau fees from Jazz Pharmaceuticals, Takeda, and Novartis. M. Sohl reports consulting or advisory roles with Pfizer, MSD, BMS, Incyte, Takeda, Astellas, and Amgen; speakers’ bureau fees from Pfizer, Medac, MSD, Astellas, Jazz Pharmaceuticals, Amgen, Novartis, Gilead, Celgene, BMS, AbbVie, and Incyte; research funding from Pfizer; and travel support from Medac and Pfizer. Y.N. reports consulting or advisory role fees from Daiichi Sankyo/UCB Japan and Astellas Pharma; and speakers' bureau fees from Astellas Pharma, Daiichi Sankyo/UCB Japan, AbbVie, Amgen, BMS Japan, Chugai Pharmaceutical, CSL Behring, Janssen Pharmaceutical, Kyowa, Nippon Shinyaku, Novartis, Otsuka, Sumitomo Pharma Oncology, Takeda, MSD, and JCR Pharmaceuticals. M.O. received honoraria from Astellas Pharma; and speakers' bureau fees from Astellas Pharma, Daiichi Sankyo, Otsuka, and Novartis. C.C., N.H., M.R., J.E.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. reports consulting or advisory role fees from Medac (Inst); and research funding from Jazz Pharmaceuticals (Inst), Novartis (Inst), Sanofi (Inst), Astellas Pharma (Inst), Xenikos (Inst), and Gamida Cell (Inst). Y.-B.C. reports leadership role with ImmunoFree; stock and other ownership interests with ImmunoFree; consulting or advisory role fees from Magenta Therapeutics, Incyte, Novo Nordisk, Editas Medicine, Alexion Pharmaceuticals, Astellas Pharma, Takeda, Pharmacosmos, and Vor Biopharma. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Comparison of pre- and post-HCT MRD levels according to conditioning intensity. (A) Results for participants with any level of detectable FLT3-ITD MRD. (B) Results for participants with FLT3-ITD MRD VAF of ≥1 × 10–4. (C) Results for participants with detectable MRD but VAF <1 × 10–4. pts, patients; VAF, variant allele frequency.
Figure 2.
Figure 2.
Cumulative incidence of relapse according to conditioning intensity, MRD, and randomization arm. (A) Pre-HCT FLT3-ITD MRD negative; placebo arm; MAC vs RIC. (B) Pre-HCT FLT3-ITD MRD positive; placebo arm; MAC vs RIC. (C) Pre-HCT FLT3-ITD MRD negative; gilteritinib arm; MAC vs RIC. (D) Pre-HCT FLT3-ITD MRD positive; gilteritinib arm; MAC vs RIC. HR, hazard ratio.
Figure 3.
Figure 3.
RFS for participants according to peri-HCT MRD, NPM1 comutation at initial diagnosis, and randomization arm. (A) NPM1 comutation; gilteritinib vs placebo. (B) NPM1 comutation; peri-HCT MRD positive; gilteritinib vs placebo. (C) NPM1 comutation; peri-HCT MRD negative; gilteritinib vs placebo. (D) NPM1 wild type; gilteritinib vs placebo. (E) NPM1 wild type; peri-HCT MRD positive; gilteritinib vs placebo. (F) NPM1 wild type; peri-HCT MRD negative; gilteritinib vs placebo. HR, hazard ratio.
Figure 4.
Figure 4.
RFS for participants according to NPM1 comutation status and conditioning intensity. HR, hazard ratio.
Figure 5.
Figure 5.
Cumulative incidence of relapse for participants according to pre-HCT MRD status, NPM1 comutation status, and conditioning intensity. HR, hazard ratio.
Figure 6.
Figure 6.
Flow chart for suggested management of FLT3-ITD AML, incorporating MRD, NPM1 mutation status, and relative fitness of the patient. CR1, first remission.
See this image and copyright information in PMC

Comment in

References

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