-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

973 Post-Hoc Analysis of Measurable Residual Disease from BMT-CTN 1506/Morpho: FLT3-ITD Variant Allele Frequency and Survival Are Highly CorrelatedClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Response Predictors to Targeted Therapies and Transplant
Hematology Disease Topics & Pathways:
AML, Acute Myeloid Malignancies, clinical trials, Research, Clinical Research, drug development, Diseases, Therapies, Myeloid Malignancies, Minimal Residual Disease
Monday, December 11, 2023: 4:30 PM

Mark J. Levis, MD, PhD1, Mehdi Hamadani, MD2, Brent R. Logan, PhD3*, Richard J. Jones, MD4, Anurag K. Singh, MD5, Mark R. Litzow, MD6, John R. Wingard, MD7, Esperanza B. Papadopoulos, MD8, Alexander Perl9, Robert J. Soiffer, MD10, Celalettin Ustun, MD11, Masumi Ueda Oshima, MD12, Geoffrey L Uy, MD13, Edmund K. Waller, MD14, Sumithira Vasu, MD, MBBS15, Melhem M. Solh, MD16, Asmita Mishra, MD, MBA17, Lori S. Muffly, MD18, Hee-Je Kim19*, Matthias Stelljes, MD20, Yuho Najima, MD, PhD21, Masahiro Onozawa, M.D., Ph.D.22, Kirsty Thomson, MB ChB23*, Arnon Nagler, MD, M.Sc24*, Andrew H. Wei, MBBS, PhD25, Guido Marcucci, MD26, Nahla Hasabou, MD27*, Mathew Rosales, PhD27*, Jason Hill, PhD27*, Stanley C. Gill, PhD27*, Rishita Nuthethi, PhD27*, Denise King, MS, CCRA28*, Heather Wittsack, MPH28*, Adam Mendizabel, PhD28*, Steven M. Devine, MD29, Mary M. Horowitz, MD30 and Yi-Bin Chen, MD, MS31

1Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, MD
2Division of Hematology and Oncology, The Medical College of Wisconsin Inc, Milwaukee, WI
3Division of Biostatistics, Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, WI
4Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD
5University of Kansas Medical Center, Westwood, KS
6Division of Hematology, Mayo Clinic, Rochester, MN
7University of Florida Division of Hematology/Oncology, Gainesville, FL
8Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
9Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
11Rush University Medical Center, Chicago, IL
12University Hospitals Case Medical Center, Seattle, WA
13Division of Oncology, Washington University School of Medicine, Saint Louis, MO
14Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA
15Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
16Northside Hospital, Atlanta, GA
17Moffitt Cancer Center, Tampa, FL
18Division of Blood and Marrow Transplantation & Cellular Therapy, Stanford University School of Medicine, Palo Alto, CA
19Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Seoul, Korea, Republic of (South)
20Department of Internal Medicine A, University of Muenster, Muenster, Germany
21Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, TKY, Japan
22Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
23UCLH, London, GBR
24Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center,, Tel-Hashomer, Israel
25Peter Maccallum Cancer Centre, Melbourne, VIC, Australia
26Department of Hematologic Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA
27Astellas Pharma Global Development, Northbrook, IL
28The Emmes Corporation, Rockville, MD
29Be the Match Foundation, Minneapolis, MN
30Center for International Blood and Marrow Transplant Research, Milwaukee, WI
31Massachusetts General Hospital, Boston, MA


BMT CTN 1506/MORPHO was a randomized study of the FLT3 inhibitor gilteritinib versus placebo as post-transplant (HCT) maintenance therapy for patients (pts) with FLT3-ITD acute myeloid leukemia (AML). Patients with FLT3-ITD AML in first remission underwent HCT and then were randomized, in double-blind fashion, to either gilteritinib or placebo for 24 months. The primary endpoint was relapse-free survival (RFS), and a pre-specified secondary endpoint was the effect of measurable residual disease (MRD) on survival as detected by a highly sensitive assay for FLT3-ITD mutations. In the primary analysis, while RFS was higher for pts randomized to gilteritinib, the difference did not reach the pre-determined threshold for significance (HR: 0.679; 95% CI: 0.459, 1.005; 2-sided p-value: 0.0518). However, in the secondary analysis, the 50.6% of pts who had MRD detectable pre- or post-HCT had significantly higher RFS with gilteritinib (HR of relapse or death=0.515, 95% CI: 0.316, 0.838, p = 0.0065). In this post-hoc analysis, we examined 1) the impact on RFS of different levels of FLT3-ITD variant allele frequency (VAF) pre-randomization (immediately before or after HCT but prior to randomization to gilteritinib or placebo); 2) the impact of the presence of multiple mutations detected as MRD pre-HCT; and 3) the eradication of FLT3-ITD clones detected post-HCT during follow up on gilteritinib or placebo.


First-pull marrow aspirates were collected from pts at two time points pre-randomization (pre-HCT and between 30-90 days post-HCT), as well as at 3, 6, 12, 18, and 24 months post-randomization. For MRD detection (performed at Invivoscribe; San Diego, CA), 700 ng input DNA was amplified by polymerase chain-reaction (PCR) using 25 cycles and primers flanking exons 14 and 15 of FLT3, followed by next-generation sequencing (NGS) analysis of the amplicons. Variant allele frequency (VAF) was calculated as FLT3 mutant reads/total FLT3 reads. For pts with multiple FLT3-ITD mutations, the VAF used in analysis was the sum of the VAFs for each FLT3-ITD variant. The lower limit of blank (LOB) of the assay is estimated to be 1 x 10-6 VAF. For terminology, VAF > 1 x 10-6 and < 1 x 10-5 is referred to as MRD6, VAF > 1 x 10-5 and < 1 x 10-4 is MRD5, VAF > 1 x 10-4 or greater is MRD4, and MRD0 equals no detectable MRD.


MRD was evaluated in 350/356 (98.3%) pts pre-HCT and 347/356 (97.5%) pts post-HCT. MRD was detected in 46% of pts pre-HCT and 19.9% prior to randomization, including 4.5% who did not have detectable MRD pre-HCT. The variant allele frequency (VAF) of detectable MRD ranged from a low of 1.09 x 10-6 to a high of 3.0 x 10-1. More than a single mutation was detected in 51 pts pre-HCT. Most of these 51 pts had 2 clones, but the total ranged from 2-9. The presence of more than one mutation detected as MRD immediately pre-HCT was associated with worse RFS compared with all other pts (MRD-positive with only one clone and MRD-negative), irrespective of treatment arm (Figure 1A; HR=2.428, 95% CI: 1.555, 3.792, P < 0.001). There was no significant difference in age, mutation length, VAF, or karyotype between pts with more than one mutation and those with single mutations. However, if the VAFs of pts with multiple FLT3-ITD mutations were summed and treated as a single value, then the median VAF for pts with multiple mutations was higher than for those with single mutations (2.14 x 10-4 vs. 3.12 x 10-5). The VAF (including the summed VAFs of pts with multiple mutations) at multiple levels correlated very closely with RFS after HCT. To illustrate this quantitative effect of peri-HCT FLT3-ITD VAF on RFS, Kaplan-Meier analysis of pts on the placebo arm grouped by MRD level is displayed in Figure 1B. In the 71 pts with MRD detectable post-HCT, the MRD was eradicated in 69% of pts on gilteritinib versus 44% of pts on placebo.


Pts with multiple FLT3-ITD mutations have a worse prognosis, which may simply be a reflection of increased disease burden (VAF). The quantity of FLT3-ITD MRD appears to highly correlate with outcome. Gilteritinib appears to augment the effect of HCT, as evidenced by increased eradication of MRD post-HCT. These data illustrate the potential utility of the PCR-NGS FLT3-ITD MRD assay in the management of pts with FLT3-ITD AML.

Disclosures: Levis: Daiichi-Sankyo: Consultancy; Bristol Myers Squibb: Consultancy; Abbvie: Consultancy; Jazz: Consultancy; Astellas Global Pharma: Research Funding; FujiFilm: Research Funding; Amgen: Consultancy; Menarini: Consultancy; Takeda: Consultancy; Pfizer: Consultancy. Hamadani: Gamida Cell: Consultancy; BeiGene: Speakers Bureau; Incyte: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Caribou: Consultancy; Bristol Myers Squibb: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy; Omeros: Consultancy; CRISPR: Consultancy; Genmab: Consultancy; AstraZeneca: Speakers Bureau; Genmab: Consultancy; Kadmon: Consultancy; Legend Biotech: Consultancy; MorphoSys: Consultancy; Novartis: Consultancy; SeaGen: Consultancy; Astra Zeneca: Speakers Bureau; BeiGene: Speakers Bureau; Sanofi Genzyme: Speakers Bureau; Astellas: Research Funding; Spectrum Pharmaceuticals: Research Funding; Takeda: Research Funding; Genentech: Honoraria; Myeloid Therapeutics: Honoraria. Logan: Enlivex: Consultancy. Wingard: Takeda: Consultancy; F2G: Consultancy; Celgene: Consultancy; Cidara: Consultancy; Orca: Consultancy. Perl: Forma: Consultancy; BerGen Bio: Honoraria; FujiFilm: Research Funding; Syndax: Research Funding; Beat AML: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Foghorn: Consultancy; Immunogen: Honoraria; Aptose: Honoraria; Bayer: Research Funding; Genentech: Honoraria; Rigel: Honoraria; Actinium: Honoraria; BMS: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Soiffer: NMPD – Be the Match, USA: Membership on an entity's Board of Directors or advisory committees; Jasper: Consultancy; Smart Immune: Consultancy; Neovii: Consultancy; Astellas: Consultancy; Vor Bipharma: Consultancy; Juno Therapeutics/ BMS/Celgene USA: Other: Data Safety Monitoring Board; Bluesphere Bio: Consultancy. Uy: Jazz: Other: Advisory Board. Waller: CSL Behring: Consultancy, Research Funding; ORCA: Research Funding; BMS: Research Funding; Sanofi: Research Funding; NCI R01: Research Funding; PartnersTherapeutics: Research Funding; Cambium Medical Technologies: Current equity holder in private company, Other: Founder; Cambium Oncology: Current equity holder in private company, Other: Founder; Secura: Research Funding; Allovir: Consultancy; Verastem: Consultancy, Research Funding; CRISPR: Consultancy; Novartis: Consultancy, Research Funding. Vasu: Sanofi Inc: Research Funding; Omeros Inc: Research Funding. Solh: Bristol-Myers Squibb: Speakers Bureau. Muffly: autolus: Consultancy; kite: Consultancy, Honoraria, Research Funding; pfizer: Consultancy; amgen: Consultancy; bms: Research Funding; jasper: Research Funding; adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; astellas: Consultancy, Research Funding; orca bio: Research Funding. Kim: AIS biosicienc: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BL & H: Research Funding; Sanofi: Consultancy, Honoraria; Meiji Pharm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Boryung Pharm Co.: Consultancy, Honoraria; AML-Hub: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Daiichi-Sankyo: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Greencross Pharm: Consultancy, Honoraria; LG Chem: Consultancy, Honoraria. Najima: Daiichi Sankyo Co. Ltd.: Consultancy, Speakers Bureau; Sumitomo Pharma Co., Ltd.: Speakers Bureau; Takeda Pharmaceutical Company Limited.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Novartis Pharma K.K.: Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Kyowa Kirin Co., Ltd.: Speakers Bureau; AbbVie GK: Speakers Bureau; CSL Behring K.K.: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Speakers Bureau; Bristol-Myers Squibb K.K.: Speakers Bureau; Amgen Inc.: Speakers Bureau; Astellas Pharma Inc.: Consultancy, Speakers Bureau. Wei: Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Patents & Royalties: MCL1 use, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Beigene: Consultancy, Honoraria; Shoreline: Consultancy; Aculeus: Consultancy; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Syndax: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Marcucci: Ostentus Therapeutics: Current equity holder in private company, Research Funding. Hasabou: Astellas Pharma Global Development: Current Employment. Rosales: Astellas Pharma Global Development: Current Employment. Hill: Astellas Pharma Global Development: Current Employment. Gill: Astellas Pharma Global Development: Current Employment. Nuthethi: Astellas Pharma Global Development: Current Employment.

OffLabel Disclosure: Gilteritinib is currently approved only for relapsed/refractory FLT3-mutated AML. This trial explores its use as post-transplant maintenance.

Previous Abstract | Next Abstract >>
*signifies non-member of ASH