Background:

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.

Methods:

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.

Results:

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.

Conclusions

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.

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:Novartis: Consultancy; SeaGen: Consultancy; MorphoSys: Consultancy; Legend Biotech: Consultancy; Sanofi Genzyme: Speakers Bureau; Myeloid Therapeutics: Honoraria; Genentech: Honoraria; Takeda: Research Funding; Spectrum Pharmaceuticals: Research Funding; Astellas: Research Funding; BeiGene: Speakers Bureau; Astra Zeneca: Speakers Bureau; Kadmon: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Gamida Cell: Consultancy; BeiGene: Speakers Bureau; Kite, a Gilead Company: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Caribou: Consultancy; Bristol Myers Squibb: Consultancy; Genmab: Consultancy; CRISPR: Consultancy; Omeros: Consultancy; Abbvie: Consultancy; ADC therapeutics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Logan:Enlivex: Consultancy. Wingard:Takeda: Consultancy; F2G: Consultancy; Celgene: Consultancy; Cidara: Consultancy; Orca: Consultancy. Perl:Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria; Syndax: Research Funding; Immunogen: Honoraria; Foghorn: Consultancy; BMS: Honoraria; BerGen Bio: Honoraria; Forma: Consultancy; Aptose: Honoraria; FujiFilm: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Beat AML: Other: Participation on a Data Safety Monitoring Board or Advisory Board; Rigel: Honoraria; Actinium: Honoraria. 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怀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.

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

Figure 1
Figure 1
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2023
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