Quantum-First Trial: FLT3-ITD-Specific MRD Clearance Is Associated with Improved Overall Survival

Background Detection of measurable residual disease (MRD) by flow cytometry or gene fusion transcript quantitation has an established prognostic role in AML and is increasingly used to guide treatment decisions. Molecular monitoring of recurrent gene mutations for MRD detection is an alternative strategy but, other than for nucleophosmin 1 (NPM1) gene quantitation, remains controversial. This is due to variable prognostic effects conferred by the persistence of specific mutations, as well as technical limitations. FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is among the most common recurrent mutations in AML and, when present at diagnosis or relapse, confers a worse prognosis versus FLT3-wild-type and FLT3-TKD+ AML. Routine use of FLT3-ITD detection in remission as a predictor of relapse risk or overall survival (OS) has been limited by the low sensitivity of both conventional PCR-based detection methods and broad NGS platforms in clinical practice settings. More recently, FLT3-ITD-specific PCR-NGS assays such as getITD (Blätte, Leukemia 2019) show greater sensitivity and ease of interpretation that point to eventual routine clinical application. However, the clinical value of these measurements has not been evaluated prospectively in the context of FLT3-targeted therapy. QuANTUM-First (NCT02668653, sponsored by Daiichi Sankyo) is a phase 3, global, randomized, double-blind, placebo-controlled trial evaluating the novel, potent, and highly selective, type II FLT3 inhibitor quizartinib (Quiz) for patients (pts) with newly diagnosed FLT3-ITD+ AML treated with curative intent. This pivotal trial demonstrated that Quiz added to intensive induction and consolidation and given as single-agent continuation therapy resulted in a significant improvement in OS in this population (Erba, EHA 2022). We analyzed if FLT3-ITD-specific MRD in QuANTUM-First pts impacted the clinical outcomes or clarified Quiz benefits.

Methods Genomic DNA was isolated from bone marrow aspirates or peripheral blood from pts following achievement of remission after 1 or 2 courses of induction. The DNA was analyzed with a FLT3-ITD PCR-NGS assay specifically developed for this trial (Levis, Blood 2020). ITD mutations detected after induction were cross-validated against the ITD detected at enrollment for each patient. Using a custom bioinformatics program, ITD mutations were identified, and variant mutant allelic frequencies (VAFs) were calculated with a sensitivity of 1 × 10⁻⁵. These results were analyzed in the context of clinical endpoints. MRD was classified as undetectable or detectable above or below the cutoff of 1 × 10⁻⁴. Comparisons of complete response (CR), composite complete response (CRc=CR+CRi), and the rate of pts achieving CR during induction with no MRD between treatment groups was made using a stratified Cochran-Mantel-Haenszel test. Comparison of the FLT3-ITD+ VAF during induction between treatment arms was made using Wilcoxon rank sum test. All P-values were not adjusted for multiplicity.

Results In QuANTUM-First, 539 pts with FLT3-ITD+ AML were randomized to Quiz (n=268) or placebo (PBO; n=271). Of the 539 randomized pts, 368 (68.3%) achieved CRc after 1 or 2 courses of induction, and MRD analysis was performed on 318 (86.4%) pts (161 pts in Quiz and 157 pts in PBO) using samples collected at the time of response assessment during the induction phase, prior to any further therapy. A best response of CRc with MRD of <10⁻⁴, correlated with improved OS for all pts (Fig. 1). The percentage of pts in CRc with FLT3-ITD MRD of <10⁻⁴ was similar across study arms (24.6% quiz vs 21.4% PBO, P = 0.385), whereas the percentage of pts in CRc with undetectable MRD (ie, < 1 x 10⁻⁵) was greater with Quiz treatment (13.8% vs 7.4%, P = 0.017). The median FLT3-ITD+ VAF was 3-fold lower (P = 0.0204) among pts in the Quiz arm versus PBO (Fig. 2). Additional data about MRD impact on pts with or without allogeneic hematopoietic stem cell transplantation in this trial will be presented.

Conclusions This is the first evidence of the prognostic effect of FLT3-ITD-specific MRD in a prospective clinical trial and demonstrates the potential utility of this type of assay in the clinical management of pts with FLT3-ITD+ AML. Additionally, we show that the long-term survival benefits conferred by quizartinib in the QuANTUM-First trial may in part derive from an early and deep reduction of the FLT3-ITD+ leukemia burden.

Levis:AbbVie, Amgen, Astellas, Bristol Myers Squibb, Daiichi-Sankyo, FujiFilm, Jazz Pharmaceuticals, and Menarini: Consultancy; Astellas, and FujiFilm: Research Funding. Erba:Trillium Therapeutics: Consultancy; Janssen Oncology: Consultancy; Covance (Abbvie): Consultancy, Other: Independent Review Committee, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other, Speakers Bureau; Astellas Pharma: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy; Kura Oncology: Consultancy; Forma Therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; PTC therapeutics: Research Funding; ALX Oncology: Research Funding; Pfizer: Consultancy. Montesinos:JAZZPHARMA: Consultancy, Research Funding, Speakers Bureau; BEIGENE: Consultancy; ASTELLAS: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; ABBVIE: Consultancy, Research Funding, Speakers Bureau; OTSUKA: Consultancy; PFIZER: Consultancy, Research Funding, Speakers Bureau; KURA ONCOLOGY: Consultancy; NOVARTIS: Consultancy, Research Funding, Speakers Bureau; GILEAD: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding; RYVU: Consultancy; NERVIANO: Consultancy; INCYTE: Consultancy; MENARINI/STEMLINE: Consultancy, Research Funding. Vrhovac:Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pharmas: Consultancy, Honoraria; MSD: Honoraria; Novartis: Honoraria; Servier: Honoraria; Teva: Honoraria. Patkowska:AMGEN: Honoraria; Servier: Honoraria; NOVARTIS: Honoraria; Angelini Pharma: Honoraria; KCR: Consultancy; Astellas Pharma: Honoraria. Rohrbach:Daiichi Sankyo, Inc: Current Employment. Chang:Daiichi Sankyo, Inc: Current Employment. Hanyok:Daiichi Sankyo, Inc: Current Employment, Current equity holder in publicly-traded company. Liu:Daiichi Sankyo, Inc: Current Employment, Current equity holder in publicly-traded company. Kamel:Daiichi Sankyo, Inc: Current Employment. Lesegretain:Daiichi Sankyo, Inc: Current Employment, Current equity holder in publicly-traded company. Cortes:Gilead: Consultancy; Biopath Holdings Inc: Consultancy, Current equity holder in private company; Abbvie: Consultancy, Research Funding; Forma Therapeutic: Consultancy; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Sekeres:Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Kurome: Membership on an entity's Board of Directors or advisory committees. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Schlenk:BergenBio: Honoraria; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; AstraZeneca: Research Funding; Novartis: Honoraria; PharmaMar: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Perl:Astellas, Daiichi Sankyo, AbbVie, Forma, Sumitomo Dainippon, BeatAML LLC: Consultancy; Astellas, Abbvie, Daiichi Sankyo, FujiFilm, Syndax: Research Funding; Astellas, Daiichi Sankyo, Abbvie, Genentech, BerGenBio, Immunogen, BMS/Celgene, Actinium: Membership on an entity's Board of Directors or advisory committees.