Background Patients with acute myeloid leukemia (AML) exhibiting an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD+), face particularly poor outcomes, even after allogeneic hematopoietic cell transplantation (allo-HCT), which appears to only partially mitigate the poor prognosis associated with this mutation. (Döhner H et al., Blood 2017, Stone RM et al., NEJM 2017; Larson RA et al., Leukemia 2021). QuANTUM-First (NCT02668653) is a phase 3, global, randomized, double-blind, placebo-controlled trial evaluating the novel, highly potent, and selective type II FLT3 inhibitor quizartinib (Quiz) for patients with newly diagnosed FLT3-ITD+ AML who were treated with curative intent. This pivotal trial demonstrated that the addition of Quiz to intensive induction, consolidation including allo-HCT in CR1, followed by single-agent continuation therapy for up to 3 years resulted in a significant improvement in overall survival (OS) for this population. The objectives of our analyses were to evaluate the impact of allo-HCT in CR1 and the interrelationship with Quiz on clinical outcomes of QuANTUM-First and on the feasibility of continuation therapy with Quiz after allo-HCT.

Methods Patients aged 18-75 years with newly diagnosed AML were centrally screened for FLT3-ITD before initiation of standard induction therapy. Patients were randomized to Quiz (40 mg/d, on days 8-21) or placebo (PBO) and stratified by region (North/South America, Europe, and Asia/other regions), age (<60 years, ≥60 years), and white blood cell count (WBC; <40 × 109/L, ≥40 × 109/L) at diagnosis. Patients who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) received up to 4 cycles of high-dose cytarabine plus Quiz (40 mg/d) or PBO and/or allo-HCT followed by up to 3 years of continuation therapy with Quiz (30-60 mg/d) or PBO. Patients who underwent allo-HCT could start continuation therapy 30 to 180 days after allo-HCT. The primary endpoint was OS. The impact of allo-HCT in CR1 on OS was assessed as a time-dependent covariable in univariable and multivariable regression analyses.

Results In QuANTUM-First, 539 patients with FLT3-ITD+ AML were randomized to Quiz (n=268) or PBO (n=271). There were 294 (54.5%) females and 245 (45.5%) males. Of the 539 randomized patients (median age, 56 years; range, 20-75 years), 297 (55.1% [297/539]; Quiz, 54.9% [147/268]; PBO, 55.4% [150/271]) achieved CR and 71 (13.2% [71/539]; Quiz, 16.8% [45/268]; PBO, 9.6% [26/271]) achieved CRi after 1 to 2 courses of induction. Allo-HCT was performed in CR1 in 157 patients (52.9% of CR patients [157/297]; Quiz, 57.1% [84/147]; PBO, 48.7% [73/150]) predominantly with grafts from unrelated donors (49.7%), followed by siblings (32.5%) and other related donors (17.8%). Patients proceeding toward allo-HCT in CR1 were younger (median age, 51 years) and had a slightly higher proportion of WBC ≥40 × 109/L at diagnosis compared with patients who did not undergo allo-HCT in CR1. After completion of allo-HCT, 61 patients in the Quiz arm (72.6%) and 36 patients in the PBO arm (49.3%) started 3 years of continuation therapy. An additional 115 allo-HCTs were performed within the trial outside CR1 (Quiz, n=60; PBO, n=55). Multivariable regression analysis was stratified by region, age, and WBC, including allo-HCT in CR1 as time dependent and adjusted for FLT3-ITD variant allelic frequency, as well for sex. The analysis revealed Quiz treatment (hazard ratio [HR], 0.770; 95% confidence interval (CI), 0.609-0.973; P = 0.0284) and allo-HCT in CR1 (HR, 0.424; 95% CI, 0.301-0.597; P < 0.0001) as favorable factors with respect to OS. Based on this model, at any given time, the HR was 0.326 (95% CI, 0.216-0.493) for the patients randomized to Quiz and proceeding to allo-HCT in CR1 compared with patients randomized to PBO who had not yet received allo-HCT in CR1 by that time.

Conclusions In patients who underwent allo-HCT in CR1, longer survival was observed in those treated with quizartinib versus placebo. Furthermore, irrespective of allo-HCT performed in CR1, quizartinib when combined with standard induction and consolidation therapy and continued for up to 3 years as a single agent improves survival over placebo in patients with newly diagnosed FLT3-ITD+ AML.

Schlenk:Novartis: Honoraria; BergenBio: Honoraria; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; AstraZeneca: Research Funding; PharmaMar: Research Funding; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Montesinos:Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Menarini/Stemline: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding; Astellas: Consultancy, Speakers Bureau; Otsuka: Consultancy; Kura Oncology: Consultancy; Incyte: Consultancy; Ryvu: Consultancy; Nerviano: Consultancy; Beigene: Consultancy. Vrhovac:Pfizer: Consultancy, Honoraria; Pharmas: Consultancy, Honoraria; MSD: Honoraria; Servier: Honoraria; Novartis: Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Teva: Honoraria. Patkowska:Angelini Pharma: Honoraria, Other: Support for attending meetings and/or travel; Squibb: Other: Support for attending meetings and/or travel; Jazz Pharmaceuticals: Other: Support for attending meetings and/or travel; Pfizer: Other: Support for attending meetings and/or travel; Servier: Honoraria, Other: Support for attending meetings and/or travel; Amgen: Honoraria; Novartis: Honoraria, Other: Support for attending meetings and/or travel; Bristol Myers: Other: Support for attending meetings and/or travel; Astellas Pharma: Honoraria, Other: Support for attending meetings and/or travel; KCR US, Inc: Consultancy. 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. Benzohra:Daiichi-Sankyo: Current Employment, Current equity holder in publicly-traded company. Lesegretain:Daiichi Sankyo, Inc: Current Employment, Current equity holder in publicly-traded company. Cortes:Gilead: Consultancy; Abbvie: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Forma Therapuetic: Consultancy; Biopath Holdings: Consultancy, Current equity holder in private company; Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kartos: 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. Dombret:Immunogen: Consultancy; Cellectis: Consultancy; Jazz Pharma: Consultancy, Other: Grants; Sunesis: Consultancy; Celgene: Consultancy; Pfizer: Consultancy, Other: Grants; Incyte: Consultancy; Novartis: Consultancy, Other: Grants; Daiichi-Sankyo: Consultancy; Amgen: Consultancy, Other: Grants; Astellas: Consultancy; Janssen: Consultancy; Servier: Consultancy, Other: Grants; Shire-Baxalta: Consultancy; Abbvie: Consultancy; Otsuka: Consultancy; Menarini: Consultancy; Incyte: Other: Grants. Wang:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Perl:Astellas, Daiichi Sankyo, AbbVie, Forma, Sumitomo Dainippon, BeatAML LLC, Loxo, LLS/Beat AML, Forma, New Link Genetics, Bayer, Biomed Valley Discoveries: Consultancy; Astellas, Daiichi Sankyo, Abbvie, Genentech, BerGenBio, Immunogen, BMS/Celgene, Actinium: Membership on an entity's Board of Directors or advisory committees; Astellas, Abbvie, Daiichi Sankyo, FujiFilm, Syndax: Research Funding. Levis:Astellas, and FujiFilm: Research Funding; AbbVie, Amgen, Astellas, Bristol Myers Squibb, Daiichi-Sankyo, FujiFilm, Jazz Pharmaceuticals, and Menarini: Consultancy. Erba:Astellas Pharma: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Other, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Consultancy, Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Trillium Therapeutics: Consultancy; Takeda: Consultancy; MacroGenics: Consultancy, Research Funding; Covance (Abbvie): Consultancy, Other: Independent Review Committee, Research Funding; Kura Oncology: Consultancy; Forma Therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; PTC therapeutics: Research Funding; ALX Oncology: Research Funding; Pfizer: Consultancy.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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