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878 Impact of Allogeneic Hematopoietic Cell Transplantation in First Complete Remission in Addition to FLT3 Inhibition with Quizartinib in Acute Myeloid Leukemia with FLT3–Internal Tandem Duplication: Results from the Quantum-First Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Clinical Outcome: Results of Large Prospective Studies
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, adult, clinical trials, AML, Clinical Research, drug development, Diseases, Therapies, Myeloid Malignancies, Study Population, Human
Monday, December 12, 2022: 3:00 PM

Richard F. Schlenk, MD1, Pau Montesinos, MD, PhD2*, Antonio Romero-Aguilar, MD3*, Radovan Vrhovac, MD, PhD4*, Elżbieta Patkowska, MD5*, Hee-Je Kim, M.D., Ph.D.6, Pavel Zak, MD, PhD7*, Po-Nan Wang, MD8*, James Hanyok, PharmD9*, Li Liu9*, Yasser Mostafa Kamel, MD10*, Aziz Benzohra9*, Arnaud Lesegretain9*, Jorge E. Cortes, MD11, Mikkael A. Sekeres, MD12, Hervé Dombret, MD, PhD13*, Sergio Amadori, MD14, Jianxiang Wang, MD15, Alexander E. Perl, MD16, Mark J. Levis, MD17 and Harry P. Erba, MD, PhD18

1Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
2La Fe University and Polytechnic Hospital, Valencia, Spain
3University Hospital Virgen de las Nieves, Granada, Spain
4University Hospital Centre Zagreb, Zagreb, Croatia
5Institute of Hematology and Transfusion Medicine, Warsaw, Poland
6Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of (South)
7University Hospital Hradec Kralove, Hradec Kralove, Czech Republic
8Chang Gung Medical Foundation, Linkou, Taiwan
9Daiichi Sankyo, Inc, Basking Ridge, NJ
10Daiichi Sankyo, Inc., Basking Ridge, NJ
11Augusta University Medical Center, Augusta, GA
12University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL
13Saint Louis Hospital, University of Paris, Paris, France
14Tor Vergata Polyclinic Hospital Rome, Rome, RM, Italy
15Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
16University of Pennsylvania, Philadelphia, PA
17Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, MD
18Leukemia Program, Duke University Medical Center, Durham, NC

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.

Disclosures: 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; Kurome: 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. 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: MacroGenics: Consultancy, Research Funding; ALX Oncology: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Trillium Therapeutics: Consultancy; Janssen Oncology: Consultancy; PTC therapeutics: Research Funding; Gilead/Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Kura Oncology: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Glycomimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Covance (Abbvie): Consultancy, Other: Independent Review Committee, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; 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.

*signifies non-member of ASH