A Phase II Study of Cladribine, Idarubicin, and Cytarabine (CLIA) in Combination with Gilteritinib for Patients with Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia

Introduction: Incorporation of FLT3 inhibitors such as midostaurin and quizartinib in combination with intensive chemotherapy (IC) have significantly improved outcomes for patients with newly diagnosed FLT3-mutated AML. The addition of cladribine to IC was found to prolong survival in pts with FLT3-ITD mutated AML (Libura et al. Blood 2016). Gilteritinib is a second generation type I FLT3 inhibitor which is currently approved for patients with relapsed and/or refractory FLT3-mutated AML. Here, we report the results of a phase II study exploring the safety and efficacy of gilteritinib added to cladribine, idarubicin, and cytarabine (CLIA) in patients with newly diagnosed AML.

Methods: Patients aged 18 - 65 years old with newly diagnosed FLT3-mutated AML, fit for intensive chemotherapy, received induction with cladribine 5 mg/m2 intravenously (IV) on D1-5, cytarabine 1.5 - 2.0 g/m2 IV on D1-5, idarubicin 10 mg/m2 IV on D1-3 (CLIA) and gilteritinib 120 mg on D1-14. Patients who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) could receive consolidation, consisting of cladribine 5 mg/m2 IV on D1-3, cytarabine 750 mg/m2 IV on D1-3, and idarubicin 8 mg/m2 IV on D1-2, with gilteritinib 80-120 mg administered continuously. We assessed responses rates, relapse-free survival (RFS), overall-survival (OS), and incidence of adverse events in this updated analysis of patients.

Results: Between February of 2020 and March of 2024, a total of 21 patients were enrolled, with a median age of 50 years (range, 20 - 62 years). The median bone marrow blast percentage was 66 (21 - 94). Eighteen patients (86%) had diploid cytogenetics, 2 (10%) patients had indeterminate risk cytogenetics, and 1 (4%) patient had adverse/complex cytogenetics. By ELN 2022 risk stratification, 8 patients were favorable risk, 7 patients were intermediate risk, and 6 patients were adverse risk. 15/21 (71%) patients had a mutation in FLT3-ITD alone, 3/21 (14%) patients had a FLT3-D835 mutation alone, and 3/21 (14%) had co-occurring FLT3-ITD and D835 mutations. The median allelic ratio (AR) of FLT3-ITD was 0.2395 (0.01 - 0.96) and median AR of FLT3-D835 was 0.155 (0.1 - 1.56). The most commonly co-occurring mutations included NPM1 (14/21, 67%), DNMT3A (9/21, 43%), IDH2 (4/21, 19%), NRAS/KRAS (4/21, 19%), ASXL1 (3/21, 14%), IDH1 (2/21, 10%).

Patients received a median of 3 (1 - 6) cycles of treatment with CLIA plus gilteritinib. After a median of 1 (1 - 2) cycles to best response, the CR/CRi rate was 81% (17/21), including a CR rate of 76% (16/21). The measurable residual disease (MRD)-negative response by multiparameter flow cytometry was achieved in 16/17 (94%) patients. 13/17 (76%) patients in CR/CRi successfully proceeded to allogeneic stem cell transplant (allo-SCT). After a median follow-up of 27 months, both the median OS and RFS were not reached (NR). The estimated 12- and 24-month OS were 85% and 72%, respectively, with 12- and 24-month RFS both at 80%.

There were no early deaths within 4 or 8 weeks. The most common adverse events were as follows: fatigue (n = 10), nausea (n = 7), febrile neutropenia (n = 6), pain (n = 5), elevated ALT (n = 5), rash (n = 4), with all grade 3 or greater adverse events attributed to elevated ALT (n = 3) and febrile neutropenia (n = 4).

Conclusion: The combination of CLIA and gilteritinib was safe in our cohort of patients with no unexpected toxicities or early deaths. This regimen was highly effective, with high rates of MRD negative CR/CRi and a 2-year survival of 72%. With continued long-term follow up with additional patients, the combination of CLIA and gilteritinib can be viewed as a potential option for newly diagnosed FLT3-mutated AML patients who are eligible to receive intensive chemotherapy.

Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Daver:Trillium: Consultancy, Research Funding; KITE: Research Funding; Syndax: Consultancy; Menarini Group: Consultancy; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Arog: Consultancy; Novartis: Consultancy; Novimmune: Research Funding; Hanmi: Research Funding; Jazz: Consultancy; Shattuck Labs: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Trovagene: Research Funding; Agios: Consultancy; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding. Yilmaz:daiichi sankyo: Honoraria, Research Funding. Garcia-Manero:Aprea: Research Funding; Astex: Other: Personal fees; Genentech: Other: Personal fees; Merck: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Helsinn: Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Curis: Research Funding; Helsinn: Other: Personal fees; Forty Seven: Research Funding; AbbVie: Research Funding; Onconova: Research Funding; Astex: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Amphivena: Research Funding. Chien:Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Burger:AstraZeneca: Research Funding; Janssen: Consultancy; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau. Pemmaraju:Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Triptych Health Partners: Consultancy; Cellectis: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; Aptitude Health: Honoraria; Incyte: Honoraria; Pacylex: Consultancy; CareDx: Honoraria; Springer Science + Business Media: Honoraria; ClearView Healthcare Partners: Consultancy; Immunogen: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Other: Travel Expenses; Plexxikon: Research Funding; DAVA Oncology: Honoraria, Other: Travel Expenses; Neopharm: Honoraria; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Protagonist Therapeutics: Consultancy; LFB Biotechnologies: Honoraria; Bristol-Myers Squibb: Consultancy; CTI BioPharma: Consultancy; Blueprint Medicines: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. DiNardo:Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Jazz: Consultancy, Honoraria; Stemline: Consultancy; Astex: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Immunogen: Honoraria; Schrodinger: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Gilead: Consultancy; Notable Labs: Honoraria; Riegel: Honoraria; Rigel: Research Funding; Amgen: Consultancy; GenMab: Consultancy, Honoraria, Other: data safety board; Loxo: Research Funding; Foghorn: Research Funding; Cleave: Research Funding; ImmuneOnc: Research Funding; Genetech: Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria. Short:Sanofi: Honoraria; Takeda Oncology: Honoraria, Research Funding; BeiGene: Honoraria; Pfizer Inc.: Honoraria; GSK: Consultancy, Research Funding; Autolus: Honoraria; Xencor: Research Funding; Amgen: Honoraria; NextCure: Research Funding; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Maiti:Indapta Therapeutics: Research Funding; Inspirna: Research Funding; Hibercell Inc.: Research Funding; Chimeric Therapeutics: Research Funding; CytoMed Therapeutics: Research Funding; Lin Biosciences: Research Funding. Issa:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Celgene: Research Funding; Merck: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Ravandi:Prelude: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding; Amgen: Research Funding; Xencor: Research Funding. Kadia:AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Research Funding; Regeneron: Research Funding; JAZZ: Research Funding; Incyte: Research Funding; Sellas: Consultancy, Research Funding; Rigel: Honoraria; Servier: Consultancy; Novartis: Honoraria; Cellenkos: Research Funding; Ascentage: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; ASTEX: Research Funding; DrenBio: Consultancy, Research Funding; BMS: Consultancy, Research Funding.