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.