Initial Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndrome and Myelodysplastic/Myeloproliferative Neoplasm with FLT3 or CBL Mutations
Authors: Abuasab Tareq , Jabbour Elias J. , Short Nicholas J. , Konopleva Marina , Chien Kelly S. , Mohamed Shehab Fareed , Daver Naval , Kanagal-Shamanna Rashmi , Kantarjian Hagop , Garcia-Manero Guillermo , Montalban-Bravo Guillermo 
Published: November 2021

Abstract
Introduction: FMS-like tyrosine kinase 3 (FLT3) mutations occur in about 1% of patients with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% at time of failure of hypomethylating agent (HMA). In addition, Casitas B-lineage Lymphoma mutations (CBL) are observed in 10% of patients with MDS/MPN and up to 13-15% of patients with CMML (mainly proliferative type). Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Specific targeting of FLT3 and CBL mutations in MDS and MDS/MPN has not been thoroughly evaluated.
Methods: We designed a phase I/II clinical trial of Azacitidine in Combination with quizartinib for newly diagnosed patients with MDS and MDS/MPN with detectable FLT3 mutation and/or CBL exon 8 or 9 deletions or point mutations Mutation on patients that are HMA naïve or had prior treatment with HMA. The study included phase I dose escalation portion, following 3+3 design, followed by phase II dose expansion portion. Dose escalation included 3 dose levels of quizartinib on days 1-28 of every cycle: 30, 40 and 60 mg in the addition to azacitidine (75 mg/m 2/day) on days 1-5 each 28-day cycle. The phase II/expansion phase will include two cohorts, Cohort A hypomethylating agent naïve patients and cohort B patients with prior hypomethylating agent. The primary objective of this study is to determine the safety, tolerability and maximum tolerable dose (MTD) of quizartinib. Secondary objectives include evaluation of overall response per IWG 2006 criteria, in addition to overall survival (OS), duration of response, leukemia-free survival (LFS), relapse-free survival (RFS).
Results: At the end date of July 30 th 2021, a total of 6 patients have been enrolled: 4 patients with CMML, one with MDS excess blast and one with atypical Chronic myeloid leukemia (aCML). A total of 5 patients (83%) had normal karyotype and one patient (17%) had complex karyotype. Four patients were enrolled due to FLT3 mutations and 2 due to CBL mutations. Patients characteristics are summarized in Figure 1a. Median number of cycles administered was 3.5 (range 1-6). All patients have achieved response so far with a total of 5 patients (67%) having achieved marrow CR (mCR) including HI in 1 patient, 1 patient had hematologic improvement-erythropoietic (HI-E) with control of leukocytosis and thrombocytosis to normal levels. Response dynamics and clonal changes through the course of therapy are shown in Figure 1b. Reduction of clearance of FLT3-ITD or other FLT3 mutations was observed in all evaluable FLT3-mutant patients with no significant changes in CBL mutant variant allele frequencies observed thus far. With a median follow up of 3.1 months (range 1-12 months), the median response duration is 2.1 months (range 0.5-6.3 months) and the median OS has not been reached with all patients alive at the time of evaluation. A total of 3 patients (50%) have stopped the treatment: 1 patient due to disease relapse, 1 due to progression and the other to proceed to allogenic stem cell transplantation after achieving response to therapy. No dose limiting toxicities (DLT) have been observed to date up to the maximum dose of 40 mg of quizartinib. One patient required dose reductions due to cytopenias with the rest of the patients having recovery of counts to pre-treatment levels. Regarding the grade 3 or more adverse events (AEs): Two patients (33%) had skin infection, one patient (17%) had cardiac arrythmia with Mobitz II AV block and one patient (17%) had lumbar epidural lesion most likely of infectious origin.
Conclusion: Preliminary data suggest azacitidine in combination with quizartinib for patients with MDS and MDS/MPN with FLT3 or CBL mutations have acceptable toxicity profile and associated with promising responses. Further follow up with a larger patient cohort are required to emphasize the safety and efficacy of this combination and evaluate depth and duration of response.
Figure 1 Figure 1.

Disclosures
Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Short: Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Konopleva: Ablynx: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Daver: Amgen: Consultancy, Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; FATE Therapeutics: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kantarjian: Aptitude Health: Honoraria; Jazz: Research Funding; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.