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3238 Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with FLT3 or CBL Mutations

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Guillermo Montalban-Bravo, MD1, Elias Jabbour2, Kelly S. Chien, MD1, Danielle E. Hammond, MD1, Nicholas J. Short, MD1, Farhad Ravandi, MD, MBBS1, Marina Y. Konopleva1, Gautam Borthakur, MD1, Naval Daver, MD1, Rashmi Kanagal-Shamanna, MD3, Wei Qiao, PhD4*, Xuelin Huang, PhD4*, Heather Schneider, BSN, RN5*, Meghan Anne Meyer, BSN, RN5*, Hagop M. Kantarjian, MD5 and Guillermo Garcia-Manero, MD6

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2University of Texas M.D. Anderson Cancer Ctr., Houston, TX
3Hematopathology, MD Anderson Cancer Center, Houston, TX
4Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
5Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
6The University of Texas MD Anderson Cancer Center, Houston, TX

Introduction: FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 1% of patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% of pts at time of failure to hypomethylating agents (HMA). In addition, mutations in the Casitas B-lineage Lymphoma gene (CBL) are observed in 10% of pts with MDS/MPN and up to 15% of pts with CMML. Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Here we present results of a phase I-II study of the FLT3 inhibitor quizartinib in combination with azacitidine for pts with FLT3 and CBL mutant MDS and MDS/MPN.

Methods: We conducted a phase I/II clinical trial of azacitidine in combination with quizartinib for pts with MDS and MDS/MPN with detectable FLT3 and/or CBL mutations and with/without prior failure to HMA (HMA-F). The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 3 dose levels of quizartinib: 30, 40 and 60 mg administered p.o daily on days 1-28 of each 28 day cycle. Therapy consisted on quizartinib (at corresponding dose level) in combination with azacitidine 75 mg/m2/day i.v os s.c on days 1-5. The primary endpoint was to evaluate safety, tolerability and maximum tolerated dose of quizartinib. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meier product-limit method was used to estimate median survival.

Results: Between July 2020 and June 2023 a total of 16 pts have been treated: 12 in the phase I portion and 4 in the phase II. A total of 4 pts had MDS with excess blasts, 2 had MDS/MPN with neutrophilia and 10 had CMML. Eight (50%) pts had FLT3-ITD mutations and 8 (50%) had CBL mutations. Four (25%) pts had HMA-F one of which had received 4 lines of therapy including hematopoietic stem-cell transplant (HSCT) prior to enrollment. Based on the Molecular IPSS, 8 (50%), 3 (19%) and 5 (31%) pts had very high, high and moderate high risk disease. Among CMML pts, 3 (30%) pts had high and 7 (70%) had intermediate-2 risk by CPSS-Molecular score.

In the phase I portion, 3 pts received quizartinib at dose level 1, 3 at dose level 2 and 6 at dose level 3. No dose limiting toxicities were detected during the 28-day DLT evaluation window. Dose level 2 was selected as the P2RD.

Most common adverse events (AEs) were constipation (56%), fatigue (50%), insomnia (44%), anorexia (38%), cough (38%), diarrhea (38%) and arthralgia (31%). Most common grade 3-4 AEs were anemia (31%), thrombocytopenia (31%), lung infection (13%), skin infection (13%), hyponatremia (13%) and sepsis (13%). Arrythmias were observed 5 pts: atrial fibrillation (grade 2, n=2; grade 3, n=1), Mobitz type II atrioventricular block (grade 3, n=1), atrial flutter (grade 2, n=1), QTC prolongation (grade 2, n=1). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of days to cycle 2 was 30 (range 27-51). Median number of days to cycle 2 of therapy by dose level were: 30, 30 and 37 days for dose levels 1, 2 and 3, respectively (p=0.301). Dose reductions due to myelosuppression were required in 5 (31%) pts including dose reductions of azacitidine in 3 pts and of quizartinib in 3 pts. Median number of cycles was 4 (range 1-17). Median cycles to to best response was 1 (range 1-6). The overall response rate was 69% (n=11): CR in 1 (6%), mCR with HI in 2 (13%), mCR in 8 (50%) pts. FLT3 mutant pts were more likely to respond to therapy (100% vs 50%, p=0.038). Clearance (n=6, 75%) or allelic burden reductions (n=2, 25%) of FLT3-ITD mutations were observed in all FLT3 mutant pts. No clearance of CBL mutations were observed. Dynamics of absolute neutrophil count, platelets and hemoglobin during cycle 1 are shown in Figure 1A. Median response duration was 3.5 months (range 0-22 moths). With a median follow up of 19.1 months (95% CI 2.6-35.6), the median event-free survival has not been reached and the median overall survival is 17.5 months (NR vs 10.1 months in FLT3 vs CBL mutant pts, p=0.084, Figure 1B)

Five (31%) pts discontinued study to proceed with HSCT at time of best response, 3 (19%) due to transformation to AML, 2 (12%) due to pt choice, 1 (6%) due to treating physician choice and 1 (6%) due to relapse. Four (25%) pts remain on study.

Conclusion: Therapy with azacitidine in combination with quizartinib for pts with higher-risk MDS and MDS/MPN with FLT3 or CBL mutations has acceptable toxicity profile and is associated with promising responses mainly among FLT3-mutant pts.

Disclosures: Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Jabbour: Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Astex: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Chien: Rigel Pharmaceuticals: Consultancy; AbbVie: Consultancy. Short: Takeda: Consultancy, Research Funding; Novartis: Consultancy; AstraZeneca: Consultancy; Stemline therapeutics: Research Funding; Astellas: Research Funding; Amgen: Honoraria; Pfizer: Consultancy. Ravandi: Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomea fusion: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Konopleva: Reata Pharmaceuticals.: Current holder of stock options in a privately-held company, Patents & Royalties; AbbVie, Ablynx, Allogene, AstraZeneca, Cellectis, Daiichi, FortySeven, Genentech, Gilead, Immunogen, MEI Pharma, Precision Biosciences, Rafael Pharmaceutical, Sanofi Aventis, Stemline-Menarini: Research Funding; AbbVie, AstraZeneca, Genentech, Gilead, Janssen, MEI Pharma, Sanofi Aventis, Stemline-Menarini, Vincerx: Consultancy. Borthakur: Pacylex, Novartis, Cytomx, Bio Ascend:: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Daver: Hanmi: Research Funding; Novartis: Consultancy; Novimmune: Research Funding; Glycomimetics: Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; FATE: Research Funding; ImmunoGen: Consultancy, Research Funding; Syndax: Consultancy; Trovagene: Research Funding; Trillium: Consultancy, Research Funding; Jazz: Consultancy; Shattuck Labs: Consultancy; AbbVie: Consultancy, Research Funding; AROG: Consultancy; Amgen: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Gilead: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Kantarjian: Pfizer: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Orsinex: Honoraria; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Actinium: Honoraria; Astex: Research Funding; Immunogen: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria. Garcia-Manero: Genentech: Research Funding; AbbVie: Research Funding; Bristol Myers Squibb: Other: Medical writing support, Research Funding.

*signifies non-member of ASH