No abstract

Background: Gilteritinib improves response rates and overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML). For older pts with newly diagnosed (ND) FLT3-mutated AML who are unfit for intensive chemotherapy, azacitidine plus venetoclax is the current standard of care, although remission durations are relatively short, largely due to FLT3-driven relapses. We therefore sought to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib for older pts with ND FLT3-mutated AML, as well as for those of all ages with R/R FLT3-mutated AML. Methods: In this phase I/II study, pts with either R/R FLT3-mutated AML or high-risk MDS/CMML or pts with ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts <5% or aplastic marrow, then both venetoclax and gilteritinib were held (ND cohort) or only venetoclax was held (R/R cohort). For cycles 2 and beyond, azacitidine 75 mg/m 2 SC/IV was given for 5-7 days, venetoclax was given for 7-14 days and gilteritinib was given continuously. Results: Between 12/2019 and 7/2021, 26 pts were treated (11 ND pts and 15 R/R pts). Baseline characteristics are shown in Table 1. The median age for the ND and R/R cohorts were 71 years (range, 61-79) and 68 years (range, 19-90), respectively. In the ND cohort, 9 (82%) had a FLT3-ITD and 2 (18%) had a FLT3 TKD mutation; in the R/R cohort, 7 (47%) had a FLT3-ITD, 5 (33%) had a FLT3-TKD, and 3 (20%) had both mutations. Among pts in the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 6 (40%) had poor risk cytogenetics, 5 (33%) had undergone prior hematopoietic stem cell transplant (HSCT), and 5 (33%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib). Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). No DLTs were observed at the 80mg daily dosing. Among 3 pts in the 120mg cohort who were evaluable for DLTs, 1 achieved MLFS but had prolonged grade 4 myelosuppression that met DLT criteria. Due to good clinical activity and superior count recovery observed with the 80mg dosing (with 3 of 6 pts [50%] in the phase I cohort achieving CR/CRp), the 80mg daily dose was chosen as the phase II dose for further study. In the entire R/R cohort, the median number of cycles received was 2 (range, 1-4). The overall response rate (CR+CRi+MLFS) was 67%. One pt (7%) achieved CR as best response, 3 (20%) achieved CRi, and 6 (40%) achieved MLFS. An additional pt with extramedullary-only disease achieved PR. Four pts (27% of the entire R/R cohort, 44% of responding pts) proceeded to HSCT. Among the 10 responding pts, 4 have relapsed (1 of whom was FLT3 negative), 2 died in morphologic remission, and 4 are still alive without relapse. The 30-day and 60-day mortality rates were 0% and 13%, respectively. With a median follow-up of 9.9 months in the R/R cohort, the median duration of response was 9.0 months and the median OS was 10.5 months (Figure 1A). In the ND cohort, the median number of cycles received was 2 (range, 1-6). All pts responded and all achieved marrow remission by day 14. Eight pts (73%) achieved CR as best response, 1 (9%) achieved CRi, and 2 (18%) achieved MLFS; the 3 pts with CRi/MLFS are still recovering from cycle 1 at the time of this report. Two pts (18%) proceeded to HSCT. With a median follow-up of 3.8 months (range, 0.5-8.7 months), no pts have relapsed and 1 pt died (Figure 1B). This pt achieved MRD-negative CR and died 9 weeks into therapy due to sepsis. Conclusions: The combination of azacitidine, venetoclax and gilteritinib was effective in pts with FLT3-mutated AML. Gilteritinib dosing at 80mg daily was associated with a better safety/efficacy profile and was selected for future study; however, even with this lower dose myelosuppression was common and required attenuation of azacitidine and venetoclax. This combination appears particularly encouraging in the frontline setting where the response rate was 100% with no relapses observed to date. Figure 1 Figure 1. Disclosures Short: Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. DiNardo: Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria. Daver: Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; 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. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kadia: Genfleet: Other; Astellas: Other; AstraZeneca: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Liberum: Consultancy; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Ascentage: Other; Novartis: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Borthakur: Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; 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; Rafael Pharmaceuticals: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Gilteritinib for frontline treatment of FLT3-mutated AML

Background: Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well-defined in this entity. Methods:In a retrospective analysis, causes and rates of early mortality following induction treatment were compared between a cohort of adults with KMT2Ar AML (N = 172) and an age-matched cohort of patients with normal karyotype AML (N = 522). Results:The 60-day mortality in patients with KMT2Ar AML was 15% compared with 7% with normal karyotype (p = .04). We found a significantly higher occurrence of major bleeding events (p = .005) and total bleeding events (p = .001) in KMT2Ar AML compared with diploid AML. Among evaluable patients with KMT2Ar AML, 93% exhibited overt disseminated intravascular coagulopathy compared with 54% of patients with a normal karyotype before death (p = .03). In a multivariate analysis, KMT2Ar and a monocytic phenotypic were the only independent predictors of any bleeding event in patients who died within 60 days (odds ratio, 3.5; 95% CI, 1.4-10.4; p = .03; odds ratio, 3.2; 95% CI, 1-1-9.4; p = .04, respectively). Conclusion:In conclusion, early recognition and aggressive management of disseminated intravascular coagulopathy and coagulopathy are important considerations that could mitigate the risk of death during induction treatment in KMT2Ar AML.