Background:FLT3 gene mutations occur in approximately 30% of patients (pts) with AML and are associated with worse survival and higher relapse risk. Gilteritinib, a selective potent oral FLT3 tyrosine kinase inhibitor (FLT3i), improves survival in pts with relapsed FLT3 mutated AML. ASTX727 is an oral fixed-dose combination of decitabine (35 mg) and cedazuridine (a cytidine deaminase inhibitor; 100 mg) approved for treating pts with myelodysplastic syndrome (MDS). We are evaluating the safety and efficacy of the combination of ASTX727, gilteritinib, and venetoclax (VEN) in pts with relapsed or refractory FLT3-mutated AML and older/unfit pts unable to receive chemotherapy.

Methods: In the phase I, pts with R/R FLT3-mutated AML or high-risk (HR) MDS or chronic myelomonocytic leukemia (CMML) are eligible. FLT3-ITD and/or FLT3-TKD mutations were allowed. In the phase II, the study will also enroll newly diagnosed pts with FLT3-mutated AML ineligible for induction therapy. Pts are required to have an ECOG performance status ≤3, total bilirubin ≤2.5 x upper limit of normal (ULN), ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. Hydroxyurea or 1 dose of cytarabine up to 1000 mg was allowed in pts with proliferative disease to lower white blood count to ≤ 25 x 109/L before initiation of study therapy.

In the phase 1, we evaluated two dose levels of gilteritinib (80 mg and 120 mg daily) continuously with fixed dosages of ASTX727 (35/100 mg daily on days 1-5) and VEN (400 mg daily, dose adjusted for concomitant azoles, for up to 28 days). Cycles are repeated every 28 days for up to 24 cycles, followed by indefinite therapy with gilteritinib as maintenance. During cycle 1, VEN was given at a dose of 100 mg on day 1, 200 mg on day 2, and 400 mg daily onwards. Bone marrow (BM) aspiration was performed on day 21, and VEN was held in pts with BM blasts <5% or aplasia. During cycles 2-24, VEN was given at 400 mg daily (dose adjusted for concomitant azoles) on days 1-21 but dose reductions depending on tolerance were permitted. Gilteritinib continued at the enrolled dose in cycles 2-24.

Results: Between 11/2021 and 6/2022, 8 patients (7 AML and 1 HR-CMML) have been enrolled in the phase 1 portion of the trial (Table 1). Their median age was 57 years (range, 38-83). Median number of prior lines of therapy was 1 (range, 1-10). Four pts (50%) had a previous allogeneic hematopoietic stem cell transplant (HSCT), 6 pts (75%) had prior treatment with hypomethylating agent (HMA)+VEN, and 3 pts (27%) received prior FLT3i. None received prior gilteritinib. Cytogenetics was diploid in 4 pts, complex in 3 pts, and miscellaneous in 1 pt. The median FLT3-ITD allelic ratio (AR) was 0.4 (range, 0.11-10.60), with 50% having a high AR (≥0.5). All pts had a FLT3-ITD mutation and no pt had a FLT3-TKD mutation. NPM1 co-mutation was present in 4 pts (50%), followed by DNMT3A (37%) and IDH2 (37%).

Six pts have been enrolled on dose level 1 (gilteritinib 80 mg) and 2 pt on dose level 2 (gilteritinib 120 mg). No DLTs have been observed in either dose level. Myelosuppression was frequent, requiring dose adjustment of ASTX727 and/or VEN in cycle 2 onward in 5 pts. Grade 3 non-hematologic adverse events included: sepsis (25%), bacteremia (25%), pneumonia (13%), and other infection (25%). No tumor lysis syndrome, differentiation syndrome, or QTc prolongation was observed. The 30-day and 60-day mortality rates were 0% and 13%, respectively.

The overall response rate (ORR) was 87% with 4 (50%) pts achieving CR/CRi (1 CR, 3 CRi) and 3 (37%) pts achieving MLFS. One pt withdrew from the study in cycle 1 and was not evaluable for response. The ORR in pts with prior HMA+VEN was 83% (3 CRi, 2 MLFS). Five of 7 responders (71%) achieved the best response within 1 cycle and 2 (29%) within 2 cycles. Pts received a median of 2 cycles of therapy (range, 1-6). With a median follow-up of 6 months, median overall survival was not reached (range, 1.2-8+ months), and the estimated 6-month overall survival is 70%. One responding pt proceeded to HSCT. Two pts have died, 1 in CRi due to an unknown cause, and 1 due to disease progression and sepsis.

Conclusion: The combination therapy with ASTX727, VEN, and gilteritinib appears to be effective and safe in R/R FLT3 mutated AML and HR-MDS. Myelosuppression was frequent but manageable. Continued accrual is anticipated to define the optimal triplet regimen in both R/R and newly diagnosed FLT3-mutated AML.

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Short:Takeda Oncology: Consultancy, Research Funding; Astellas: Research Funding; Stemline Therapeutics: Research Funding; Pfizer: Consultancy; Novartis: Consultancy; Amgen: Consultancy, Honoraria; AstraZeneca: Consultancy. Daver:Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Kadia:Genfleet: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; cyclacel: Research Funding; Genentech: Consultancy, Research Funding; JAZZ: Consultancy, Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Servier: Consultancy; cellenkos: Research Funding; Novartis: Consultancy; Ascentage: Research Funding; Delta-Fly: Research Funding; PinotBio: Consultancy; Iterion: Research Funding; Glycomimetics: Research Funding; Astex: Honoraria; Regeneron: Research Funding; BMS: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding. DiNardo:Forma: Research Funding; Astex: Research Funding; Takeda: Honoraria; Novartis: Honoraria; Cleave: Research Funding; Astellas: Honoraria; GenMab: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: 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; Servier: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria; AbbVie: Consultancy, Research Funding; LOXO: Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Bluebird Bio: Honoraria; Foghorn: Honoraria, Research Funding. Yilmaz:Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. Alvarado:FibroGen: Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Daiichi-Sankyo/Lilly: Research Funding. Kantarjian:NOVA Research: Honoraria; AbbVie: Honoraria, Research Funding; ImmunoGen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Garcia-Manero:BMS: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Acceleron Pharma: Consultancy; Aprea: Honoraria; Gilead Sciences: Research Funding; Curis: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding. Ravandi:BMS/Celgene: Consultancy, Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Biomea Fusion, Inc.: Research Funding; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Research Funding; AstraZeneca: Consultancy; Novartis: Consultancy; Amgen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding.

ASTX727 is not approved for AML. The use of Gilteritinib in combination with ASTX727 and/or Venetoclax is investigational.

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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