Session: 616. Acute Myeloid Leukemias: Investigational Drug and Cellular Therapies: Poster III
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, Research, Clinical trials, AML, Drug development, Clinical Research, Diseases, Treatment Considerations, Myeloid Malignancies
Aims: The primary objectives were to determine the recommended phase 2 dose (RP2D) and optimal schedule of DAC + VEN + Quiz in R/R or newly diagnosed FLT3m AML.
Methods: The study included newly diagnosed pts ineligible for IC and R/R pts who had received ≤ 6 prior treatments for AML. On cycle 1 Day 14, all pts underwent bone marrow (BM) evaluation, and VEN (400 mg/day or equivalent with azole) was discontinued on cycle 1 Day 14 for pts with BM blasts ≤ 5% (or marrow aplasia/hypocellularity). Pts with cycle 1 Day 14 BM blast >5% continued VEN for 21 days. Pts received 10 days of DAC (20 mg/m2) for induction, followed by 5-day DAC in subsequent cycles. Quiz (30 or 40 mg/day) was continuously administered daily.
Results: A total of 66 pts were enrolled, including 47 R/R and 19 newly FLT3-ITD mutated AML pts. A detailed demographic data will be reported at the time of presentation. The 47 R/R AML pts were heavily pretreated (median 3 [range 1-5] prior AML therapies), 85% (40/47) had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib, and 38% having undergone prior allogeneic stem cell transplantation (ASCT). The rates of CRc, CR+CRi, measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC, sensitivity 10-4), and FLT3-PCR (sensitivity 10-2 - 10-3) negativity among the R/R pts were 60%, 28%, 29% (8/28), and 32% (9/28), respectively). The 60-day mortality in R/R cohort was 13%. With a median follow-up of 29 months, the median OS was 6.3 months, the 1-year OS rate was 20%, and 34% (16 out of 47) underwent ASCT in R/R cohort. Among 40 prior FLT3 inhibitor exposed pts the CRc, CR+CRi, median OS and 1-year OS were 58%, 22%, 6.3 month, and 19%. Among the seven prior FLT3 inhibitor naïve pts the CRc, CR+CRi, median OS and 1-year OS were 71%, 57%, 10.3 months and 28%.
We enrolled 19 newly diagnosed AML (median age 70 years, 26% >/= 75 years), 12 with diploid cytogenetics, and 11 ELN adverse. Overall 95% (18/19) achieved CRc (12 CR, 6CRi), with 14/17 (82%) and 11/16 (69%) evaluable responders being FLT3-PCR and MFC negative, respectively. All 18 responders had achieved BM <5% or aplasia/hypocellularity on cycle 1 Day 14. The 60-day mortality was 5%. The median time to ANC>0.5, ANC>1.0, and PLT>50K after cycle 1 were 40 [range 28-56], 40 [range 28-58], and 36 [range 22-56] days. A total of 4 pts have relapsed (all 4 had secondary / therapy related AML, 2 of 4 had RAS/MAPK emergent/expanded mutations at relapse, no TKD emergence detected) and 4 pts died (2 deaths in CR, 2 deaths due to progressive leukemia). 26% (5 out of 19) frontline patients underwent ASCT. With a median follow-up of 17 months, the median OS was not reached with 1-year OS of 78%.
No pts experienced dose-limiting toxicity (DLT) with Quiz 30 mg/day; however, with Quiz 40 mg/day, the first 2 pts treated developed hematologic DLT (grade 4 neutropenia with a <5% cellular bone marrow with no residual AML lasting ≥42 days). Consequently, Quiz 30 mg/day was declared the RP2D for this combination. In the R/R cohort, grade ≥3 non-hematologic toxicities regardless of attribution, in >10% of pts, included pneumonia (73%), neutropenic fever (53%), sepsis (18%), other infections involving the skin (18%)bacteremia (15%), and gastrointestinal tract (13%), with 8% experiencing grade 3 QTcF prolongations. Grade ≥3 non-hematologic toxicities was less common in the frontline cohort, with pneumonia (40%), neutropenic fever (50%), sepsis (10%), bacteremia (20%), and no grade 3 QTcF prolongations observed.
Conclusion: The combination of DAC + VEN + Quiz demonstrated activity in heavily pretreated and prior FLT3i-exposed (including 78% with prior gilteritinib exposure) R/R FLT3-ITDm pts, with a CRc rate of 60% and a median OS of 6.3 months. In the frontline setting, 95% of pts achieved CRc with a median platelet and ANC recovery of 36 and 40 days, and a median OS not reached. The study continues to accrue, and updated results will be reported at the meeting.
Disclosures: Yilmaz: daiichi sankyo: Honoraria, Research Funding. Short: Xencor: Research Funding; Takeda Oncology: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria; Adaptive Biotechnologies: Honoraria; Astellas Pharma, Inc.: Honoraria, Research Funding; Stemline Therapeutics: Research Funding; NextCure: Research Funding; Autolus: Honoraria; Novartis: Honoraria; Pfizer Inc.: Honoraria; GSK: Consultancy, Research Funding; Amgen: Honoraria. Loghavi: Pathology Education Partners; VJ HemeOnc, College of American Pathologists, OncLive, ICCS, MD Education, NCCN, MashUp Media, NCTN, Aptitude Health: Honoraria; Guidepoint; QualWorld; Gerson Lehrman Group, AlphaSight, Arima, Qiagen, Opinion Health: Consultancy; Astellas, Amgen: Research Funding; Abbvie: Current holder of stock options in a privately-held company; Syndx, Servier, BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie, Daiichi Sankyo, BluePrint Medicine, Caris Diagnostics, Recordati, Servier: Consultancy. Kadia: Novartis: Honoraria; Sellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; JAZZ: Research Funding; Servier: Consultancy; Incyte: Research Funding; BMS: Consultancy, Research Funding; ASTEX: Research Funding; Cellenkos: Research Funding; Abbvie: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Pfizer: Research Funding; Rigel: Honoraria; DrenBio: Consultancy, Research Funding; Amgen: Research Funding; Regeneron: Research Funding. DiNardo: AstraZeneca: Honoraria; Riegel: Honoraria; Immunogen: Honoraria; GenMab: Consultancy, Honoraria, Other: data safety board; Genetech: Honoraria; Notable Labs: Honoraria; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; Astex: Research Funding; Cleave: Research Funding; Foghorn: Research Funding; Jazz: Consultancy, Honoraria; Schrodinger: Consultancy, Honoraria; Gilead: Consultancy; Loxo: Research Funding; Astellas: Consultancy, Honoraria; GSK: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Rigel: Research Funding; Amgen: Consultancy; ImmuneOnc: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Stemline: Consultancy. Borthakur: Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Pemmaraju: Novartis: Honoraria, Research Funding; Protagonist Therapeutics: Consultancy; DAVA Oncology: Honoraria, Other: Travel Expenses; Incyte: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Other: Travel Expenses; Cellectis: Research Funding; Affymetrix/Thermo Fisher Scientific: Research Funding; ClearView Healthcare Partners: Consultancy; Aptitude Health: Honoraria; Plexxikon: Research Funding; Bristol-Myers Squibb: Consultancy; Pacylex: Consultancy; Samus Therapeutics: Research Funding; Triptych Health Partners: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Neopharm: Honoraria; Roche Molecular Diagnostics: Honoraria; Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; LFB Biotechnologies: Honoraria; CareDx: Honoraria; Blueprint Medicines: Consultancy, Honoraria; Immunogen: Consultancy; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Maiti: Lin Biosciences: Research Funding; CytoMed Therapeutics: Research Funding; Inspirna: Research Funding; Indapta Therapeutics: Research Funding; Chimeric Therapeutics: Research Funding; Hibercell Inc.: Research Funding. Konopleva: Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Other: clinical trials; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive: Consultancy; Vincerx: Consultancy; Intellisphere: Speakers Bureau; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy; Curis: Consultancy; Servier: Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: clinical trials, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Klondike Biopharma: Research Funding; Auxenion GmbH: Membership on an entity's Board of Directors or advisory committees. Masarova: GSK: Consultancy, Other: Travel support; MorphoSys: Other: Advisory Board Participant; Cogent: Other: Advisory Board Participant; PharmaEssentia: Other: Advisory Board Participant. Montalban-Bravo: Takeda: Research Funding; Rigel: Research Funding. Jabbour: AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Garcia-Manero: Janssen: Research Funding; Helsinn: Research Funding; Aprea: Research Funding; Forty Seven: Research Funding; Curis: Research Funding; Astex: Other: Personal fees; Genentech: Research Funding; Amphivena: Research Funding; Bristol Myers Squibb: Other: Personal fees, Research Funding; Onconova: Research Funding; Astex: Research Funding; Helsinn: Other: Personal fees; Genentech: Other: Personal fees; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Novartis: Research Funding. Andreeff: Boehringer-Ingelheim: Honoraria; Sellas: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Eterna: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Syndax: Honoraria, Research Funding; SentiBio: Current holder of stock options in a privately-held company, Honoraria, Research Funding; Oxford Biomedical: Research Funding; Chimerix: Current holder of stock options in a privately-held company; Oncolyze: Current holder of stock options in a privately-held company; Ellipses: Research Funding; Glycomimetics: Honoraria; Aptose: Honoraria; Ona: Honoraria; Kintor Pharmaceutical: Research Funding; Paraza: Honoraria; Roivant: Honoraria. Ravandi: Amgen: Research Funding; Prelude: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Syndax: Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Syros: Consultancy, Honoraria, Research Funding; Astyex/Taiho: Research Funding. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Daver: Syndax: Consultancy; Celgene: Consultancy; Jazz: Consultancy; Agios: Consultancy; KITE: Research Funding; Astellas: Consultancy, Research Funding; Shattuck Labs: Consultancy; Pfizer: Consultancy, Research Funding; Arog: Consultancy; Gilead: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Menarini Group: Consultancy; Hanmi: Research Funding; Trovagene: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding.