Maximal Tolerated Dose of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction in Previously Untreated Adults with Acute Myeloid Leukemia (AML)

Background: Although daunorubicin/cytarabine (“3+7”)-based chemotherapy produces complete remission (CR) rates of 70% in younger adults, a significant proportion require re-induction to achieve CR or are refractory. Among those achieving CR, relapse after post-remission therapy is common and limits cure. Venetoclax (VEN) is an oral, selective BCL-2 inhibitor that promotes mitochondrial-mediated apoptosis in myeloblasts during cytotoxic stress. VEN plus hypomethylating agents in untreated unfit elderly AML patients (pts) elicits high response rates and improves overall survival. We hypothesize that VEN in combination with “3+7” could lead to a higher rate of measurable residual disease (MRD)-negative CR, perhaps obviating the need for reinduction as well as limiting relapse without undue toxicity. Methods: The primary objective of this phase 1 study was to determine the maximum tolerated dose (MTD) of VEN plus “3+7” induction and cytarabine-based consolidation therapy in previously untreated AML pts. Pt eligibility includes previously untreated AML, Results: Two of the first 6 pts on VEN 200 experienced DLTs (rapidly resolving grade 4 DIC after a single dose of VEN 50 mg and death at day 14 of sepsis in a 73 year old man). Given 2/6 DLT events, an amendment allowed further accrual at the starting dose of VEN 200 mg but restricted accrual to age 18-60 years. All 3 pts on the expanded cohort and 3/3 at the 400 mg cohort have responded, and none experienced a DLT. The trial expanded to treat pts with 600 mg of VEN, but a 24 yo F experienced a septic death on day 9. Therefore, the 400 mg dose level was determined to be the MTD. At the VEN 200 dose level (n=7), the median time to ANC recovery ≥ 0.5K/ul and platelet recovery ≥ 50 K/ul was 33 days (range 24-38) and 29 days (range 17-55), respectively; at VEN 400 (n=3) 29 days (range 22-34) and 24 days (23-25), respectively. All 10 evaluable pts responded (9CR/1CRi); each achieved CR with a single induction cycle. 6/8 assessed achieved MRD negativity by flow cytometry. The table lists the specific pt characteristics, adverse events and outcome. Conclusions: VEN 400 mg/d d1-11 with “3+7” induction starting on d 2 can be given safely in pts age 18-60 with newly diagnosed AML. The regimen appears highly active. Moving forward, pts will be treated with 3+7/VEN 400 induction followed by high dose cytarabine starting on day 2 plus VEN 200 (and 400 or 600 potential cohorts) d1-8. Prophylactic anti-gut flora antibiotics will accompany all courses. The 3+7/VEN 400 induction regimen derived from this trial will be compared to 3+7 in non-favorable risk newly diagnosed AML pts ages 18-60 and VEN/high dose cytarabine post-remission therapy evaluated in the context of North American Intergroup studies. Download : Download high-res image (385KB) Download : Download full-size image Table . Disclosures Stone: Stemline: Consultancy; Astellas: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Actinium: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Takeda: Other: DSMB; Syntrix: Other: DSMB; Syndax: Consultancy, Research Funding; Trovagene: Consultancy; Biolinerx: Consultancy; Macrogenics: Consultancy; Argenix: Other; Jazz: Consultancy; Janssen: Consultancy; Aztra-Zeneca: Consultancy; Celgene: Consultancy, Other; Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding. DeAngelo: Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Agios: Consultancy; Autolos: Consultancy; Amgen: Consultancy; Incyte Corporation: Consultancy; Glycomimetics: Research Funding; Abbvie: Research Funding; Takeda: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy. Letai: Dialectic: Membership on an entity’s Board of Directors or advisory committees; Flash Therapeutics: Membership on an entity’s Board of Directors or advisory committees; Zentalis: Membership on an entity’s Board of Directors or advisory committees; AstraZeneca: Consultancy; AbbVie: Consultancy; Novartis: Research Funding; Chugai: Other: Lecture Fees. Konopleva: Ablynx: Research Funding; Calithera: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; AstraZeneca: Research Funding; Forty-Seven: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; Amgen: Consultancy; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Garcia: Genentech: Research Funding; Eli Lily: Research Funding; Pfizer: Research Funding; AbbVie: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Venetoclax used with standard AML induction therapy