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, <5% FLT3 mutant VAF, non-CBF positive, no strong CYP3A inhibitors/inducers (days -7 to 11), normal organ function, WBC<25 K/ul at day 1 (hydroxyurea allowed pre VEN), and age ≥18. The study was amended to restrict age to 18-60 after the first 6 pts. VEN was given during induction for 11 days (d 1-11) in cohorts of 200, 400, and 600 mg/d (after ramp-up: 50, 50, 100, 200; 50, 100, 200, 400; 50, 100, 200, 400, 600, respectively) plus daunorubicin 60 mg/m²/d IVP d 2-4 and cytarabine 200 mg/m²/d IVCI d 2-8. A day 15 marrow determines the need for a second induction consisting of the same doses of VEN d 1-8, daunorubicin d 2-3 and cytarabine IVCI d 2-6. VEN escalation is carried out in 3+3 fashion. After the MTD for VEN during induction was determined pts are treated at that dose during induction and remitting pts given escalating doses of VEN (cohorts of 200, 400, 600 mg) d1-8 in a 3+3 fashion beginning one dose level below the MTD, with a single cycle of cytarabine 3g/m² over 3 h q12h on days 1, 3, and 5. A 10 pt confirmation cohort will be accrued at the MTDs for induction (VEN 400) and consolidation. Dose-limiting toxicity (DLT) is defined as any death, delayed neutrophil recovery (failure to achieve absolute neutrophil count (ANC) ≥ 500/mL by day 42 in pts without residual AML), or any grade 3/4 non-heme toxicity not clearly due to chemotherapy alone. A marrow exam, including an assessment of MRD by multiparameter flow cytometry with a sensitivity of 0.02%, is carried out at the time of count recovery during induction, or by day 42. Correlative studies include BH3 profiling (Vo TT, Cell 2012) and CyTOF conducted on pre-treatment leukemic blasts to preliminarily assess biomarkers of response.

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.

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