In January 2018, preliminary data (cut-off date of June 2016) from a dual-stage, non-randomized phase Ib study (NCT02203773), which is assessing the safety and efficacy of venetoclax, a BCL2 inhibitor, in combination with hypomethylating agents (HMA), decitabine or azacitidine in elderly patients with treatment naïve acute myeloid leukemia (AML) patients who are ineligible for standard induction therapy were published in Lancet Oncology. The findings from the study demonstrated that venetoclax plus azacitidine or decitabine was well tolerated in newly diagnosed patients with AML who are unfit for standard chemotherapy with promising preliminary efficacy and low early mortality rate.
In a first edition article published in Blood on 25 October 2018, Courtney D. DiNardo from The University Texas MD Anderson Cancer Center, Houston, TX, and colleagues reported efficacy and safety data (cut-off date of July 7, 2017) from the combined dose-escalation and expansion phases of this study with an extended follow-up.
Oral venetoclax was co-administered at 400, 800, or 1200 mg daily with 20 mg/m2 of decitabine on days 1–5 or 75 mg/m2 of AZA on days 1–7, each 28-day cycle. One-hundred and forty-five patients (median age = 74 years, range: 65–86) received either venetoclax at a dose of 400 mg (n = 60 [29 azacitidine, 31 decitabine]), 800 mg (n = 74 [37 each azacitidine or decitabine]) or 1200 mg (n = 11 [6 azacitidine, 5 decitabine]).
- Most common grade 3–4 adverse events (AEs) occurring in > 30% of patients included febrile neutropenia (43%), thrombocytopenia (24%), decreased WBC count (31%), pneumonia (13%), neutropenia (17%) and anemia 25%)
- No tumor lysis syndrome was observed
- ≤ 30-day mortality rate: 3% (5/145)
- ≤ 60-day mortality rate: 8% (11/145)
- Median duration of follow-up: 15.1 months (range, 9.8–31.7)
- Overall response rate (ORR): 68% (99/145)
- Forty-five percent of responders maintained response of > 12 months
- Median duration of response
- Complete remission (CR): 37%
- CR with incomplete blood count recovery (CRi): 30%
- Median duration of CR/CRi: 11.3 months (95% CI, 8.9–NR)
- Overall leukemia response rate (CR + CRi + partial remission + morphologic leukemia-free state): 83% (120/145)
- CR/CRi rate in patients receiving venetoclax (400 mg) plus HMA: 73%
- Median duration of response CR/CRi: 12.5 months (95% CI, 7.8–NR)
- CR/CRi rate in patients receiving venetoclax (800 mg) plus HMA: 65%
- Median duration of response CR/CRi: 11 months (95% CI, 6.5–12.9)
- Median OS: 17.5 months (95% CI, 12.3–NR)
- Median OS in patients receiving 400 mg venetoclax plus HMA: NR (95% CI, 11.0–NR)
- Median OS in patients receiving 800 mg venetoclax plus HMA: 17.5 months (95% CI, 10.3–NR)
- Minimal residual disease (MRD) assessment demonstrated that 29% (28/97) of patients with CR/CRi achieved MRD negative status (MRD negativity was defined as less than 10-3 leukemic cells at any measurement in bone marrow aspirates)
In summary, “the low-intensity regimen of venetoclax combined with decitabine or azacitidine demonstrated promising efficacy and a tolerable safety profile in elderly patients with AML unfit for intensive chemotherapy, with a high CR+CRi rate of 73% in the 400-mg venetoclax + HMA cohort, low early mortality rates, and OS extending beyond 17 months”. Courtney DiNardo discusses this study in an interview with the AML Global Portal.
Based on the findings of this study, a phase III study (NCT02993523) which is evaluating venetoclax 400 mg combined with azacitidine in adults with untreated AML ineligible for intensive chemotherapy is currently underway.