The efficacy and safety of VENCLEXTA (venetoclax tablets) in combination with low-dose cytarabine (VEN+LDAC; N=143) vs placebo with low-dose cytarabine (PBO+LDAC; N=68) were evaluated in VIALE-C, a double-blind, randomized trial in patients with newly diagnosed AML.
At baseline, patients were ≥75 years of age, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria:
- Baseline ECOG performance status of 2-3
- Severe cardiac or pulmonary comorbidity
- Moderate hepatic impairment
- CLcr <45 mL/min, or
- Other comorbidity
- Patients received VENCLEXTA 600 mg orally once daily on Days 1-28 following completion of the ramp-up dosing schedule or placebo in combination with cytarabine 20 mg/m2 subcutaneously once daily on Days 1-10 of each 28-day cycle beginning on Cycle 1, Day 1
- During the 4-day ramp-up phase, patients received TLS prophylaxis and were hospitalized for monitoring
Bone marrow assessment:
- A bone marrow assessment was performed following Cycle 1 of treatment. If bone marrow assessment confirmed a remission, defined as less than 5% leukemia blasts with cytopenia, VENCLEXTA or placebo was interrupted up to 14 days or until ANC ≥500/microliter and platelet count ≥50 × 103/microliter
- For patients with resistant disease at the end of Cycle 1, a bone marrow assessment was performed after Cycle 2 or 3 and as clinically indicated
- LDAC was resumed on the same day as VENCLEXTA or placebo following interruption
- Patients continued to
receive treatment until disease progression or unacceptable
The median age of patients treated with VEN+LDAC was 76 years (range: 36-93 years). ECOG performance status at baseline was 0-1 for 52% of patients, 2 for 44% of patients, and 3 for 4.2% of patients.
Mutations identified were as follows:
- 20% (22/112) with TP53
- 19% (21/112) with IDH1 or IDH2
- 18% (20/112) with FLT3
- 16% (18/112) with NPM1
Intermediate or poor cytogenetic risk was present in 63% and 33% of patients, respectively.
The median age of patients treated with PBO+LDAC was 76 years (range: 41-88 years). ECOG performance status at baseline was 0-1 for 50% of patients, 2 for 37% of patients, and 3 for 13% of patients.
Mutations identified were as follows:
- 23% (12/52) with IDH1 or IDH2
- 17% (9/52) with FLT3
- 17% (9/52) with TP53
- 13% (7/52) with NPM1
Intermediate or poor cytogenetic risk was present in 63% and 29% of patients, respectively.
Efficacy was based on the rate of CR and duration of CR with supportive evidence of rate of CR+CRh, duration of CR+CRh, and the rate of conversion from transfusion dependence to transfusion independence.
- VEN+LDAC: 27% (95% CI: 20, 35); mDOCR: 11.1 months (95% CI: 6.1, –)
- PBO+LDAC: 7.4% (95% CI: 2.4, 16); mDOCR: 8.3 months (95% CI: 3.1, –)
- VEN+LDAC: 47% (95% CI: 39, 55); mDOCR+CRh: 11.1 months
- PBO+LDAC: 15% (95% CI: 7.3, 25); mDOCR+CRh: 6.2 months
- The median time to first response of CR or CRh was 1.0 month (range: 0.7-5.8 months) with VEN+LDAC treatment
- The rate of RBC and/or
platelet transfusion dependence to independence* was 33% (37/111) in
the VEN+LDAC arm vs 13% (7/55) in the PBO+LDAC arm
VEN+LDAC did not significantly improve OS vs PBO+LDAC. HR for OS was 0.75 (95% CI: 0.52, 1.07); P=0.114. The median OS for the VEN+LDAC arm was 7.2 months (95% CI: 5.6, 10.1) and for the PBO+LDAC arm was 4.1 months (95% CI: 3.1, 8.8).
Complete remission (CR) was defined as ANC >1,000/microliter, platelets >100,000/microliter, red blood cell transfusion independence, and bone marrow with <5% blasts. Absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease. 1
Complete remission with partial hematologic recovery (CRh) was defined as <5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets >50,000/microliter and ANC >500/microliter). 1
*Transfusion independence was defined as no RBC and no platelet transfusion during any consecutive ≥56-day post-baseline period.
CI=confidence interval; FLT=fms-like tyrosine kinase; NPM=nucleophosmin; IDH=isocitrate dehydrogenase; TP53=tumor protein 53; TTFR=time to first response; ECOG=Eastern Cooperative Oncology Group; CLcr=creatinine clearance; ANC=absolute neutrophil count; mDOCR+CRh=median duration of complete remission and complete remission with partial hematologic recovery.