Triplet Therapy with Acalabrutinib, Venetoclax, and Obinutuzumab in Patients with Treatment-Naïve Chronic Lymphocytic Leukemia
In a recent clinical trial of time-limited use of venetoclax plus obinutuzumab, approximately one-third of treatment-naïve patients with chronic lymphocytic leukemia (CLL) and coexisting conditions achieved undetectable minimal residual disease (uMRD) in bone marrow. Because acalabrutinib, a more selective inhibitor of Bruton tyrosine kinase, has been shown to sensitize CLL cells to venetoclax, researchers sought to determine whether a time-limited triplet combination of acalabrutinib, venetoclax, and obinutuzumab (AVO) could result in a high rate of uMRD in bone marrow with acceptable tolerability. At ASH 2019, researchers reported the first assessment of this combination in treatment-naïve patients with CLL.
The ongoing open-label, single-arm, phase 2, investigator-initiated study enrolled treatment-naive patients with CLL without restriction by prognostic marker status. Eligibility criteria included requiring treatment by International Workshop on Chronic Lymphocytic Leukemia criteria, Eastern Cooperative Oncology Group performance status ≤2, and acceptable organ function. Patients received AVO treatment in 28-day treatment cycles, with each agent started sequentially as follows: cycle 1, lead-in with acalabrutinib 100 mg twice daily; cycles 2-3, acalabrutinib plus standard-dose obinutuzumab; cycle 4, venetoclax ramp-up; cycles 5-7, triplet AVO therapy. After 6 months of obinutuzumab, the acalabrutinib plus venetoclax doublet therapy was continued through cycle 15. Patients with uMRD-negative complete response (CR) after cycle 15 could discontinue therapy. All other participants continued treatment with acalabrutinib and venetoclax until completing cycle 24, with the option of discontinuing therapy if they had an MRD-negative CR at that time.
In mid-July 2019, data were cut for an interim analysis. The median age of patients was 63 years (range, 41-78 years). Baseline prognostic features included unmutated IGHV in 62% of patients; TP53-aberrant disease (defined as del(17p) and/or TP53 mutation) in 27% of patients; del(11q) in 30% of patients, and complex karyotype in 19% of patients. Thirty-six of the 37 patients enrolled in the trial continued treatment with a median time on therapy of 8 months (range, 2-11 months). One patient withdrew consent after 6 cycles because of gastrointestinal toxicity.
The overall response rate for the 32 patients who completed restaging at cycle 8 was 100%–25% achieved a CR and 75% had a partial response (PR). At cycle 8 restaging, 68% of patients had uMRD using peripheral blood, and 48% of patients had uMRD based on bone marrow testing. Five (17%) patients had bone marrow–based uMRD and a CR. In 9 patients with TP53-aberrant disease who reached cycle 8, 6 achieved PR and 3 achieved CR, with 3 patients having uMRD in bone marrow.
The most frequent adverse events associated with AVO were fatigue (84% total; 3% grade ≥3) and headache (76% total; 3% grade ≥3). Bruising was reported by 46% of patients (all grade 1/2).
The most frequent grade 3/4 adverse event was neutropenia (70% total; 32% grade ≥3). Infusion-related reactions occurred in 8 patients (22%; 3% grade ≥3). One case of grade 3 atrial fibrillation was reported. No cases of hemorrhage or febrile neutropenia were observed.
Laboratory tumor lysis syndrome (TLS) occurred in 2 patients, both grade 3 immediately after starting obinutuzumab and prior to starting venetoclax. Both patients continued treatment with obinutuzumab. Of 37 patients, 98% were medium-to-high risk for TLS on cycle 1 day 1, but only 2% were medium-to-high risk at venetoclax initiation on cycle 4 day 1, with 4 medium-to-low–risk patients electively admitted for venetoclax initiation.
The researchers concluded that treatment with AVO results in a high proportion of patients with uMRD in bone marrow and a high rate of CR, including patients with TP53-aberrant disease. They also reported that this regimen is well-tolerated with a low rate of infusion reactions and no significant cardiac or bleeding toxicities. Based on these results, researchers are currently enrolling patients in CL-311 (NCT03836261), a randomized phase 3 clinical trial in which AVO will be studied head-to-head against chemoimmunotherapy and a doublet regimen of acalabrutinib plus venetoclax.Lampson B, et al. ASH Abstract 32. Session 642.