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Combining BTK and BCL2 Inhibitors in Front-Line Treatment of CLL: Phase II Trial

By: Jenna Carter, PhD
Posted: Wednesday, December 1, 2021

The current use of BTK and BCL2 inhibitors as front-line treatments for chronic lymphocytic leukemia (CLL) may provide durable responses but requires continuous long-term therapy and monitoring. However, a group of researchers examined a combination of a more specific BTK inhibitor with other first-generation drugs to assess its efficacy in a preclinical setting. The findings from this phase II clinical trial were published in The Lancet Oncology. Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute, Boston, and colleagues reported that 38% of participants had complete remission with undetectable minimal residual disease (MRD) in the bone marrow.

“We and others have previously found that BTK and BCL2 inhibitors are synergistic in the preclinical setting in CLL. We hypothesized that combining the more specific BTK inhibitor acalabrutinib with venetoclax and obinutuzumab in an MRD-guided, time-limited regimen would lead to deep remissions with good tolerability…,” stated Dr. Brown and colleagues.

A total of 37 patients with CLL were enrolled in this study. Patients were treated in 28-day cycles of acalabrutinib monotherapy orally at 100 mg twice daily for cycle 1, then combined with six cycles of intravenous obinutuzumab. From the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up dosage scale. The primary endpoint was complete remission with undetectable MRD in the bone marrow; safety and activity endpoints were assessed in all patients.

Findings revealed that 38% (95% confidence interval (CI) = 22%–55%) of participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 hematologic adverse event was neutropenia, and the most common grade 3 or 4 nonhematologic adverse events were hyperglycemia and hypophosphatemia. Furthermore, there were no deaths reported in this study.

Disclosure: For full disclosures of the study authors, visit, thelancet.com.



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