Venetoclax Active in Ibrutinib-Refractory CLL

The BCL-2 inhibitor venetoclax has durable clinical activity in the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) whose disease progressed during or after treatment with Bruton tyrosine kinase–targeting ibrutinib, according to the results of a phase II study published in Lancet Oncology.

“Few effective options are available for patients with CLL progressing on or after ibrutinib therapy; our data support the use of venetoclax monotherapy in this population,” wrote Jeffrey A. Jones, MD, of the Ohio State University, and colleagues. “As novel targeted drugs become more widely available, continued investigation of treatment in patients with disease while on or progression after BCR inhibitor therapy is crucial to advance the treatment of CLL.”

Although ibrutinib has changed treatment of CLL, many patients will become refractory to or relapse after treatment with the drug. Venetoclax is a small-molecule inhibitor of BCL-2 and is approved for patients with CLL with del(17p13.1) chromosomal abnormality with at least one prior therapy.

In this study, Jones and colleagues wanted to test the clinical activity of venetoclax in patients with relapsed disease or those refractory to ibrutinib. The trial included 127 patients with previously treated disease. Ninety-one patients had received ibrutinib as the last BCR therapy before trial enrollment; 43 patients were enrolled in a main cohort and 48 in an expansion cohort. The study was amended to include an expansion cohort that could have previous BCR inhibitor exposure with a 3-day washout period.

With a median follow-up of 14 months, 65% of patients had an overall response; 70% of patients in the main cohort and 60% in the expansion cohort responded. More than half of patients (56%) had a partial response or a nodular partial response, and 9% had a complete response or a complete response with incomplete bone marrow recovery.

“Responses were also observed in patients with historically poor outcomes, including those who discontinued previous ibrutinib because of disease progression and those with high-risk chromosomal abnormalities,” the researchers wrote.

At data cutoff, 26 patients had a disease progression event. The median time to progression was 24.7 months; 80% of patients had not progressed at 12 months.

The most common treatment-emergent grade 3 or worse adverse events were neutropenia (51%), thrombocytopenia (29%), anemia (29%), decreased white blood cell count (19%), and decreased lymphocyte count (15%). Nineteen percent of enrolled patients died including seven patients who died from disease progression. No treatment-related deaths occurred.

“The interim analysis of this trial shows that venetoclax treatment was associated with a high proportion of overall responses in patients progressing after ibrutinib, including in those with ibrutinib resistance mutations, many of whom were heavily pretreated and harbored high-risk genetic aberrations,” the researchers wrote. “The results of this study are consistent with others showing that venetoclax has a meaningful clinical activity and favorable tolerability across high-risk patient groups with CLL.”

According to the researchers, data on the patients who received idelalisib as their last therapy will be reported separately.