In 2016, the U.S. Food and Drug Administration granted venetoclax accelerated approval for the treatment of adults with previously treated chronic lymphocytic leukemia (CLL) with del17p, based on results from a single-arm, phase II trial that enrolled 107 patients. In a report published in the Journal of Clinical Oncology, investigators reported results from an extended analysis of the full trial population, which further support the BCL2 inhibitor’s role in treating patients with either treatment-naïve or relapsed/refractory CLL.
“With up to an additional 11 months on therapy across all 158 enrolled patients, we now report an objective response rate (ORR) of 77 percent, with a 20 percent investigator-assessed complete remission rate,” the study authors, led by Stephan Stilgenbauer, MD, from Ulm University in Germany, wrote. The researchers also reported minimal residual disease (MRD) data for the first time, finding that approximately 30 percent of participants achieved MRD-negative status.
The open-label trial enrolled adults with relapsed/refractory or previously untreated CLL with the del17p mutation who had an indication for treatment according to the 2008 Modified International Workshop on CLL criteria. Participants also had Eastern Cooperative Oncology Group performance status scores of 0-2 and adequate bone marrow function. Those who had undergone an allogeneic hematopoietic cell transplantation were excluded from the trial.
A total of 158 patients (median age = 67 years; range = 29-85 years) were enrolled, including five patients with previously untreated CLL. Patients had received a median of two prior therapies (range = 0-10 therapies); the most common prior therapy was a fludarabine-containing regimen (n=103; 65%) and 16 patients had received a kinase inhibitor (10%). In addition to del17p, many patients also had high-risk prognostic features, including unmutated IGHV status (78%), TP53 mutation (71%), or del11q (24%).
Single-agent venetoclax was administered in a stepwise dose ramp-up to mitigate the risk of tumor lysis syndrome (TLS), from 20 mg on day 1 to a target dose of 400 mg once daily over four to five weeks.
As of April 4, 2017 (data cutoff date), median time on venetoclax was 23.1 months (range = 0-44.2 months) and median time on study was 26.6 months (range = 0-44.2 months). Half of patients (n=79) were still on study, and 72 were still on study drug. Fifty-three patient deaths occurred during study follow-up, 44 of which (83%) were related to disease progression.
Investigator-assessed ORR for all patients was 77 percent (n=122/158). Complete details about response rates are presented in the TABLE.
Disease response occurred rapidly, the authors noted, with a median time to first response of one month (range = 0.5-4.4 months). Among responders, two-thirds (n=81) were still responding at 24 months, with an estimated median duration of response of 33.2 months (range = 26.7 months to not reached).
In the entire intent-to-treat population, the rates of 24-month progression-free survival (PFS) and overall survival (OS) were 54 percent and 73 percent, respectively. While estimated median PFS was 27.2 months (range = 21.9 months to not reached) in the intention-to-treat population, it was not reached in those with complete remission (CR) or CR with incomplete hematologic recovery. Median OS could not be estimated, the researchers noted.
Thirty percent (n=48/158) of patients achieved MRD-negative status (defined as MRD <10-4 cells/kg on flow cytometry), including one patient whose disease failed to respond to kinase inhibitor therapy. “For patients who achieved MRD negativity in the peripheral blood at any time during the study, estimated PFS was 78 percent at 18 months after attainment of MRD-negativity, compared with estimated PFS of 51 percent for MRD-positive patients,” the authors reported.
The safety profile of venetoclax “was consistent with that of previous reports of monotherapy in relapsed/refractory CLL,” the researchers noted. The most common all-grade adverse events (AEs) were neutropenia (42%), diarrhea (39%), nausea (37%), and anemia (25%). Grade 3/4 AEs were primarily hematologic, including neutropenia (40%), thrombocytopenia (15%), and anemia (15%). Cytopenias were “common but manageable with supportive care and/or dose adjustments,” they added.
No episodes of clinical TLS were observed, while eight patients (5%) experienced episodes of laboratory TLS – all of which occurred during the dose ramp-up period. However, these were managed with intravenous hydration, standard management of laboratory abnormalities, and/ or dose interruptions. “Clinicians who start venetoclax in patients with del17p CLL outside of a clinical trial setting should closely follow label recommendations to minimize the risk of TLS and to manage any cases that occur so that treatment can continue at the target dose of 400 mg once daily,” the investigators wrote.
The study’s findings are limited by its single-arm design and the relatively short follow-up. “Continued observation of patients in this trial is needed to provide additional data on the potential for venetoclax to achieve long-term PFS for patients with CLL,” the authors concluded. The small number of enrolled patients with previously untreated CLL also may limit the findings’ applicability to this population.
The authors report financial relationships with AbbVie and Genentech, which are joint manufacturers of venetoclax and supported this study.
Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018;36:1973-80.