Venetoclax Demonstrates Strong Activity in CLL After BCR Inhibitor

John Byrd, MD

Patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who failed on previous treatment with a BCR signaling pathway inhibitor had an overall response rate of 65% following treatment with venetoclax (Venclexta).¹

In this interim analysis of a multicenter, open-label, nonrandomized, phase II trial, researchers observed an ORR of 70% (95% CI, 54-83) among patients enrolled in the main cohort (n = 43) and 60% (95% CI, 43-72) for those enrolled in the expansion cohort (n = 48). ORR was 65% (95% CI, 53-74) for the entire cohort (N = 91).

At the time of analysis, the median follow-up was 19 months (IQR, 9-27) for the main cohort and 12 months (IQR, 8-15) for the expansion cohort. Forty-six patients remained on treatment.

“Few effective options are available for patients with chronic lymphocytic leukemia progressing on or after ibrutinib [Imbruvica] therapy; our data support the use of venetoclax monotherapy in this population,” first author John C. Byrd, MD, division of hematology, department of medicine, The Ohio State University, et al wrote.

“Data for ibrutinib resistance mutations show the potential for venetoclax to eradicate ibrutinib-resistant clones—a finding that has not previously been reported in the context of a prospective clinical trial and represents an important advance in the management of ibrutinib-resistant chronic lymphocytic leukemia. 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 chronic lymphocytic leukemia,” added Byrd et al.

Venetoclax is a first-in-class, oral, selective inhibitor of BCL-2 that regulates cell apoptosis. The agent is approved by the FDA for the treatment of patients with CLL who have a 17p deletion and have received at least 1 prior therapy.

Patients were initially enrolled in the main cohort of the study, but a protocol amendment permitted enrollment to an expansion cohort to further establish the activity of venetoclax in this population. The washout period for a previous BCR inhibitor was 7 days in the main cohort and 3 days in the expansion cohort.

Eligible adults had received previous BCR signaling pathway inhibitor therapy with ibrutinib or idelalisib (Zydelig) as their last previous BCR inhibitor, required therapy according to the 2008 IWCLL criteria, ECOG performance score of 2 or lower, adequate bone marrow function, and creatinine clearance of 50 mL/min or higher. Patients with all CLL molecular subtypes were included.

Patients were assigned to 20 mg of oral venetoclax once daily for 1 week, followed by weekly ramp-up to a daily 50 mg, 100 mg, and 200 mg dose, up to the final daily dose of 400 mg per day by week 5. In the expansion cohort, an accelerated dose ramp-up to 400 mg daily by week 3 was permitted for patients who had a high tumor burden with clinical signs of rapid progression during screening. Dose escalation of venetoclax to 600 mg was allowed in the expansion cohort for patients who did not respond to treatment after response assessment at week 12.

Treatment continued for up to 2 years or until disease progression or discontinuation because of other reasons, and patients were removed from the study at that time.

At data cutoff, 26 patients had experienced a disease progression event. Investigator-assessed median time to progression for all patients was 24.7 months (95% CI, 19.6 to not reached). At 12 months, an estimated 80% (95% CI, 69-87) of patients had not progressed. Thirty-three patients had a progression-free survival (PFS) event at data cutoff. Median PFS was 24.7 months (95% CI, 19.2 to not reached) and estimated 12-month PFS was 75% (95% CI, 64-83).

Median overall survival (OS) was not reached (95% CI, 27.8-not reached) and estimated 12-month OS was 91% (95% CI, 83-95). Fifteen patients had recurrence or disease progression.

Among responding patients, median duration of response was not reached (95% CI, 17.6-not reached). An estimated 88% (95% CI, 76-95) of patients were still responding at 12 months.

Seventeen patients died during the study, including 6 deaths due to adverse events (AEs) within 30 days after the last dose of venetoclax and 7 who died due to progression.

In total, 45 patients discontinued venetoclax during the study, 27 in the main cohort and 18 in the expansion cohort. Progression (24%) was the primary reason for discontinuation, followed by Richter's transformation (5%).

Overall, the most common AEs of any grade were neutropenia (62%), nausea (57%), anemia (53%), diarrhea (52%), and thrombocytopenia (47%). The frequency of these AEs was similar in the main and expansion cohorts.

Grade 3/4 treatment-emergent adverse events (TEAEs) were primarily hematological and included neutropenia (51%), anemia (29%), thrombocytopenia (29%), decreased white blood cell count (19%), and decreased lymphocyte count (15%).

Forty-five patients (50%) experienced a serious AE, including febrile neutropenia (11%) and pneumonia (6%). Serious adverse events possibly related to venetoclax treatment were febrile neutropenia (n = 2), pneumonia (n = 1), increased potassium levels (n = 1), hyperphosphatasemia (n = 1), and hyperkaliemia (n = 1).

Writing in an accompanying editorial, Francesca R. Mauro, MD, PhD, and Robin Foá, MD, department of cellular biotechnologies and haematology, Sapienza University, Rome, Italy, discussed the value of venetoclax after BCR signaling pathway inhibition.²

“The results of this trial show the capacity of venetoclax, through BCL-2 inhibition, to overcome not only the negative effect of a TP53 mutation, but also ibrutinib resistance due to the emergence of mutations,” they wrote. “This new information is important for optimal management of patients with chronic lymphocytic leukemia progressing on ibrutinib. Taken together, the results of this trial are reassuring and have relevant clinical implications, especially now that ibrutinib has been approved as a first-line treatment for patients with chronic lymphocytic leukemia. As ongoing randomized trials investigate frontline combination regimens involving venetoclax, the next question to be addressed will be how to treat patients who progress after initial therapy with this drug.”

References

1. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial [published online December 12, 2017]. Lancet Oncol doi: 10.1016/S1470-2045(17)30909-9.
2. Mauro FR, Foá R. Venetoclax: a chance for patients with chronic lymphocytic leukaemia previously treated with ibrutinib [published online December 12, 2017]. Lancet Oncol doi: 10.1016/S1470-2045(17)30910-5.