In a single-institution phase II trial reported in the Journal of Clinical Oncology, Rogers et al found that the combination of obinutuzumab, ibrutinib, and venetoclax produced high response rates in both treatment-naive and relapsed or refractory chronic lymphocytic leukemia.

Study Details

A total of 50 patients were enrolled at The Ohio State University between August 2015 and April 2017, including 25 treatment-naive patients and 25 patients with relapsed or refractory disease. Treatment was given in 14 28-day cycles.

Obinutuzumab was given at 1,000 mg on days 1 to 2 (split dose), 8, and 15 of cycle 1 and day 1 of cycles 2 to 8. Ibrutinib at 420 mg daily was given continuously in cycles 2 to 14; single-agent ibrutinib could be continued after cycle 14 at investigator discretion. Venetoclax was started on day 1 of cycle 3 at 20 mg daily with a ramp-up every 7 days to 50 mg, 100 mg, 200 mg, and the target dose of 400 mg, with treatment continuing through cycle 14. The primary endpoint was rate of complete remission with undetectable minimal residual disease (MRD) in both blood and bone marrow at 2 months after completion of treatment.

Responses

After eight cycles of treatment, response was observed in 24 patients (96%) in the treatment-naive cohort, including complete remission in 1 (4%), complete remission with incomplete marrow recovery in 7 (28%), and partial remission in 16 (64%). At this time point, responses were observed in 23 patients (92%) in the relapsed/refractory cohort, including complete remission in 3 (12%), complete remission with incomplete marrow recovery in 3 (12%), and partial remission in 17 (68%).

At 2 months after the end of treatment, response was observed in 21 patients (84%) in the treatment-naive cohort, including complete remission in 6 (24%), complete remission with incomplete marrow recovery in 2 (8%), and partial remission in 13 (52%). At this time, response was observed in 22 patients (88%) in the relapsed/refractory cohort, including complete remission in 10 (40%), complete remission with incomplete marrow recovery in 2 (8%), and partial remission in 13 (52%).

At 2 months after the end of treatment, complete remission with undetectable MRD in blood and bone marrow was observed in seven patients (28%) in each cohort. No detectable MRD in both blood and marrow was observed in 7 (54%) of 13 patients in the treatment-naive cohort with partial remission and in 4 (36%) of 11 patients in the relapsed/refractory cohort with partial remission. Among patients who completed the study regimen, no detectable MRD was found in 14 (67%) of 21 patients in the treatment-naive cohort and 11 (50%) of 22 in the relapsed/refractory cohort.

At a median follow-up of 24.2 months in the treatment-naive cohort and 21.5 months in the relapsed/refractory cohort, median progression-free and overall survival were not reached, with one patient having disease progression and one patient dying.  

Adverse Events

The most common treatment-related adverse events of any grade were neutropenia (94%), thrombocytopenia (90%), hypertension (82%), and hypocalcemia (82%). The most common treatment-related grade 3 or 4 adverse event was neutropenia (66%, including 56% of the treatment-naive cohort and 76% of the relapsed/refractory cohort). The most common treatment-related grade 3 or 4 nonhematologic adverse events were hypertension (38%) and hyponatremia (10%).

Atrial fibrillation was observed in 10% of patients. Febrile neutropenia was observed in one patient. No patients developed tumor-lysis syndrome. Adverse events led to discontinuation of treatment in three patients (6%).

The investigators concluded: “The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials [ClinicalTrials.gov identifiers NCT03701282 and NCT03737981].”

Kerry A. Rogers, MD, of The Ohio State University, Columbus, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Genentech and in part by the Four Winds Foundation, Leukemia and Lymphoma Society, Vysis (part of Abbott Molecular), and grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.