Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia

Abstract

PURPOSE The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION 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.

Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia

“…mutated IGHV genes), the chemoimmunotherapy combination regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) allows the achievement of undetectable minimal residual disease and long-term remissions (18). More recently, combinations including multiple targeted drugs with a different mechanism of action, such as BTK and Bcl-2 inhibitors with or without anti-CD20 monoclonal antibodies (mAb), have shown very promising results in terms of depth and durability of response, although data are not yet mature (19)(20)(21).…”

Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

“…Roger et al tested the triplet regimen of ibrutinib, venetoclax, and obinutuzumab in patients with previously untreated and relapsed/refractory CLL 84 . This is another example of successful time-limited trial for a total of 14 cycles.…”

Novel Agents in Chronic Lymphocytic Leukemia: New Combination Therapies and Strategies to Overcome Resistance

“…While more recently, ibrutinib and acalabrutinib have been tested within fixed-duration combinations, these combinations of novel agents are not yet approved. Hence, their main use remains as monotherapy that is given until disease progression or unacceptable toxicity [ 27 , 28 , 29 , 30 ]. Adding to the financial burden and side effects associated with an indefinite therapy, the continued exposure to BTKi seems to promote the acquisition of resistance mutations.…”

“…Venetoclax, a BH3 mimetic, has been developed to bind Bcl-2 at the same site as BH3-only proteins to effectively inhibit Bcl-2 [ 60 ]. After clinical studies in CLL have consistently shown impressive activity of venetoclax in all therapeutic settings as monotherapy as well as in combinations, it has been approved for the treatment of patients with previously untreated and relapsed/refractory CLL [ 7 , 8 , 27 , 28 , 29 , 30 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…The shorter triple combination of ibrutinib, venetoclax and obinutuzumab was studied extensively as well. A phase 2 study of the combination in treatment-naïve and relapsed/refractory patients with CLL was recently published and yielded high response rates, high rates of uMRD and durable remissions [ 30 ]. The same combination was studied in the phase 2 CLL2-GIVe trial, in which patients with detectable post-treatment MRD could continue ibrutinib treatment until cycle 36.…”