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.

Trial registration: ClinicalTrials.gov NCT02427451.

FIG 1.

Response to treatment. Response to treatment is shown for both the treatment-naïve (TN) and relapsed or refractory (RR) cohorts at the midtherapy assessment after cycle 8 and at the end-of-treatment assessment 2 months after completion of cycle 14. In the TN cohort at the midtherapy assessment, responses were 1 complete remission (CR; 4%), 7 CRs with incomplete marrow recovery (CRis; 28%), 16 partial remissions (PRs; 64%), and 1 not reached (NR; 4%). At end of treatment in TN patients, responses were 6 CRs (24%), 2 CRis (8%), 13 PRs (52%), and 4 NRs (16%). In the RR cohort at the midtherapy assessment, responses were 3 CRs (12%), 3 CRis (12%), 17 PRs (68%), and 2 NRs (8%). At end of treatment in RR patients, responses were 10 CRs (40%), 1 CRi (4%), 11 PRs (44%), and 3 NRs (12%).

FIG 2.

Minimal residual disease in the blood. Changes in detectable chronic lymphocytic leukemia (CLL) in blood during the first 9 cycles of treatment and by month of posttreatment follow-up are shown (n = 50). Circulating leukemia cells were determined by standard 10-color flow cytometry using the cutoff of 10⁻⁴ for detectable disease. Testing was performed on the first day of each cycle up to cycle 9 or the denoted number of months after completion of cycle 14 of treatment. C, cycle; D, day; MRD, minimal residual disease.

FIG 3.

(A) Progression-free survival (PFS) and (B) overall survival (OS) for all patients are shown by cohort. The median PFS and OS times were not reached in either cohort. RR, relapsed or refractory; TN, treatment naïve.

FIG 4.

Changes in measures of cognitive function and health-related quality of life. Estimated marginal means and 95% CIs for (A) Reported Outcomes Measurement Information System Version 2.0 Cognitive Function-Concerns (PROMIS-CF-Concerns) T-scores, (B) Auditory Verbal Learning Test Z-scores, and (C) Controlled Oral Word Association Test (COWAT) Z-scores, with age- and sex-matched control means (dotted line), are shown at several time points during treatment. Estimated marginal means and 95% CIs for the (D) Short Form-36 Health Survey (SF-36) Physical Component Scale T-scores and (E) Mental Component Scale T-scores (E) are also shown with US general population norms (dotted line). In all cases, higher scores indicate better performance or fewer difficulties. C, cycle; D, day.