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

J Clin Oncol. 2020 Nov 1;38(31):3626-3637. doi: 10.1200/JCO.20.00491. Epub 2020 Aug 14.


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: NCT02427451.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives
  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
  • CD4 Lymphocyte Count
  • Cognition / drug effects*
  • Female
  • Follow-Up Studies
  • Humans
  • Hypertension / chemically induced
  • Hyponatremia / chemically induced
  • Killer Cells, Natural*
  • Leukemia, Lymphocytic, Chronic, B-Cell / blood
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Male
  • Middle Aged
  • Neoplasm, Residual
  • Neutropenia / chemically induced
  • Piperidines / administration & dosage
  • Progression-Free Survival
  • Quality of Life
  • Remission Induction
  • Retreatment
  • Sulfonamides / administration & dosage
  • Survival Rate
  • Thrombocytopenia / chemically induced
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • Bridged Bicyclo Compounds, Heterocyclic
  • Piperidines
  • Sulfonamides
  • ibrutinib
  • Adenine
  • venetoclax
  • obinutuzumab

Associated data