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A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia


This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL.

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Fig. 1: Trial schema.
Fig. 2: Clinical response and minimal residual disease (MRD).
Fig. 3: Survival analysis for all patients.
Fig. 4: Cytokine and BH3 profiling assays.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.


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The authors would like to thank the patients and caregivers who participated in this study, as well as all the clinical support staff involved in their care. The authors additionally acknowledge the support of the ICCB-Longwood Screening Facility at Harvard Medical School and specifically Jennifer Smith and Richard Siu in relation to production of the BH3 profiling plates. Genentech, Inc. provided support and research funding for this study.

Author information

Authors and Affiliations



MSD and JRB designed the study, and MSD is the principal investigator and Sponsor-investigator for the study. DMB, PMB, JRB, and MSD treated patients and supervised data analysis. CER, JSA, EDJ, ASL, and DCF treated patients and contributed to data acquisition. MCC, SMF, MMM, HAW, and MRM collected data. SV, YR, and YZ performed statistical analysis. CER and LRH performed BH3 profiling studies and data analysis. CER and MSD wrote the manuscript. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Matthew S. Davids.

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Competing interests

CER has received an honorarium from Research to Practice. DMB has served as a consultant for AbbVie, Pharmacyclics, Pfizer, and TG Therapeutics, and has received institutional research funding from AbbVie, ArQule/Merck, Ascentage (transitioning), AstraZeneca/Acerta, BeiGene, Catapult, DTRM, Genentech, Juno/Celgene/BMS, MEI Pharma, NeWave, Pharmacyclics, and TG Therapeutics. PMB has received consulting income from Abbvie, Adaptive, AstraZeneca, BeiGene, Celgene/BMS, Genentech, Gilead, Janssen, Merck, Morphosys, TG therapeutics, and Seattle Genetics. JSA has received institutional research support from AbbVie, BeiGene, Bristol-Myers Squibb, Genentech and Seagen, and consulting income from AbbVie, AstraZeneca, Bristol-Myers Squibb, Caribou Biosciences, Century Therapeutics, Epizyme, Genentech, Genmab, Incyte, Janssen, Lilly, MorphoSys, Mustang Bio and Regeneron. ASL has received personal consulting income from Research to Practice. JRB has served as a consultant for Abbvie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Hutchmed, iOnctura, Janssen, Loxo, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Pharmacyclics, Rigel; received research funding from BeiGene, Gilead, Loxo/Lilly, MEI Pharma, Sun, Verastem/SecuraBio, and TG Therapeutics; and served on data safety monitoring committees for Invectys and Morphosys. MSD has received institutional research funding from AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics and personal consulting income from AbbVie, Adaptive Biosciences, Aptitude Health, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Celgene, Curio Science, Eli Lilly, Genentech, Janssen, Merck, ONO Pharmaceuticals, Research to Practice, TG Therapeutics, and Takeda. ST, LRH, MCC, SMF, YR, YZ, MMM, HAW, MRM, EDJ, and DCF declare no relevant competing interests.

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Ryan, C.E., Brander, D.M., Barr, P.M. et al. A phase 1b study of ibrutinib in combination with obinutuzumab in patients with relapsed or refractory chronic lymphocytic leukemia. Leukemia (2023).

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