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Jump to Key Points Outcomes were positive, but toxicities were concerning in patients with chronic lymphocytic leukemia (CLL) treated with a combination of the noncovalent Bruton tyrosine kinase inhibitor (BTKi) pirtobrutinib with venetoclax and obinutuzumab in the first-line setting.
The participants in the phase 2 trial had deep remissions and favorable overall survival (OS); their notable toxicities were consistent with similar triplet regimens.
“Our study provides the first combination targeted therapy with a noncovalent BTK inhibitor in first-line CLL,” first author Nitin Jain, MD, told Medscape Medical News.
Jain, who is also a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, presented the findings of the PIVOT-CLL trial at the Society of Hematologic Oncology (SOHO) 2026.
- PIVOT-CLL: first-line pirtobrutinib + venetoclax + obinutuzumab in treatment-naive CLL.
- 80 pts; 79% IGHV-unmutated, 13% del(17p)/TP53-mutated.
- 2-year PFS and OS both 99%; deep MRD responses after 13 cycles.
- Grade 3-4 neutropenia 69%; thrombocytopenia 17%; G-CSF used in 63%.
- Dose reductions common; atrial fibrillation occurred in 2 pts; infection-related death reported.
In the setting of relapsed or refractory CLL, the combination therapy of a covalent BTKi, such as ibrutinib, with the B-cell leukemia/lymphoma 2 (BCL2) inhibitor venetoclax, with or without a CD20 monoclonal antibody such as obinutuzumab, has shown highly favorable rates of remission, Jain explained.
Limitations of covalent BTKi can include tolerability and the development of resistance over time, particularly with common C481 mutations. Pirtobrutinib, a highly selective noncovalent BTKi with unique reversible binding to BTK, has shown efficacy even in patients who have developed C481 resistance, as demonstrated in this paper.
Based on previous significant benefits observed in patients with relapsed or refractory CLL, pirtobrutinib received accelerated approval from the FDA in 2023 for adults with CLL or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy, including a BTKi and a BCL2 inhibitor. In 2025, the FDA further granted traditional approval to adults with CLL/SLL previously treated with covalent BTKi.
Methods and Results
The PIVOT-CLL trial enrolled 80 patients with a median age of 63 years with treatment-naive CLL. The treatment regimen included starting with pirtobrutinib and obinutuzumab in cycle 1, followed by the initiation of venetoclax as a standard ramp-up in cycle 2, with each cycle lasting 28 days. Obinutuzumab was given for six cycles, while treatment with pirtobrutinib and venetoclax continued through cycle 13. Patients with detectable measurable residual disease (MRD; ≥ 10-5) at the end of cycle 13 were able to further continue pirtobrutinib and venetoclax for another 12 cycles. Of the study participants, 79% had IGHV-unmutated CLL and 13% had higher-risk del(17p) and/or TP53 mutations.
Among 77 patients followed for 30.9 months, the undetectable MRD (10-6 sensitivity) rates were 74% vs 86% in the bone marrow vs the peripheral blood after 13 cycles of the triplet therapy. The progression-free survival and OS rates among patients at 2 years were each 99%.
In addition to the MRD (10-6) results, using the more traditional cutoff of undetectable MRD (10-4), at the end of cycle 13, rates were 100% vs 96% in the peripheral blood vs the bone marrow.
Among all study participants, one had disease progression at 13.6 months following treatment completion, and there was one death at 8.7 months after treatment completion.
Grade 3-4 neutropenia occurred in 69% of patients, with thrombocytopenia occurring among 17%. More than half of patients (63%) required granulocyte colony-stimulating factor treatment to boost neutrophils and fight infection.
Dose reductions of venetoclax and pirtobrutinib were required in 29 (36%) and 17 (21%) patients, respectively, with the most common reason for dose reduction being neutropenia.
Two patients developed atrial fibrillation, including one who had SARS-CoV-2 infection.
Toxicities a Concern
While the grade 3 or 4 neutropenia rates in the study were said to be in line with other CLL triplet trials, Jain noted that “more patients had grade 3 or higher neutropenia with this regimen (vs the other trials) and needs to be watched closely for infectious complications.”
Hematologist Kerry A. Rogers, MD, who co-moderated the session, expressed concerns regarding toxicities with such triplet regimens with an anti-CD20 monoclonal antibody, particularly neutropenia and infection.
“The finding that the only death seen in this study resulted from infection in a patient who had completed therapy ‘supports this being a risk in this population,’” she said.
“I worry that the results cannot be generalized to an older and less fit population of CLL patients seen in community practices and that the toxicity is too high for some patients,” added Rogers, who is also an assistant professor in the Department of Internal Medicine, Division of Hematology at The Ohio State University in Columbus.
The regimen used in this study is currently not approved by the FDA. PIVOT-CLL has been expanded to include 160 patients being treated in the frontline CLL setting.
Jain reported disclosures including consulting and/or other relationships with Pharmacyclics; Janssen; AbbVie; Genentech; AstraZeneca; BeOne Medicines; Eli Lilly and Company; Nurix; Bristol Myers Squibb; Adaptive Biotechnologies; Kite Pharma/Gilead Sciences; Cellectis; Autolus Therapeutics; ADC Therapeutics; Newave Pharmaceutical Inc.; Carna Biosciences, Inc.; Bioheng Therapeutics; Ubix Therapeutics; and Ascentage Pharma. Rogers reported receiving research funding from AbbVie, AstraZeneca, Eli Lilly and Company, and Genentech and consulting for AbbVie, AstraZeneca, BeOne Medicines, Genentech, Johnson & Johnson, and Eli Lilly and Company.
