Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs

Triplet regimens induce high rates of undetectable MRD at ≤10-4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) CLL, but the optimal treatment duration to minimize the risk of neutropenia/infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL (NCT03824483). Our MRD-driven treatment/retreatment study was designed to optimize treatment duration balancing efficacy against toxicities associated with extended treatment exposure, and evaluate zanubrutinib-venetoclax (Z+V) retreatment. With a median observation time of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary endpoint). BOVen was well-tolerated with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; none grade 5). Median MRD4-free survival was 34.1 months (95% CI 23.1-50.5) and 48-month PFS was 79.7% (95% CI 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD by immunosequencing at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, p<0.001), and longer MRD4-free survival (50.5 vs 18.1 months, p<0.001) despite a shorter treatment duration (8 vs 13 mo, p<0.001). This manuscript also reports on the safety/efficacy of Z+V retreatment and describes pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent, early uMRD4 and durable remissions in TN CLL with a short treatment duration (median 10 months). ΔMRD400 is undergoing evaluation for use as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL.

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Journal
Blood Advances
Published
2026-06-30
DOI
https://doi.org/10.1182/bloodadvances.2026020221
Primary Topic
Chronic Lymphocytic Leukemia Research
Type
article
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article

Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs

Jeremy S. Abramson, Ashlee Joseph, M. Lia Palomba, Paul A. Hamlin et al.
Blood Advances
Chronic Lymphocytic Leukemia Research
article

Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs

Jeremy S. Abramson, Ashlee Joseph, M. Lia Palomba, Paul A. Hamlin, Kevin A. David, Ariela Noy, Paola Ghione, Ronald W. Takvorian, Prioty Islam, Rosalba Martignetti, Morgan Choma, Ahmet Doǧan, Jeffrey A. Barnes, Jennifer Kimberly Lue, Clare Grieve, Colleen Dorsey, J. Erika Haydu, Mark Blaine Geyer, Venkatraman Seshan, Lindsey E. Roeker, Elizabeth Simkins, Pallawi Torka, R. Steiner, Colette Owens, Mina Shahkarami, Zachary D. Epstein‐Peterson, Andrew David Zelenetz, Alison J. Moskowitz, Meghan C. Thompson, Neena Mahajan, Philip C. Caron, Patrick Connor Johnson, Allison P. Jacob, Gilles Salles, Robert N. Stuver, Jacob D. Soumerai, Anita Kumar, Lorenzo Falchi, Sherry Ratcliff, Natalie Slupe, Maria Chabowska, A. Labarre, Joanna Mi, Eshani Baez, Cameron Gordan, Akshata Kakolu, Rachel Nazzaro, Tamanna Haque, Jamie Hirata, Ephraim Hochberg, Omar Abdel-Wahab, Jayne Coyle, De Zoysa Meemanage, Jessica Pendleton, Jamila Brutus, Jason Carter, Olivia Grace Maas, Athina Apazidis, Kelsey Flaherty, Bernadette Beatty, Michelle Gulotta
article en

Abstract

Triplet regimens induce high rates of undetectable MRD at ≤10-4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) CLL, but the optimal treatment duration to minimize the risk of neutropenia/infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL (NCT03824483). Our MRD-driven treatment/retreatment study was designed to optimize treatment duration balancing efficacy against toxicities associated with extended treatment exposure, and evaluate zanubrutinib-venetoclax (Z+V) retreatment. With a median observation time of 69 months and median treatment duration of 10 cycles, 96% achieved blood uMRD4, and 92% achieved uMRD4 in both blood and bone marrow (primary endpoint). BOVen was well-tolerated with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; none grade 5). Median MRD4-free survival was 34.1 months (95% CI 23.1-50.5) and 48-month PFS was 79.7% (95% CI 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD by immunosequencing at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, p<0.001), and longer MRD4-free survival (50.5 vs 18.1 months, p<0.001) despite a shorter treatment duration (8 vs 13 mo, p<0.001). This manuscript also reports on the safety/efficacy of Z+V retreatment and describes pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent, early uMRD4 and durable remissions in TN CLL with a short treatment duration (median 10 months). ΔMRD400 is undergoing evaluation for use as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL.

Blood Advances
Memorial Sloan Kettering Cancer Center (US), Harvard University (US), Massachusetts General Hospital (US), Adaptive Biotechnologies (United States) (US), Global Cancer Institute (US), Center for Cancer Research (US), Universidad San Carlos (PY)
Openalex Percentile: Top 8%
Chronic Lymphocytic Leukemia Research
DOIOpen Access PDFOpenAlex
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