Zanubrutinib, Obinutuzumab, and Venetoclax in CLL: Long-Term Follow Up, MRD Kinetics, Retreatment, T-Cell Profiling, PKs
Jacob D Soumerai, Meghan C. Thompson, Ahmet Dogan, Venkatraman E Seshan, Kelsey Flaherty, Natalie Slupe, Jason Carter, Ephraim Hochberg, Jeffrey A. Barnes, Jeremy S Abramson, Ariela Noy, Colette N Owens, M. Lia Palomba, Anita Kumar, Lindsey Elizabeth Roeker, Ronald W. Takvorian, Zachary D Epstein-Peterson, Mark B Geyer, Gilles A. Salles, Robert N Stuver, Philip C Caron, Prioty Islam, Tamanna Haque, Paola Ghione, Raphael E. Steiner, Pallawi Torka, Kevin A. David, Jennifer K Lue, Paul A. Hamlin, Alison J Moskowitz, Lorenzo Falchi, Julie E Haydu, Patrick Connor Johnson, Joanna Mi, Neena Mahajan, Jessica Pendleton, Alyssa Labarre, Maria Chabowska, Morgan Choma, Clare Grieve, Ashlee Joseph, Colleen Dorsey, Jamila Brutus, Rosalba Martignetti, Rachel Nazzaro, Jayne Coyle, Olivia Grace Maas, De Zoysa Meemanage, Elizabeth Simkins, Akshata Kakolu, Cameron Gordan, Eshani Baez, Bernadette Beatty, Athina Apazidis, Michelle Gulotta, Sherry Ratcliff, Jamie Hirata, Mina Shahkarami, Allison P Jacob, Omar Abdel-Wahab, Andrew D. ZelenetzTriplet 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.