Article
作者: Coyle, Jayne ; Geyer, Mark B. ; Grieve, Clare ; Shahkarami, Mina ; Roeker, Lindsey ; Epstein-Peterson, Zachary D. ; Thompson, Meghan C. ; Lue, Jennifer K. ; Baez, Eshani ; Beatty, Bernadette ; Hirata, Jamie ; Seshan, Venkatraman ; David, Kevin A. ; Hamlin, Paul A. ; Stuver, Robert ; Nazzaro, Rachel ; Carter, Jason ; Abramson, Jeremy S. ; Apazidis, Athina ; Falchi, Lorenzo ; Simkins, Elizabeth ; Dogan, Ahmet ; Johnson, P. Connor ; Moskowitz, Alison ; Gordon, Cameron ; Ghione, Paola ; Chabowska, Maria ; Gulotta, Michelle ; Mi, Joanna ; Maas, Olivia ; Abdel-Wahab, Omar ; Caron, Philip ; Martignetti, Rosalba ; Hochberg, Ephraim ; Zelenetz, Andrew D. ; Haydu, J. Erika ; Flaherty, Kelsey L. ; Choma, Morgan ; Pendleton, Jessica ; Barnes, Jeffrey A. ; Torka, Pallawi ; Kumar, Anita ; Meemanage, De Voysa ; Palomba, Maria Lia ; Takvorian, Ronald W. ; Owens, Colette ; Labarre, Alyssa ; Islam, Prioty ; Ratcliff, Sherry ; Joseph, Ashlee ; Noy, Ariela ; Mahajan, Neena ; Slupe, Natalie ; Steiner, Raphael E. ; Jacob, Allison P. ; Soumerai, Jacob D. ; Salles, Gilles ; Brutus, Jamila ; Dorsey, Colleen ; Kakolu, Akshata ; Haque, Tamanna
Abstract:Triplet regimens induce high rates of undetectable measurable residual disease (MRD) at ≤10−4 (uMRD4) and appear to prolong progression-free survival (PFS) in treatment-naïve (TN) chronic lymphocytic leukemia (CLL), but the optimal treatment duration to minimize the risk of infections is unknown. In this phase 2 trial, we evaluated zanubrutinib, obinutuzumab, and venetoclax (BOVen) in TN CLL. Our MRD-driven study was designed to optimize treatment duration, balancing efficacy against toxicities associated with extended treatment exposure, and to evaluate zanubrutinib with venetoclax (Z+V) retreatment. With a median observation 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 end point). BOVen was well-tolerated, with low rates of grade 3-4 neutropenia (25%) and infections (9.6%; no grade 5). Median MRD4-free survival was 34.1 months (95% confidence interval [CI], 23.1-50.5), and the 48-month PFS was 79.7% (95% CI, 68.6-92.5). ΔMRD400 (≥400-fold reduction in blood MRD [immunosequencing] at 4 months) identified patients with earlier bone marrow uMRD4 (6 vs 12 months, P< .001) and longer MRD4-free survival (50.5 vs 18.1 months, P< .001), despite shorter treatment duration (8 vs 13 months, P< .001). This manuscript also reports safety/efficacy of Z+V retreatment and pharmacokinetic and T-cell profiling studies. In summary, BOVen was well-tolerated and resulted in frequent uMRD4 and durable remissions in TN CLL with a short treatment duration (median, 10 months). ΔMRD400 is undergoing evaluation as a predictive biomarker to guide treatment duration in two prospective trials of venetoclax- and sonrotoclax-based triplets in TN CLL. This trial was registered at www.clinicaltrials.gov (#NCT03824483).