Evaluating Sonrotoclax Trial Endpoints and MRD-Guided Decision-Making in CLL

Dr. Lipsky outlines different conceptual frameworks for evaluating the 2 CELESTIAL trials. For CELESTIAL-1 comparing sonrotoclax-zanubrutinib against venetoclax-obinutuzumab, he emphasizes the convenience advantage of eliminating obinutuzumab infusions and their associated infusion reactions and myelosuppression, so even rough parity in MRD rates and early PFS would favor the all-oral doublet.

For CELESTIAL-2 comparing 2 oral doublets, his bar is higher since administration convenience is roughly equivalent. He anticipates MRD rates substantially above the 34% undetectable MRD by intent-to-treat seen in AMPLIFY's acalabrutinib-venetoclax arm would be compelling evidence. Early 3-year PFS data would be particularly informative given AMPLIFY's comparable timeframe.

Dr. Coombs agrees, noting that for CELESTIAL-1, even a small efficacy margin would favor sonrotoclax-zanubrutinib due to convenience, provided safety is not meaningfully worse. Infusion reactions from obinutuzumab and potentially worse myelosuppression with venetoclax-obinutuzumab represent meaningful quality-of-life considerations. The panel concludes these represent genuinely exciting data to anticipate, with results potentially shifting standard frontline CLL practice.

Dr. Shadman reviews MRD testing in routine clinical practice. For venetoclax-obinutuzumab, he checks MRD at end of treatment for prognostic understanding without acting on results, since evidence for extending venetoclax beyond one year remains insufficient. For BTK inhibitor-venetoclax doublets in high-risk patients (IGHV-unmutated or TP53-aberrant), he extends therapy an additional year for those with detectable MRD at one year, extrapolating from SEQUOIA ARMD data showing improved undetectable MRD rates between years 1 and 2. He also incorporates post-CAR-T MRD monitoring at 3 months to guide consolidation discussions.