Fixed-duration VenO vs FCR/BR in fit patients with untreated CLL: primary analysis of the phase 3 CRISTALLO trial.

The phase 3 CRISTALLO trial (NCT04285567) compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia, using undetectable minimal residual disease (uMRD) as the sole primary endpoint. Previously untreated patients with a cumulative illness rating scale score ≤6, creatinine clearance ≥70 mL/min, without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary endpoint was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary endpoints included uMRD (<10-4) in PB and bone marrow (BM) at end of treatment (EOT), and progression-free survival (PFS). uMRD at deeper cutoffs were explored. At data cutoff (March 19, 2024), 80 patients received VenO and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary endpoint was met: 81.3% (VenO) and 54.7% (FCR/BR) achieved uMRD (<10-4) in PB at month 15 (P = .0004). uMRD (<10-4) in PB and BM at EOT was also higher with VenO vs FCR/BR. Short follow-up precluded evaluation of PFS at the first planned interim analysis; however, fewer patients progressed/died with VenO vs FCR/BR (7 vs 13). At month 15, 65.0% (VenO) and 25.6% (FCR/BR) achieved uMRD (<10-6) in PB. The overall safety profile was consistent with the known safety profile of each drug. No patient in the VenO arm was deemed high-risk for tumor lysis syndrome following obinutuzumab debulking; no clinical TLS occurred. These results confirm and extend the findings from the GAIA-CLL13 trial, validating increased depth of response with VenO vs chemoimmunotherapies.