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

Clinical Snapshot

Key Findings

• P Value: P = .0004

• Effect Size: 26.6% absolute difference in uMRD achievement favouring VenO

• Primary Outcome: uMRD (<10⁻⁴) in peripheral blood at month 15: 81.3% (VenO) vs 54.7% (FCR/BR)

• Nnt Or Sensitivity: NNT = 4 (approximately 1 in 4 patients treated with VenO instead of FCR/BR will achieve additional uMRD response)

• Confidence Interval: Not reported in abstract

Clinical Application

VenO regimen feasible in Australian centres with experience in venetoclax monitoring and TLS prevention protocols Venetoclax and obinutuzumab both PBS-listed for CLL. Results support VenO as preferred first-line option over traditional chemoimmunotherapy in eligible patients, aligning with evolving RACGP and haematology society guidelines favouring targeted therapy Fit, previously untreated CLL patients without del(17p)/TP53 mutations, adequate renal function, and low comorbidity burden

Abstract

The phase 3 CRISTALLO trial compared first-line fixed-duration venetoclax-obinutuzumab (VenO) vs fludarabine, cyclophosphamide, and rituximab (FCR)/bendamustine-rituximab (BR) in patients with chronic lymphocytic leukemia (CLL), using undetectable minimal residual disease (uMRD) as the sole primary end point. Previously untreated patients with a cumulative illness rating scale score ≤6 and creatinine clearance ≥70 mL/min without del(17p)/TP53 mutations were randomized 1:1 to VenO or FCR/BR. The primary end point was uMRD (<10-4) in peripheral blood (PB) using next-generation sequencing at month 15. Key secondary end points 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 (19 March 2024), 80 patients received VenO, and 86 received FCR/BR. Baseline characteristics were generally balanced across arms. The primary end point 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 (TLS) after 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. This trial was registered at www.clinicaltrials.gov as NCT04285567.

References

1. 1.Sharman, J. P., Laurenti, L., Ferrant, E., Casado Montero, L. F., Mulligan, S. P., Harrup, R., Opat, S., Ibatici, A., Marasca, R., Sportoletti, P., Thadani-Mulero, M., Cazares, O., Huang, W., Jiang, Y., Clark, E., Jin, H. Y., Boyer, M., & Morschhauser, F. (2026). Fixed-duration VenO vs FCR/BR in fit patients with untreated CLL: primary analysis of the phase 3 CRISTALLO trial. Blood. https://doi.org/10.1182/blood.2025030630