TOPLINE

In fit patients with untreated chronic lymphocytic leukemia (CLL), first-line treatment with fixed-duration venetoclax-obinutuzumab was associated with higher undetectable minimal residual disease (MRD) rates than fludarabine, cyclophosphamide, and rituximab/bendamustine-rituximab in the phase 3 CRISTALLO trial.

METHODOLOGY

• Standard first-line options for CLL include chemoimmunotherapy, continuous Bruton tyrosine kinase inhibitor therapy, and fixed-duration venetoclax-based treatment. Although undetectable MRD is strongly associated with progression-free and overall survival after fixed-duration therapy, MRD is rarely used as a sole primary endpoint.
• To test that strategy, researchers conducted an open-label, multicenter, randomized phase 3 trial (CRISTALLO) comparing fixed-duration venetoclax-obinutuzumab to fludarabine, cyclophosphamide, and rituximab/bendamustine-rituximab in fit patients aged 18 or older with previously untreated CLL, without del(17p) or TP53 mutations. Overall, 166 patients were randomly assigned to receive either venetoclax-obinutuzumab (median age, 62 years; n = 80) or fludarabine, cyclophosphamide, and rituximab/bendamustine-rituximab (median age, 61 years; n = 86).
• Patients were assigned to receive fixed-duration venetoclax-obinutuzumab for 12 cycles or six cycles of investigator-selected chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab or bendamustine-rituximab.
• The primary endpoint was undetectable MRD rate, defined as the proportion of patients achieving < 1 CLL cell in 10,000 leukocytes (< 10^-4) in peripheral blood at month 15. Secondary endpoints included undetectable MRD rates in peripheral blood and bone marrow at the end of treatment and investigator-assessed progression-free survival.
• Overall, 78.8% of patients completed venetoclax-obinutuzumab treatment, 83.8% completed all 12 cycles of venetoclax, and 75.6% completed chemoimmunotherapy.

TAKEAWAY

• At month 15, 81.3% of patients treated with venetoclax-obinutuzumab achieved undetectable MRD in peripheral blood vs 54.7% of patients treated with chemoimmunotherapy, with a difference of 26.6% (P = .0004).
• Undetectable MRD rates in bone marrow at the end of treatment were higher with venetoclax-obinutuzumab than with chemoimmunotherapy (70.0% vs 38.4%; difference, 31.6%; P < .0001). Peripheral blood and bone marrow MRD assessments showed high concordance (82.7%).
• Fewer patients experienced a progression-free survival event with venetoclax-obinutuzumab (8.8% vs 15.1%; hazard ratio, 0.49), although the difference was not statistically significant at the first planned interim analysis because follow-up was immature (P = .13).
• Grade 3-4 neutropenia was common in both arms, while grade 3-4 thrombocytopenia was more frequent with venetoclax-obinutuzumab (29.9% vs 12.9%). Serious infections occurred in both groups, and three deaths occurred in each arm, though none were considered treatment-related.

IN PRACTICE

The CRISTALLO trial demonstrated significant improvement in undetectable MRD rates at month 15 with fixed-duration venetoclax-obinutuzumab vs fludarabine, cyclophosphamide, and rituximab/bendamustine-rituximab in patients with previously untreated CLL, the authors wrote, concluding that “results from this trial confirm and extend the findings from the GAIA-CLL13 trial, validating the increased depth of response with [venetoclax-obinutuzumab] vs existing chemoimmunotherapies.”

SOURCE

The study, led by Jeff P. Sharman, Willamette Valley Cancer Institute, Sarah Cannon Research, Eugene, Oregon, was published online in Blood.

LIMITATIONS

Since follow-up was short, progression-free survival data were immature and did not reach statistical significance. Additionally, MRD was the sole primary endpoint, and hence, clinical benefit was inferred from a surrogate marker rather than mature survival data.

DISCLOSURES

This study was funded by F. Hoffmann-La Roche Ltd. Sharman disclosed receiving honoraria, consulting, or advisory role fees from AbbVie, AstraZeneca, BeiGene, Genentech, Genmab, Lilly, and Janssen. Two authors were employed with Roche and held equity or stock ownership with Roche, and five were employed with Genentech and held equity with Roche. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.