Venetoclax Plus Obinutuzumab Superior to FCR-BR for Patients With CLL

Venetoclax plus obinutuzumab demonstrates superior safety and efficacy compared with fludarabine-cyclophosphamide-rituximab (FCR) and bendamustine-rituximab (BR) in patients with untreated chronic lymphocytic leukemia (CLL).

The results were derived from the international, open-label, randomized, phase III CRISTALLO study presented at the 66th American Society of Hematology Annual Meeting & Exposition.

Adult patients without del(17p) or TP53 mutations were randomized 1:1 to receive either six cycles of venetoclax plus obinutuzumab plus six cycles of venetoclax (n=80) or six cycles of FCR-BR (n=86). A five-week ramp-up period of oral daily venetoclax was initiated on cycle 1 day 22, and 400 mg was administered from cycle 3 day 1 onward. Intravenous obinutuzumab was administered for six cycles on cycle 1 days 1, 2, 8, and 15 and on day 1 of the remaining cycles. The median follow-up was 32 months.

The researchers reported undetectable measurable residual disease (uMRD) in peripheral blood, defined as less than one CLL cell in 10,000 leukocytes, less than 10^-4, using next-generation sequencing. More patients treated with venetoclax plus obinutuzumab achieved uMRD at month 15 than patients treated with FCR-BR (81.3% vs 54.7%, respectively; 95% CI, 12.3-40.9; P=.0004). The uMRD rates in peripheral blood at end of treatment (EOT) were also higher with venetoclax plus obinutuzumab versus FCR-BR (81.3% vs 60.5%, respectively; 95% CI, 6.7-34.9; P=.0053), a trend also seen with uMRD rates in bone marrow at EOT (70.0% vs 38.4%, respectively; 95% CI, 16.6-46.7; P<.0001).

Progression-free survival (PFS) was immature at the data cutoff, but fewer patients treated with venetoclax plus obinutuzumab had disease progression or died. The two-year PFS rates were 95.7% for venetoclax plus obinutuzumab and 90.4% for FCR-BR.

Common treatment-related adverse events (AEs) in both cohorts included infusion-related reaction, COVID-19 infection, thrombocytopenia, diarrhea, and nausea. The rate of AEs was 97.4% for patients treated with venetoclax plus obinutuzumab and 89.4% for patients treated with FCR-BR. Patients treated with venetoclax plus obinutuzumab had a lower rate of discontinuation due to AEs (6.5% vs 15.3%, respectively).

“At the primary analysis, VenO [venetoclax plus obinutuzumab] demonstrated superiority over FCR-BR in driving deep molecular remissions; uMRD rate at Month 15 in PB [peripheral blood] was significantly higher in pts treated with VenO versus FCR-BR,” the researchers concluded. “There was a numerical but non-significant PFS benefit at this immature timepoint. No new safety signals were identified with VenO.”

Reference

Sharman JP, Laurenti L, Ferrant E, et al. CRISTALLO: results from a phase III trial of venetoclax–obinutuzumab versus fludarabine, cyclophosphamide and rituximab or bendamustine–rituximab in patients with untreated chronic lymphocytic leukemia without del(17p) or TP53 mutations. Abstract #3237. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.