Venetoclax Plus Obinutuzumab Improves MRD Clearance in Previously Untreated CLL

Treatment with venetoclax (Venclexta) plus obinutuzumab (Gazyva) resulted in significantly higher rates of undetectable minimal residual disease (MRD) compared with fludarabine plus cyclophosphamide, and rituximab (Rituxan; FCR) or bendamustine plus rituximab (BR) in patients with previously untreated chronic lymphocytic leukemia who did not harbor 17p deletions or TP53 mutations, according to data from the phase 3 CRISTALLO trial (NCT04285567).

Data presented at the 2024 ASH Annual Meeting demonstrated that 81.3% of patients treated with venetoclax plus obinutuzumab (n = 80) achieved undetectable MRD at a sensitivity of less than 10⁻⁴ in peripheral blood at month 15 compared with 54.7% of those treated with FCR or BR (n = 86; P = .0004). At the end of treatment, the undetectable MRD rates in the peripheral blood and bone marrow in the venetoclax plus obinutuzumab arm were 81.3% and 70.0%, respectively. In the FCR/BR arm, these respective rates were 60.5% (P = .0053) and 38.4% (P < .0001). Notably, statistical significance could not be determined for the end-of-treatment tests due to hierarchical testing procedures.

At deeper undetectable minimal residual disease cutoffs, 76.3% and 63.8% of patients in the venetoclax plus obinutuzumab arm achieved undetectable MRD at thresholds of 10⁻⁵ and 10⁻⁶, respectively, at month 15, compared with 43.0% and 22.1%, respectively, for those in the FCR/BR arm.

“Results from this trial confirm and extend the findings observed in from the [phase 3] GAIA-CLL 13 trial [NCT02950051], validating increased depth of response with novel therapies compared with existing chemoimmunotherapies,” lead study author Jeff P. Sharman, MD, and colleagues wrote in a poster presentation of the data. Sharman is director of research at the Willamette Valley Cancer Institute in Eugene, Oregon, and medical director of hematology research for The US Oncology Network.

Study Design

CRISTALLO was an international, open-label, randomized trial that enrolled patients with previously untreated CLL who required systemic therapy. Eligible patients needed to have a cumulative illness rating scale (CIRS) score of 6 or less and a creatinine clearance of at least 70 mL/min. Patients with 17p deletions or TP53 mutations were excluded. Randomization was stratified based on Binet stage, IGHV mutation status, and age.

Patients were randomly assigned 1:1 to receive venetoclax and obinutuzumab, or FCR or BR. Venetoclax was administered orally for 12 cycles, beginning with a 5-week ramp-up period before reaching the target dose of 400 mg from cycle 3, day 1 onward. Obinutuzumab was given intravenously for 6 cycles before venetoclax was continued alone for the final 6 cycles. Patients in the control arm received FCR or BR for 6 cycles.

The trial’s primary end point was the rate of undetectable MRD in peripheral blood at month 15. Secondary end points included progression-free survival (PFS); undetectable MRD rates in peripheral blood and bone marrow at the end of treatment; overall response rate (ORR); duration of response (DOR); and overall survival (OS). Exploratory endpoints included deeper undetectable MRD cutoffs.

Baseline Patient Demographics

The median age was 62.0 years (range, 40-83) in the venetoclax plus obinutuzumab arm and 61.0 years (range, 36-77) in the FCR/BR arm. The majority of patients in both cohorts were male (venetoclax/obinutuzumab, 68.8%; FCR/BR, 66.3%), had mutatedIGHV (56.3%; 55.8%), had Binet stage B disease (52.5%; 52.3%), and were classified as medium risk for tumor-lysis syndrome (TLS; 62.5%; 59.3%).

At the time of data cutoff, 83.8% of patients in the venetoclax plus obinutuzumab group completed 12 cycles of venetoclax. Additionally, 78.8% completed 6 cycles of venetoclax plus obinutuzumab, and 75.6% of patients in the control group completed 6 cycles of therapy.

Additional Efficacy and Safety Findings

PFS data were not mature at the time of analysis. Fewer patients had experienced a PFS event in the venetoclax plus obinutuzumab arm (8.8%) compared with the FCR/BR arm (15.1%; HR, 0.49; 95% CI, 0.2-1.3; P = .13). The 2-year PFS rates were 95.7% and 90.4%, respectively.

OS data also remained immature. There was no significant OS difference between treatment arms, and the median OS was not evaluable in either group. Adverse effects (AEs) led to death in 3 patients in each arm, including COVID-19 pneumonia (n = 2) and pneumonia (n = 1) in the venetoclax plus obinutuzumab arm; and COVID-19, COVID-19 pneumonia, and sepsis (n = 1 each) in the FCR/BR arm.

Regarding safety, AEs occurring in at least 10% of patients included infusion-related reactions (experimental arm, 70.1%; control arm, 42.4%), COVID-19 infections (45.5%; 35.3%), thrombocytopenia (39.0%; 21.2%), diarrhea (35.1%; 12.9%), and nausea (20.8% vs 40.0%).

Laboratory TLS was reported in 10.4% of patients treated with venetoclax plus obinutuzumab compared with 2.4% of those receiving one of the control regimens. No clinical TLS occurred in either arm. Notably, all TLS in the venetoclax plus obinutuzumab arm occurred during obinutuzumab debulking before venetoclax initiation.

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. Blood. 2024;144(supp 1):3237. doi:10.1182/blood-2024-200632