According to results from the phase Ib CAVALLI study, treatment with the oral BCL2 inhibitor venetoclax, combined with standard immunochemotherapy, induced high response rates in patients with non-Hodgkin lymphoma (NHL), but was associated with higher-than-expected incidence of cytopenias. The findings were published in Blood by lead author Andrew D. Zelenetz, MD, PhD, from the Memorial Sloan Kettering Cancer Center in New York, and colleagues.
This multicenter, open-label study evaluated the safety and efficacy of venetoclax when combined with a CHOP-based regimen (cyclophosphamide, doxorubicin, vincristine, prednisone) plus either rituximab (R-CHOP) or obinutuzumab (G-CHOP). Fifty-six patients with treatment-naÃ¯ve or previously treated NHL were enrolled, most with follicular lymphoma (FL; 43%) or diffuse large B-cell lymphoma (DLBCL; 32%).
In the phase Ib dose-escalation portion of the study, patients were assigned to receive either R-CHOP (n=24) or G-CHOP (n=32) plus venetoclax ranging from 200 mg to 800 mg, administered once daily for 21 days per cycle.
The primary objective of the study was to identify the maximum tolerated dose of venetoclax in combination with R-CHOP/G-CHOP, determined as dose-limiting toxicities (DLTs) occurring in less than one-third of patients in a dosing cohort.
In both arms, the initial starting dose of venetoclax (cohort 1) was 200 mg/day for eight 21-day cycles; however, one patient in the R-CHOP group and two patients in the G-CHOP group experienced a DLT. This observation prompted the study's scientific oversight committee to recommended a shorter dosing schedule of venetoclax 400 mg to 800 mg on days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 through 8 in each treatment group "to mitigate the unexpectedly high hematologic toxicity," the authors noted. "High levels of cytopenias, predominantly midcycle thrombocytopenia, in the first six patients in cohort 4 (800-mg venetoclax) of [the G-CHOP arm] led to further shortening of the venetoclax dosing schedule," they added.
The median duration of treatment was 154 days in the R-CHOP arm and 152 days in the G-CHOP arm (ranges not provided). Overall, three patients received at least six cycles of chemotherapy – all in the G-CHOP group.
The most common any grade adverse events (AEs) across both arms were neutropenia (57.1%) and nausea (53.6%), and the authors reported no AE-related deaths. Cytopenias were the most common grade 3/4 AEs in each group:
- R-CHOP: neutropenia (54.2%), febrile neutropenia (33.3%), thrombocytopenia (16.7%), and anemia (12.5%)
- G-CHOP: neutropenia (59.4%), febrile neutropenia (25.0%), thrombocytopenia (37.5%), and anemia (31.3%)
In addition, three patients (5.4%) developed tumor lysis syndrome without clinical sequelae, which was a DLT in one patient who received venetoclax 600 mg. However, this patient eventually restarted venetoclax 200 mg and escalated to 600 mg without a further occurrence.
AEs led to venetoclax dose modifications in 37 patients (66.1%), mostly due to neutropenia (n=9/37; 24.3%) and febrile neutropenia (n=8/37; 21.6%). A higher percentage of patients in the G-CHOP arm than the R-CHOP arm appeared to experience AEs leading to venetoclax modification (71.9% vs. 58.3%), but p values were not reported.
Fifty-six patients were evaluable for end-of-treatment response, and, after a median follow-up of 22 months (range = 11.4-36.4 months), 49 patients experienced a complete response (CR) or partial response (PR; TABLE). This translated to an overall response rate (ORR) of 87.5% in the intent-to-treat population. The ORR was similar in both arms: 21 patients in the R-CHOP group and 28 patients in the G-CHOP group.
"Response rates for venetoclax plus R-CHOP or G-CHOP were promising in both DLBCL and FL, comparing favorably with historical rates," the researchers wrote. Patients with DLBCL had an ORR of 88.9% (all of which were CRs), while patients with FL had an ORR of 83.3% (75.0% CR and 8.3% PR).
Neither treatment arm reached a median progression-free survival (PFS), and the one-year PFS rates did not appear to differ according to CHOP regimen or disease histology (p values not reported):
- DLBCL: 70% for R-CHOP vs. 100% for G-CHOP
- FL: 100% for R-CHOP vs. 90% for G-CHOP
The study established a recommended phase II dose of venetoclax 800 mg on days 4 through 10 of cycle 1 and days 1 through 10 of cycles 2 through 8 in combination with R-CHOP.
"Although the rate of cytopenias … was higher than expected (particularly with venetoclax plus G-CHOP), … the dose intensity of the backbone remained intact, and the regimen was tolerated overall," the researchers concluded. "Moreover, the myelosuppressive effects of venetoclax plus R-CHOP or G-CHOP were manageable with prophylaxis, supportive measures, and dose modifications or delays (applied first to venetoclax)."
Limitations of the study include its lack of a randomized active control or placebo arm, its small sample size, and the short duration of follow-up.
The researchers concluded that the additional ongoing phase II study of venetoclax in combination with R-CHOP "will provide further information on the benefit-risk profile of this combination in firstline DLBCL, including higher-risk patient subgroups identified by BCL2, MYC, and COO biomarker analysis."
The authors report relationships with Roche and AbbVie, which supported the trial.
Zelenetz AD, Salles G, Mason KD, et al. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. Blood. 2019;133:1964-76.