Orelabrutinib, fludarabine, cyclophosphamide, and obinutuzumab (OFCG) for first-line treatment of chronic lymphocytic leukemia: a multicenter phase II trial (cwCLL-001 trial).

BACKGROUND

This multicenter phase II trial aimed to evaluate the orelabrutinib, fludarabine, cyclophosphamide, and obinutuzumab (OFCG) regimen as first-line therapy for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma without restriction by TP53 aberrations [del(17p) and/or TP53 mutation] and IGHV status.

METHODS

Eligible patients received OFCG (orelabrutinib, orally 150 mg/day; fludarabine, intravenously 25 mg/m2/day; cyclophosphamide, intravenously 250 mg/m2/day; obinutuzumab, intravenously 1000 mg), with treatment duration and modifications based on prespecified minimal residual disease (MRD) criteria. The primary endpoint was the rate of undetectable MRD in bone marrow (BM-uMRD) after 6 cycles by flow cytometry (10-4 sensitivity). The key secondary endpoints included the rate of BM-uMRD4 at the end of cycles 3, 12, MRD in peripheral blood (PB-uMRD4) at the end of cycles 6, and complete response rate (CRR); exploratory endpoints included the rate of BM-uMRD6 (10-6 sensitivity) at the end of cycles 3, 6, and 12.

RESULTS

Among 25 enrolled patients, 23 completed 3 cycles of OFCG therapy; of these, 13 patients achieved BM-uMRD4. After 6 cycles, 76.0 % (19/25) achieved BM-uMRD4, and 80 % (20/25) of patients achieved PB-uMRD4. CRR with BM-uMRD4 was achieved by 20.0 % (5/25), 52.0 % (13/25), and 64.0 % (16/25) of patients after 3, 6, and 12 cycles, respectively. Significant differences in BM-uMRD6 at C7D0 (odds ratio [OR], 0.03 [95 % confidence interval [CI]: 0, 0.32]; P < 0.01) and C13D0 (OR, 0.16 [95 % CI: 0.03, 0.94]; P < 0.05) were observed between IGHV-mutated (n = 10) and unmutated (n = 15) patients. Notably, 20 patients discontinued all the drugs at the data cutoff date. No treatment-related deaths occurred, and the most frequent grade 3-4 adverse effects (AEs) were neutropenia (20/25, 80.0 %), thrombocytopenia (15/25, 60.0 %), and infection (7/25, 28.0 %).

CONCLUSION

The study meet the primary endpoint, showing the potential efficacy and acceptable safety profile of the OFCG regimen as a first-line treatment for CLL. Trial registration: NCT05322733.