Abstract
Primary CD5-positive diffuse large B cell lymphoma (DLBCL) accounts for approximately 5%-10% of newly diagnosed DLBCL cases. Compared with CD5-negative DLBCL, those with this subtype demonstrate inferior responses and survival outcomes. In a post hoc analysis of the PHOENIX trial, Cooper et al. demonstrated that patients with CD5-positive DLBCL experienced improved survival outcomes with the addition of ibrutinib to R-CHOP as the first-line therapy. Orelabrutinib is a selective second-generation BTK inhibitor that offers the advantage of high selectivity and strong binding affinity. This phase II trial (NCT06647940) was conducted to evaluate the efficacy and safety of orelabrutinib combined with R-CHOP regimen as first-line treatment for CD5-positive DLBCL patients.
Patients with newly diagnosedtreatment-naïve CD5-positive DLBCL, confirmed by pathological assessment were enrolled. The induction treatment included six 21-day cycles of orelabrutinib combined with R-CHOP, followed by two additional cycles of orelabrutinib plus rituximab. To minimize the risk of tumor lysis syndrome, orelabrutinib was initiated from the second cycle at a starting dose of 150 mg, administered daily from day 1 to day 21 of each cycle. Patients who achieved a complete response (CR) after induction treatment continued orelabrutinib as maintenance treatment until disease progression (PD), or intolerable toxicity, or an expected maintenance treatment duration of six months. The primary endpoint was the 2-year event-free survival (EFS) rate.
Between October 2024 and June 2025, 9 patients were enrolled, with a median age of 57 years (IQR, 51-62). All patients had stage III-IV disease, and 8 (88.9%) had an International Prognostic Index (IPI) score of ≥2. MYC/BCL-2 double expression was observed in 5 (55.5%) patients. The median number of induction treatment cycles was 7 (range, 2-8). The CR rate was 33.3% (3/9), and the overall response rate (ORR) was 77.7% (7/9), respectively. Among the 7 patients who completed 8 cycles of induction therapy, the CR rate was 100%. With a median follow-up time of 5.1 months, the median EFS and progression free survival (PFS) were not reached. The majority of adverse events (AEs) were grade 1-2. Grade 3-4 AEs included leukopenia (n=4), neutropenia (n=5), thrombocytopenia (n=1), and transaminases elevated (n=1). All AEs were manageable with supportive care and resolved. No treatment-related deaths were observed.
The combination of orelabrutinib and R-CHOP as first-line therapy for CD5-positiveDLBCL showed promising efficacy with manageable toxicity. These initial results support the potential role of orelabrutinib in improving outcomes for this high-risk subgroup, and patient enrollment is ongoing to further validate these findings.
