Introduction: High-dose immunochemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is the second-line treatment protocol for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). However, certain patients might be unsuitable for transplantation due to age-related factors or comorbidities. Therefore, we designed this trial (ChiCTR2200056256) to evaluate the efficacy and safety of a chemotherapy-free regimen combining lenalidomide, programmed cell death-1 (PD-1) monoclonal antibody, and orelabrutinib for the treatment of R/R DLBCL.

Methods: This multicenter, open-label, single-arm, phase II study was conducted at eight hospitals in China. Patients were eligible if they met the diagnostic criteria for R/R DLBCL, and were aged 18-85 years with an Eastern Cooperative Oncology Group performance status of 0-1. Patients received lenalidomide (10-25 mg/d, oral, day 1-10), PD-1 monoclonal antibody (200 mg, IV, day 1), and orelabrutinib (150 mg/d, oral). The dose adjustment of lenalidomide was required according to the patient's blood routine. The primary endpoint was the overall response rate (ORR). The key secondary endpoints included complete remission (CR) rate, progression-free survival (PFS), and safety.

Results: From August 2021 to March 2024, 34 patients were enrolled. Seventeen patients were aged 60 years or older, with a male-to-female ratio of 1:1.4. Twelve (35.3%) patients were IHC-CD5 positive at the time of diagnosis. Besides, 28 (82.4%) patients had a history of cardiovascular and hypertensive disease. Enrolled patients received a total of 148 cycles of treatment, with a median cycle of 4 (range, 1-8). At the end of cycle 3, 5 (14.7%) patients achieved CR, 26 (76.5%) patients achieved partial response (PR), resulting in an ORR of 91.2%, and 3 patients had progressive disease (PD). By the cutoff date (March 25, 2024), ORR was 70.6%, with 11.8% (4/34) CR and 58.8% (20/34) PR. Regarding different biomarker subgroups, the ORR was 81.8% (18/22) for CD5-negative, 50% (6/12) for CD5-positive, 50% (7/14) for Ki67 ≤75%, and 85% (17/20) for Ki67 >75%. Additionally, for patients with ≤3 treatment cycles, the ORR was 50% (6/12); for >3 cycles, it reached 81.8% (18/22). At a median study follow-up of 17.0 months, the median PFS and overall survival (OS) were not reached. The estimated 24-month duration of remission, PFS, and OS rates were 70.7% (95% CI, 56.3-88.8), 64.6% (95% CI, 50.3-82.9), and 81.9 (95% CI, 69.8-96.1), respectively. In addition, the median time to remission was 2.4 months. Subgroup analysis revealed that patients with CD5-negative, Ki67 >75%, number of treatment cycles >3, and efficacy achieved PR and CR showed improved PFS (P=0.009, P=0.006, P=0.029, and P <0.001, respectively). Additionally, patients with Ki67 >75%, non-B symptoms, and efficacy achieved PR and CR had better OS (P=0.03, P=0.033, and P <0.001, respectively). Univariate analysis showed that CD5-positive (HR, 4.365; 95% CI, 1.306-14.590; P=0.017) and Ki67>75% (HR, 0.191; 95% CI, 0.051-0.711; P=0.014) were factors associated with inferior PFS. Multivariate analysis revealed that the numbers of extra-nodal sites at baseline (HR, 3.032; 95% CI, 1.013-9.070; P=0.047) and B symptoms (HR, 6.468; 95% CI, 1.082-38.642; P=0.041) were predictors of inferior PFS. Adverse events (AEs) were observed in 20 (58.8%) patients, with the most common hematologic AEs being anemia and thrombocytopenia (both grade 1). Three patients developed severe anemia, 1 patient developed a grade 3 rash, and 1 patient developed a first-degree atrioventricular block, but no malignant arrhythmic events were observed. At the data cutoff (March 25, 2024), five deaths occurred.

Conclusion: This study evaluated the efficacy and safety of a chemotherapy-free regimen combining the novel BTKi (orelabrutinib), PD-1 monoclonal antibody, and lenalidomide in R/R DLBCL. The findings indicated that this triple-drug combination, which targeted multiple mechanisms, synergistically exerted potent anti-tumor effects and demonstrated effectiveness with favorable tolerability in R/R DLBCL.

Disclosures

No relevant conflicts of interest to declare.

Off Label Disclosure:

Orelabrutinib is a newly developed BTK inhibitor with high selectivity. It is highly potent against BTK with notable less offtarget inhibition of other tyrosine kinases.High kinase selectivity, persistent BTK target occupancy, potent anti-tumor activity, and the safety profile support orelabrutinib as an alternative treatment option for DLBCL

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2024
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