Efficacy and Safety of Orelabrutinib in Relapsed/Refractory Idiopathic Multicentric Castleman Disease: A Single-Center, Retrospective Study

Introductions: Despite advances in therapy, idiopathic multicentric Castleman disease (iMCD) remains incurable, with fluctuating disease activity, leading to an urgent need for additional therapeutic options, particularly for refractory or relapsed (r/r) patients. Currently, no standardized treatment regimen for r/r iMCD exists, and approaches often rely on intensive chemotherapy strategies, such as pulse administration with or without rituximab, which might bring safety concerns and are inadequate for sustained long-term drug administration, leading to challenges in maintaining long-term disease control. Bruton's tyrosine kinase (BTK) stands as a critical component of multiple signalings that regulate B cell proliferation, survival, and functionality. Blocking BTK emerges as a promising therapeutic approach for iMCD without depleting B cells. Oral orelabrutinib is a novel, next-generation BTK inhibitor (BTKi) with a well-demonstrated efficacy and safety profiles in patients with various indolent B-cell malignancies, autoimmune diseases, and iMCD. This retrospective study aimed to investigate the efficacy and safety of orelabrutinib in patients with r/r iMCD.

Methods: This single-center study enrolled patients with r/r iMCD who received orelabrutinib treatment for more than 3 months between 2021-2022. The diagnostic criteria for iMCD were based on the Castleman Disease Collaborative Network (CDCN) consensus. Patients with relapsed disease were defined as patients who had achieved remission through prior lines of therapy but then experienced disease progression. Patients with refractory disease were defined as those newly diagnosed with iMCD who did not achieve any remission despite frontline therapy before orelabrutinib administration. For all enrolled patients, oral orelabrutinib was initiated at a daily dose of 150 mg. Dose adjustments were made based on the patient's tolerance or concurrent use of any inhibitor of cytochrome P450 3A4. All patients received a minimum daily dose of 50 mg. The primary endpoint of the study was the overall response rate (symptomatic response and biochemical response) during the study. Responder was defined as achieving at least partial remission according to the CDCN criteria. Secondary endpoints included trends in biochemical parameters (hemoglobin, C-reactive protein (CRP), albumin, and serum creatinine) at month 12 and time to next-line treatment (TTNT).

Results: Ten patients with r/r iMCD were included in the study, with a male-to-female ratio of 1:1. The median age at the initiation of orelabrutinib was 48 (31–58) years. All cases were classified as having iMCD-not otherwise specified subtype (iMCD-NOS). Six patients were classified as relapsed, and four as refractory. The median number of prior treatment lines was 2 (1–5). The median maintenance dose of orelabrutinib was 50 mg/day (range: 50–150 mg). Seven patients (70%) were assessed as responders, two of whom achieved complete response. The median time to remission for responders was 9.8 months (range: 5.9–20.5 months). Three patients (30%) were regarded as non-responders, including two with stable disease and one with disease progression. In responder group, hemoglobin levels increased from 104 to 123 g/L (p=0.039), CRP decreased from 67.33 to 14.54 mg/L (P=0.009), along with the normalization of albumin levels (increased from a minimum value of 26 to 37 g/L) and creatine (from 65 to 62 μmol/L) at month 12. In the non-responder group, despite not achieving response criteria, these patients still showed a continuous improvement in median hemoglobin (91 to 105 g/L), albumin (32 to 38 g/L), CRP (76.80 to 65.86 mg/L), and creatine (72 to 54 μmol/L) levels with treatment at month 12. The median TTNT was 29.0 months (range: 15.0–36.2 months), and no patient mortality was recorded. In terms of safety, no grade 3 or above adverse reactions occurred.

Conclusions: Orelabrutinib, with its high response rate, durable response time, and improved safety profile can be a viable alternative for the treatment of patients with r/r iMCD.