In the evolving landscape of hematology and oncology, innovative treatments for challenging conditions like relapsed or refractory marginal zone lymphoma are of paramount importance. It is in this context that the recent phase 2, multicenter, open-label study investigating the efficacy of Orelabrutinib comes to light, marking a significant advancement in the therapeutic domain. This study, meticulously carried out by a dedicated team of researchers led by Professor Haiwen Huang from The First Affiliated Hospital of Soochow University, alongside esteemed colleagues from various prestigious institutions across China, has been a beacon of hope for patients grappling with this relentless malignancy. The findings of this groundbreaking research were meticulously documented in the American Journal of Hematology, underscoring not only the potential of Orelabrutinib as a viable treatment option but also the collaborative effort and expertise that epitomizes the spirit of innovation in the field. This endeavor, emblematic of the strides being made in hematology research, was brilliantly showcased during a session at the renowned Beijing Hematologic Tumor and Immunology Summit Forum, an event that has become a cornerstone for the dissemination of cutting-edge scientific knowledge and clinical practices.
Marginal Zone Lymphoma (MZL) constitutes a significant fraction of non-Hodgkin lymphoma cases, distinguished by its origin from B cells in the marginal zones of lymph nodes and other lymphatic tissues. Despite its typically indolent course, effective treatment options remain scarce for patients with relapsed or refractory (r/r) MZL, underscoring a profound unmet need within this patient cohort. The novel Bruton’s tyrosine kinase (BTK) inhibitor, Orelabrutinib, offers a promising therapeutic avenue, warranting an extensive investigation of its efficacy and safety profiles in the treatment of r/r MZL.
This phase 2 study primarily aimed to assess the efficacy of Orelabrutinib in inducing tumor responses in patients with r/r MZL. Additionally, it sought to evaluate the drug’s safety and tolerability, alongside its pharmacokinetic properties, to provide a comprehensive overview of its potential as a therapeutic option in this challenging clinical setting.
The study was a phase 2, multicenter, open-label trial carried out across various institutions in China, targeting individuals with histologically confirmed relapsed or refractory (r/r) marginal zone lymphoma (MZL). It enrolled adult patients who had previously undergone at least one therapy but experienced a relapse or refractory disease. Participants were administered Orelabrutinib at a dose of 150 mg orally once daily across 28-day cycles. This treatment was continued until there was evidence of disease progression, the emergence of unacceptable toxicity, or if the patient chose to withdraw consent. The primary endpoint for evaluating the effectiveness of Orelabrutinib was the overall response rate (ORR), as assessed by an Independent Review Committee (IRC) in accordance with the Lugano 2014 classification. The study also focused on several secondary endpoints, including progression-free survival (PFS), overall survival (OS), duration of response (DOR), and the comprehensive safety profile of Orelabrutinib, aiming to provide a holistic view of its therapeutic potential and tolerability in treating r/r MZL.
In the study, 111 patients were enrolled, out of which 90 had their diagnosis of marginal zone lymphoma (MZL) confirmed through central review. A significant portion of these patients was dealing with advanced-stage disease, and the majority had been previously treated with anti-CD20 monoclonal antibody therapy. The efficacy of Orelabrutinib was highlighted by an Independent Review Committee (IRC)-assessed overall response rate (ORR) of 58.9%, including a complete response rate of 11.1% and a partial response rate of 47.8%. Impressively, the median duration of response reached 34.3 months, underlining Orelabrutinib’s ability to induce long-lasting tumor regression. When it came to survival outcomes, the treatment showed promising results with a 12-month progression-free survival (PFS) rate of 82.8% and a 12-month overall survival (OS) rate of 91.0%, suggesting a significant survival advantage for patients treated with Orelabrutinib. The safety profile of the drug was generally manageable, with the most common treatment-related adverse events being anemia, decreased neutrophil count, and rash. Moreover, 16.2% of the patients experienced serious treatment-related adverse events (TRAEs), with pneumonia being the most prevalent, indicating a need for careful monitoring and management of these potential side effects.
| Characteristic | Proportion of patients (N = 90) | |
| Age (years) | ||
| Mean (standard deviation) | 60.0 (10.05) | |
| Median (interquartile range) | 62.0 (54.0, 66.0) | |
| Min, max | 23, 77 | |
| ≥65 | 37 (41.1) | |
| Sex, n (%) | ||
| Male Female | 49 (54.4) 41 (45.6) | |
| ECOG performance status, n (%) | ||
| 0 | 42 (46.7) | |
| 1 | 48 (53.3) | |
| Subtype diagnosis (central pathology review), n (%) | ||
| SMZL | 5 | (5.6) |
| NMZL | 32 | (35.6) |
| MALT | 42 | (46.7) |
| Unknown | 11 | (12.2) |
| Lymphoma stage, n (%) | ||
| I | 6 | (6.7) |
| II | 10 | (11.1) |
| III | 6 | (6.7) |
| IV | 68 | (75.6) |
| Relapsed/refractory, n (%) | ||
| Relapsed | 42 (46.7) | |
| Refractory | 32 (35.6) | |
| Relapsed/refractory | 16 (17.8) | |
| Βeta 2 microglobulin, n (%) | ||
| ≤3 mg/L | 45 (50.0) | |
| >3 mg/L | 44 (48.9) | |
| LDH, n (%) | ||
| ≤upper limit of normal >upper limit of normal | 66 (73.3) 24 (26.7) | |
| Bone marrow assessment, n (%) | ||
| Negative | 58 (64.4) | |
| Positive | 30 (33.3) | |
| Unevaluable | 2 (2.2) | |
| Hepatomegaly, n (%) | ||
| Yes No | 8 (8.9) 82 (91.1) | |
| Splenomegaly, n (%) | ||
| Yes | 12 (13.3) | |
| No | 78 (86.7) | |
| B symptom assessment, n (%) | ||
| Any B symptom | 10 (11.1) | |
| Prior lines of therapy, n (%) 1 | 49 (54.4) (Continues) | |
Orelabrutinib exhibited potent efficacy in the treatment of r/r MZL, characterized by high response rates and prolonged disease remission. The drug’s safety profile was manageable, aligning with expectations for BTK inhibitors and supporting its tolerability in this patient population.
This study propels Orelabrutinib to the forefront of potential therapeutic strategies for r/r MZL, offering a glimmer of hope for patients with limited treatment options. The findings advocate for the integration of Orelabrutinib into the therapeutic landscape for MZL, meriting further exploration in larger, possibly randomized studies to confirm its efficacy and safety on a broader scale.
