Efficacy and safety of first-line orelabrutinib combined with obinutuzumab (With or Without Bendamustine) in high-risk marginal zone lymphoma: Results from the orchid study

Abstract Background: Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma with distinct subtypes, including mucosa-associated lymphoid tissue (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). MZL remains a clinical challenge in previously untreated patients with high-risk features such as advanced-stage disease (Ann Arbor Stage III-IV), elevated lactate dehydrogenase (LDH), bulky disease, or comorbidities such as autoimmune conditions or infection-related associations. Although current treatment options include CD20 monoclonal antibodies, chemotherapy, and Bruton tyrosine kinase (BTK) inhibitors, limited data exist regarding combination therapies for this high-risk population.The Orchid Study investigates the potential of orelabrutinib in combination with obinutuzumab—with or without chemotherapy—in the first-line treatment of high-risk MZL and evaluates the regimen's efficacy and safety profile. Methods Patients were stratified into two cohorts based on the investigator's assessment of disease burden and individual risk factors, Cohort A, the (OG group) received orelabrutinib (O) at 150 mg orally once daily in combination with obinutuzumab (G) at 1000 mg intravenously on Day 1, Day 8, and Day 15 in the first cycle and on Day 1 of cycles 2-6, without chemotherapy for 28 days per cycle. This cohort primarily included patients with a lower disease burden or comorbidities that were unsuitable for intensive therapy. Cohort B (OBG group) received the same orelabrutinib-obinutuzumab regimen in combination with bendamustine for 6 cycles, targeting patients with higher disease burden, bulky disease, or poor prognostic indicators. After completion of 6 treatment cycles, all patients with partial response (PR) or better entered a maintenance therapy phase, consisted of orelabrutinib monotherapy (150 mg once daily) for up to 18 cycles or until disease progression or unacceptable toxicity. The primary endpoint was complete response (CR). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), partial response, duration of response (DoR), overall survival (OS), and safety assessment, including the incidence of adverse events (AEs). Results Among the 20 patients enrolled, the median age was 65 years (range: 44-83), with a slight female predominance (55.0%), 55% of the patients aged ≥60 years. The majority of patients (70%) had advanced-stage disease (Ann Arbor Stage III-IV), and 20% had bulky disease. The study predominantly consisted of MALT lymphoma cases (70.0%), followed by SMZL (25.0%) and NMZL (5.0%). The majority of patients (95.0%) had an ECOG performance status of 1. Regarding treatment regimens, 70.0% received OG while 30.0% were administered OBG. At the data cutoff, of the 20 enrolled patients, 12 have completed the interim efficacy assessment, achieving a CR rate of 100%(12/12) and an ORR of 100%. 6 patients completed the combination therapy and entered the maintenance phase, with 100%(6/6) maintaining CR, keeping the ORR at 100%. While only 1 SMZL progressive disease (PD) was observed, underscoring the promising efficacy of the combination regimen. The duration of response was encouraging, and the 6-month PFS was estimated at 90%, suggesting that this therapy significantly delays disease progression in high-risk population. Subgroup analyses indicated that both the orelabrutinib-obinutuzumab (OG) regimen and the combination with chemotherapy (OBG) exhibited similarly high response rates. The safety profile of the combination regimen demonstrated manageable levels of toxicity. Severe adverse events (Grade 3-4) were not observed, and grade 1-2 adverse events included infections, fatigue, decreased appetite, leukopenia, ankle edema, fever, acute liver damage in chronic hepatitis B, and elevated transaminase in 3 patients. Importantly, there were no reports of bleeding events, atrial fibrillation, or renal impairment. Conclusion This phase 2 study demonstrates that orelabrutinib in combination with obinutuzumab—with or without chemotherapy—is a highly effective first-line treatment option for patients with previously untreated high-risk MZL. The regimen achieved a fast and impressive CR of 100% at interim efficacy assessment, with durable responses observed across patient subgroups, and exhibited a favorable safety profile with manageable toxicity.