Orelabrutinib plus bendamustine-rituximab (OBR) Versus Bendamustine-rituximab (BR) in transplant-ineligible, intermediate- to high-risk Mantle Cell Lymphoma (MCL)

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma. While chemoimmunotherapy remains the standard of care for MCL, patients with high-risk features (TP53 mutations, blastoid/pleomorphic histology, or high MCL International Prognostic Index [MIPI] score with Ki-67 proliferation index >30%) typically have a poor prognosis, primarily due to inevitable relapses and progression towards a more aggressive morphology. Although the FDA-approved regimen of acalabrutinib plus bendamustine and rituximab has demonstrated the potential of Bruton's tyrosine kinase inhibitor (BTKi) in frontline MCL, clinical benefits remain limited in high-risk patients. Orelabrutinib (O) is a potent, irreversible, and highly selective BTKi with optimized pharmacodynamics, offering the potential for improved efficacy and reduced off-target toxicity in high-risk MCL treatment strategies. Aims To assess the efficacy and safety of OBR versus BR in transplant-ineligible MCL patients with intermediate or high risk MIPI. Methods This open-label, randomized, multi-center study (NCT06496308) enrolled patients with previously untreated MCL, who were ineligible for transplantation and classified as intermediate-/high-risk. Eligible patients were stratified by MIPI into intermediate-risk and high-risk groups and randomized 1:1 to receive the OBR (O: 150 mg, once daily [qd]; B: 90 mg/m², days 1-2; R: 375 mg/m², day 1) or the BR regimens of each 28-day cycle for 6 induction cycles. Responders received maintenance therapy for up to 24 cycles, with O plus venetoclax (ramp-up to 200 mg qd) for those with TP53 abnormality or blastoid/pleomorphic histology, and O monotherapy for others. The primary endpoint was complete response rate (CRR) after induction therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) after induction therapy, and safety. Exploratory endpoints were the assessment of the correlation between tumor biomarkers and treatment efficacy. Results A total of 78 eligible patients were enrolled and randomly assigned to either the OBR arm (n=39) or the BR arm (n=39). The median age were 63.5 years (range 34.0-84.0). All (100%) patients had intermediate- (42.3%) or high-risk MIPI (57.7%), with 14 (17.9%) patients presenting blastoid or pleomorphic histology and 16 (20.5%) harboring TP53 mutations. Baseline characteristics were well balanced between the two treatment arms. Patients have received a median of 6 induction cycles (range 3-6) in the OBR arm and 6 cycles (range 1-6) in the BR arm. In the OBR arm, 37 of 39 (94.9%; 95% CI: 82.7–99.4) patients achieved CR versus 30 of 39 (76.9%; 95% CI: 60.7–88.9) in the BR arm. Seven patients (17.9%) in the BR arm experienced disease progression (PD), whereas no PD events were observed in the OBR arm. The ORR was 97.4% (95% CI: 86.5–99.9) in the OBR arm versus 82.1% (95% CI: 66.5–92.5) in the BR arm. At a median follow-up of 9.9 months estimated using the reverse Kaplan-Meier method, the median PFS was not reached in either arm. The 1-year PFS rate was 96.9% (95% CI: 91.0–100.0) and 77.6% (95% CI: 64.8–93.0) in the OBR and BR arm. Median OS was not reached, whether in the OBR arm or the BR arm. The 1-year OS rate was 100.0% (95% CI: 100.0–100.0) for OBR and 94.9% (95% CI: 88.2–100.0) for BR. Summary/Conclusion: The OBR regimen demonstrated a promising tumor response and favorable survival outcomes compared to the BR regimen. These findings suggest that the OBR regimen may serve as a promising treatment option for patients with transplant-ineligible, intermediate- to high-risk MCL.