Optimizing Time-Limited Therapy in Unfit CLL/SLL Patients: Orelabrutinib, Bendamustine, and Obinutuzumab Combination (OBG) Regimen

Background: In chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) fit patients, exploration of time-limited therapy models such as fixed-duration or minimal residual disease (MRD) guided therapies has shown promising results, highlighting the need for similar investigations in unfit patients. Based on orelabrutinib's selective BTK inhibition with minimal impact on ITK kinase, which preserves obinutuzumab's antibody-dependent cellular cytotoxicity (ADCC) effect, and leveraging obinutuzumab's enhanced ADCC and antibody-dependent cellular phagocytosis (ADCP) capabilities alongside bendamustine's cytotoxicity, we explored a time-limited therapy model combining orelabrutinib, bendamustine, and obinutuzumab (OBG) in unfit CLL/SLL patients. Methods: This multicenter, exploratory study enrolled previously untreated patients with unfit CLL/SLL without del 17p or TP53 mutation. Patients received one cycle of the BG regimen for tumor reduction, followed by five cycles of the OBG regimen, and finally one cycle of orelabrutinib monotherapy (bendamustine: C1 (70 mg/m2, d2, d3), C2-C6 (90 mg/m2, d1, d2); obinutuzumab: C1 (100 mg d1, 900 mg d2, 1000 mg d8, d15); C2-C6 (1000 mg, d1); orelabrutinib: oral 150 mg, once daily, 28-day cycles). The definition of an “unfit patient” is aged 65 years or older, or has a CIRS (Cumulative Illness Rating Scale) score > 6. Primary endpoints include the rate of complete response (CR) combined with undetectable minimal residual disease (uMRD) at the end of 7 cycles (CR/CRi & uMRD, with patients achieving incomplete CR categorized as CRi). Secondary endpoints encompass CR/CRu & uMRD rates at the end of 7 cycles (CRu defined as splenic longest diameter ≤ 16 cm with other criteria meeting CR/CRi standards), uMRD rate (detected via NGS at a level of 10-6)，progression-free survival (PFS), and overall survival (OS). Results: As of July 2024, eight patients have been enrolled. Data showed a 100% CR/CRi & uMRD after 7 cycles, with peripheral blood and bone marrow uMRD rates of 100% and 87.5%, respectively. CR/CRi with uMRD was achieved in 87.5% of cases, indicating potential clinical benefits. Safety analysis revealed thrombocytopenia and neutropenia in seven patients, with adverse events ≥ Grade 3 occurring in 25% of cases, all reversible. No incidences of bleeding or atrial fibrillation were reported. One patient experienced Grade 3 pulmonary infection, now resolved. Conclusion: The OBG regimen demonstrates efficacy as a promising time-limited therapy in unfit CLL/SLL patients, achieving high rates of complete response (CR) combined with undetectable minimal residual disease (uMRD). Safety analysis indicates that the OBG regimen is well-tolerated, with manageable adverse events such as reversible thrombocytopenia and neutropenia observed in a subset of patients. These findings support further investigation of the OBG regimen to optimize treatment outcomes in this patient population.