A Phase II study of time-limited treatment with orelabrutinib plus bendamustine and obinutuzumab (OBG) in patients with treatment-Naïve CLL/SLL patients Free

Background: FCR (fludarabine, cyclophosphamide, and rituximab) has been demonstrated to improve outcomes in previously untreated Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) CLL patients, but only for suitable patients, which limits it clinical application.Lower toxicity strategies, such as Bendamustine-Obinutuzumab or Bendamustine-Rituximab, demonstrated better tolerability but did not achieve comparable efficacy.BTK inhibitors (BTKi) are recommended for long-term therapy in CLL/SLL and time-limited treatment regimen has been hot topics. In fit patients, exploration of time-limited therapy models such as fixed-duration or MRD-guided therapies has shown promising results. However, such exploration were needed in unfit patients.Orelabrutinib is a novel, potent, and highly selective BTK inhibitor that offers better deep remission compared to other BTK inhibitors.Therefore, this study aims to explore a more effective treatment regimen for unfit patients with newly diagnosed CLL/SLL by using Orelabrutinib plus Bendamustine and Obinutuzumab (OBG) regimen as first-line therapy. The first stage analysis was published at 66^th ASH meeting and this time we report the update of interim analysis.

Methods: This is a multiple-center, phase II, single-arm study aimed at evaluating the efficacy and safety of OBG regimen as first-line treatment for CLL/SLL unfit patients without 17p-/TP53 mutations. Unfit defined as patients age > 65 years old or CIRS scores≥6.The 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). The secondary endpoints include CRR, ORR, and safety. Dosage regimen:Orelabrutinib 150 mg, po, qd, D1-D28;Bendamustine: 70 mg/m², intravenous injection, administered on Day 2 and Day 3 of Cycle 1, and on Day 1 and Day 2 of Cycles 2-6. Obinutuzumab: Cycle 1: 100 mg on day 1, 900 mg on day 2 (or 1000 mg on day 1), and 1000 mg on days 8 & 15. Cycle 2-6, 1000 mg/m² on Day 1. Each treatment cycle lasts 28 days. The first cycle us BG regiment to reduce tumor burden, followed by 5 cycles of OBG, and then one cycle of orelabrutinib monotherapy.

Result: From December 2023 to March 2025, a total of 13 patients were enrolled, all of whom completed at least 4 cycles of treatment, with 11 patients completing 7 cycles. The median age was 66 years (range: 53–70). 76.9% patients were males and 23.1% were females. ECOG PS scores were distributed as follows: score of 0 in 69.2% and score of 1 in 30.8%. Rai staging showed that 38.5% patients were stage I/II, while 61.5% were III/IV. IGHV mutation was present in 76.9% of the patients. Efficacy results: 72.7% (7/11) had achieved CR&uMRD at the end of all 7 cycles, with an ORR of 100% and 100% achieved PB uMRD4. Among all patients who completed at least four cycles (n=13), ORR was 92.3%, and 46.2% achieved CR. Safety results: Among all treated patients, ≥Grade-3 AEs occurred in four patients (include 3 neutropenia, 2 thrombocytopenia, 2 infections, 1 involving herpes zoster). All patients fully recovered from the adverse event without any impact on their subsequent treatment. No cases were reported for hypertension (any grade), atrial fibrillation (any grade), or bleeding events (≥Grade-3) across all participants treated during this study period.

Conclusions: The Time-Limited Treatment of OBG regimen shows efficacy in unfit CLL/SLL patients, which achieved high rates of complete response combined with undetectable minimal residual disease. Safety analysis indicates that the OBG regimen is well-tolerated and adverse events are manageable. These findings support further investigation of the OBG regimen to optimize treatment outcomes in this patient population.