Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common hematologic malignancy, and Bruton's tyrosine kinase inhibitors (BTKis) play a crucial role in its management. During monotherapy with BTKis, only a limited number of patients achieve deep remission (CR or uMRD), yet achieving deep remission is correlated with a superior prognosis. Orelabrutinib represents a new generation of BTKi featuring a higher BTK occupancy. The clinical trial outcomes reveal that the CR rate in R/R CLL/SLL amounts to as high as 26.3%. This study aims to explore novel combined treatment approaches of BTK inhibitors to achieve the uMRD rate.

Method: This is a prospective, single-arm phase II study designed to evaluate the efficacy and safety of orelabrutinib combined with/without rituximab in 28 CLL/SLL patients, treated with BTK inhibitors for at least six months without disease progression. All these patients exhibited detectable MRD by four-color flow cytometry at levels exceeding 0.01%. The primary outcome measures encompass 9 months of undetectable minimal residual disease (9m uMRD) and progression-free survival (PFS). Secondary endpoints include 3 months of MRD decline rate (3m ΔMRD), 9 months of complete response (9mCRR), and 1 year of overall survival (1yOS).

Results: To date, patient recruitment has been completed, with a total of 28 patients enrolled and a median follow-up duration of 16.3 months. The proportion of male patients was 64.3% (18/28), and the median age was 63 years (range, 38–84 years). All patients were diagnosed with CLL/SLL. Among them, 57.1% (16/28) had comorbidities, with hypertension being the most common (39.3%, 11/28). Lymph node enlargement was observed in 42.9% of patients, and 14.3% had concurrent lymph node and spleen enlargement. TP53 gene alterations were identified in 17 patients, and IGHV gene status was determined in 11 patients. Analysis of the data revealed that 29.4% (5/17) of the patients harbored TP53 mutations or deletions, whereas 72.7% (8/11) of the patients exhibited an unmutated IGHV status. Regarding disease staging, 17.9% (5/28) were classified as Binet stage B and 82.1% (23/28) as Binet stage C; 85.7% (24/28) were in Rai stage III or IV. Based on the CLL-IPI, 67.9% (19/28) of patients were categorized as intermediate or high risk. At baseline, the mean MRD levels in peripheral blood and bone marrow were 32.98% (range, 0.25%–83.60%) and 30.85% (range, 0.18%–82.00%), respectively.

Post-treatment MRD levels decreased to 18.20%, 17.49%, and 0.27% at 3, 6, and 9 months, respectively, marking a 14.77%, 15.48%, and 32.70% reduction from baseline. At 9 months, 40.0% (2/5) achieved undetectable peripheral blood MRD. Overall ORR was 60.7% (17/28), CRR was 32.1% (9/28), and 1-year OS was 100%. With regard to safety, the treatment was well-tolerated, and no significant adverse events were observed.

Conclusion: Although the number of enrolled patients was limited, orelabrutinib in combination with or without rituximab demonstrated remarkable efficacy in CLL/SLL patients with detectable MRD after BTK inhibitor treatment. All patients achieved remission, and MRD significantly decreased after 9 months, and uMRD began to emerge. Given these promising findings, this therapeutic strategy holds the potential to serve as a novel treatment option for patients with CLL/SLL.

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2025
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