Practical Application of Orelabrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL): Analysis of Real-World Evidence (OCARE Study)
Authors: Zhang Xuewu , Meng Haitao , Xu Gaixiang , Yang Min , Xie Wanzhuo , Wei Juying , Ma Liya , Ye Xingnong , Mao Liping , Mai Wenyuan , Yang Chunmei , Ren Yanling , Tong Hongyan , Zhu Yanan , Zhang Xiang , Jin Jie , Yu Wenjuan 
Published: December 2024

Background: CLL/SLL are the most prevalent B-cell malignancy characterized by chronic B-cell receptor signaling. Bruton's tyrosine kinase inhibitors (BTKi) are pivotal in managing CLL/SLL. Previous real-world research has demonstrated that the rate at which patients discontinue ibrutinib stands at 29%. Orelabrutinib demonstrates superior kinase selectivity and enhanced safety profiles, with clinical trials indicating a reduced incidence of BTK inhibitor-related adverse events. Nevertheless, the availability of real-world data remains limited. This study retrospectively analyzed data from the First Affiliated Hospital of Zhejiang University to assess the real-world efficacy and safety of orelabrutinib in CLL/SLL patients.

Method：This study included pathologically confirmed CLL/SLL patients who received orelabrutinib for ≥3 months between December 25, 2020 and July 28, 2024. The clinical outcomes we observed were: clinical characteristics, hematological response rate (HRR), including hemoglobin response (recovery or increase in Hb value by ≥50% from baseline), platelet response (recovery or increase in Plt count by ≥50% from baseline), or lymphocyte response (recovery or decrease in Lym count by ≥50% from baseline) in patients with abnormal hematological parameters; objective response rate (ORR), duration of treatment (DOT), overall survival (OS), progression-free survival (PFS), and safety was assessed by adverse event rate (AE) and discontinuation rate.

Result: The study comprised 77 patients with a median age of 65 years. 51.9% (40/77) of the patients were diagnosed with CLL. Patients aged 65 years and older were 50.6% (39/77), with 16.9% (12/77) ECOG PS of 2. Lymph node enlargement occurred in 50.6%（39/77）, and 55.9% (43/44) of the patients were Binet B and C. 53.2% (41/77) of the patients had comorbidities, of which 43.9% (18/41) were hypertensive, and 19.5% were complicated by viral hepatitis. Part of patients underwent genetic testing. The proportion of patients without IGHV mutation was 28.6% (22/77), while patients with mutation was 28.6% (22/77). Patients with 17p- mutation was 19.5% (12/77), and 10.4% (8/77) had TP53 mutations. 36.8% (28/77) of the patients were newly diagnosed with CLL/SLL, 63.2% (48/77) were relapse-refractory patients, and 45.5% (35/77) had received one prior systemic therapy. 20.8% (16/77) of the patients who had previously been treated with BTK inhibitors, including ibrutinib, zanubrutinib, avitinib and SS-001, switched to orelabrutinib due to AE intolerance or unsatisfactory efficacy.

Median follow-up time was 9.8 months (range, 0.7-25.7). The median DOT of orelabrutinib was 14.5 months（range,0.4-36.4）, and 87% (67/77) of the patients received orelabrutinib monotherapy. 75.3% (58/77) had abnormal baseline blood test. 72.7% (24/33) had a hematological response, and the incidence of HRR was 66.7% in patients with comorbidities and 77.8% in patients without comorbidities. There were no significant differences in HRR among groups in terms of comorbidities, IGHV gene, 17p-, 11q-, and TP53 gene status. During treatment, 2 patients developed disease progression. The estimated 12-month PFS rate was 97.1%, and the 12-month OS rate was 98.2%. 7.8% (6/77) of the patients had their dose of orelabrutinib adjusted, primarily due to leukopenia or infection. No unexpected adverse events were reported.

Conclusion: The study demonstrates that orelabrutinib elicits robust hematological responses in both newly diagnosed and relapsed/refractory CLL/SLL patients, with an acceptable safety profile and a prolonged DOT. Although limited by its sample size, the data provide compelling evidence that orelabrutinib is a promising therapeutic option for CLL/SLL patients.