Preliminary Data of a Single-Arm, Phase II Study of Orelabrutinib with/without Rituximab in Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma after BTK Inhibitor Therapy

Background: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a prevalent hematologic malignancy, and Bruton's tyrosine kinase inhibitors (BTKi) play a pivotal role in its management. During the monotherapy of BTKi, a scant number of patients can attain deep remission (CR or MRD negative), 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 aimed at assessing the efficacy and safety of orelabrutinib combined with/without rituximab in 29 CLL/SLL patients, treated with BTK inhibitors for at least six months without disease progression and with detectable MRD by four-color flow cytometry above 0.01×10^-2. The primary outcome measures encompass 9 months of undetectable small residual lesions (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, 11 patients have been enlisted with a median follow-up of 11.1 months including 7 males and 4 females. The average age was 60 years. CLL accounted for 81.8% (9/11), 5 patients had comorbidities (5/11, 45.5%), and 36.4% (4/11) had hypertension. The majority (90.9%) had an ECOG score of 0-1. 36.4% of the patients had lymph node enlargement, and 36.4% had both lymph node and spleen enlargement.9.1% (1/11) of the patients had TP53 mutation, 27.3% had IgHV mutation or rearrangement, 27.3% (2/11) had Binet stage B, 72.7% (9/11) had stage C, 81.8% (9/11) had Rai stage III and IV. Patients with CLL-IPI scores of 1-2 accounted for 81.8% (9/11). At baseline, the mean MRD in peripheral blood and bone marrow of 10 patients was 33.84×10^-2 (4.1×10^-2 - 83.6×10^-2) and 32.86×10^-2 (7.7×10^-2- 82×10^-2), respectively. Six patients were treated with a combination of orelabrutinib (150mg qd) and rituximab at an initial dose of 375mg/m² during C1, followed by 500mg/m² from cycle 2 to 6. In the second week, 3 patients received an increased dose of rituximab, while another three continued with the 375mg/m² dosage from cycle 2 to 6. 5 patients were switched to monotherapy with Orelabrutinib 150mg qd and continued as a long-term oral medication.

Post-treatment MRD levels decreased to 21.74×10^-2, 19.49×10^-2, and 0.07×10^-2 at 3, 6, and 9 months, respectively, marking a 12.1%, 13.37%, and 21.67% reduction from baseline. At 9 months, 66.7% (2/3) achieved undetectable peripheral blood MRD, with a 9-month CRR of 77.8% (7/9) and a 1-year OS of 100%, and no patient has progressed thus far. Treatment was suspended in 1 patient due to infection, and no significant adverse events were noted in the remaining patients.

Conclusion: Despite the currently limited follow-up period, orelabrutinib combined with or without rituximab, demonstrated favorable efficacy in CLL/SLL patients with detectable MRD post-BTK inhibitor treatment, and MRD decreased significantly after 9 months. This treatment holds the potential to emerge as a new therapeutic option for CLL/SLL patients.