Abstract
Background While BTK inhibitors (BTKi) combined with 6 cycles of FCR achieve high rates of MRD negativity and prolonged treatment-free remission (Davids MS et al. Lancet Haematol 2019), FCR is associated with significant hematologic toxicity, infection risk, and fludarabine-related secondary malignancies. The BR regimen demonstrates improved safety over FCR (Kutsch N et al. Hemasphere 2020). Orelabrutinib, a highly selective covalent BTKi, offers a favorable safety profile (Xu W et al. Am J Hematol 2023). Here we report the preliminary findings of a study on orelabrutinib combined with short-course BR in treatment-naïve CLL.
Method This prospective multicenter study enrolled untreated CLL/SLL patients aged 18-70 years. To mitigate tumor lysis syndrome (TLS) risk from triplet therapy, cycle 1 employed debulking with rituximab plus bendamustine (BR). From cycles 2-4, patients received orelabrutinib with BR. Post-cycle 4, treatment extension or observation was permitted per investigator judgment and patient preference. Orelabrutinib was capped at 18 cycles (28-day cycles).
Result As of July 24, 2025, eight patients were enrolled, with a median age of 62 years (range 50-76) and a predominance of males (75%). Binet staging included B (n=3) and C (n=3), while Rai stages were I (n=2), II (n=1), III (n=2), and IV (n=1). Among six evaluable patients, TP53 abnormalities were present in four and unmutated IGHV in two. All patients remain on treatment, with five patients completing four cycles of combination therapy evaluable for efficacy and MRD assessment. With a median follow-up of 15 months (range, 6.3-15.5)，3 achieved CR, 1 PR, and 1 SD, yielding an ORR of 80% and CR rate of 60%. Undetectable MRD (<10⁻⁴) in peripheral blood was achieved by two patients (40%) at the end of cycle 3, increasing to four patients (80%) by cycle 9. None of the 5 patients progressed. Notably, two of three patients with TP53 abnormalities achieved deep remissions (CR with undetectable MRD). Safety analysis encompassing seven patients (median follow-up 11.6 months; range 1.3-15.5) experienced ≥ grade 3 hematological toxicity, mainly including 3 cases of grade 3 lymphopenia, 1 case of grade 4 neutropenia, and 1 case of grade 3 anemia. All toxicities resolved following appropriate management.
Conclusion Orelabrutinib with short-course BR induces high rates of deep remission (CR 60%, MRD negativity 80%) and manageable toxicity in untreated CLL. This regimen is expected to provide patients with a very good drug holiday.
