Discussion
toxicity, malignant CLL
DISEASE, CLL, ADVERSE EVENTS, PATHOPHYSIOLOGY
The improved understanding of the pathophysiology of CLL has led to the development of targeted agents that leverage distinct vulnerabilities and dependencies of malignant CLL cells. Targeted agents have thus demonstrated higher efficacy than chemotherapy in all risk groups of CLLPreviously, several studies have explored the use of targeted agents in the context of RT. Covalent and non-covalent BTK inhibitors such as acalabrutinib and pirtobrutinib are very well tolerated in patients with RT; however, efficacy is limited owing to low ORRs with short durationsTo the best of our knowledge, the RT1 study is so far, one of the largest prospective phase 2 studies of a targeted treatment approach in RT. Patients with previously treated as well as untreated RT experienced response to combined checkpoint and BTK inhibition with tislelizumab and zanubrutinib, while experiencing little and manageable toxicity rates. The ORR of 58%, including a complete response rate of 19%, lasted for 6 months or more in over 70% of patients, with the median DOR not reached. While the 12-month PFS rate of 47% indicates that most patients eventually experience disease relapses, the 12-month overall survival rate of 75% is higher than historical reports on the expected overall survival of patients with RTThe regimen was generally very well tolerated, with a low number of immune-related adverse events, which have been previously observed with various checkpoint inhibitorsA conceptually similar approach to the RT1 study was previously tested in a monocentric study using nivolumab plus ibrutinib; however, while the data were encouraging with response rates of 42%, the sample size was limitedThe data generated from this first analysis of the RT1 study have limitations. As this study is non-randomized, a direct comparison of the efficacy of tislelizumab plus zanubrutinib with the current standard of care of R-CHOP/EPOCH-R is not possible; however, the clinical outcomes observed in this study are consistently more favorable than what has been reported in retrospective analyses of RTWhile the study regimen is efficacious, the outcomes are still substantially poorer than what is commonly observed in non-transformed CLLIn conclusion, combined checkpoint and BTK inhibition by tislelizumab plus zanubrutinib is an effective and well-tolerated treatment strategy for patients with RT. The response to therapy and overall survival rates at 1 year in the RT1 study are encouraging given the otherwise poor prognosis of RT.