Orelabrutinib in Combination With R2 Regimen for R/R CD20+ B-cell Lymphoma

Bruton's tyrosine kinase (BTK), a member of the TEC family of non-receptor tyrosine proteins, is expressed in B lymphocytes, mast cells, macrophages, monocytes, neutrophils, etc., and is a key molecule in the signaling of B cell antigen receptor (BCR). The development and differentiation of B cells can be controlled by activating positive cell cycle regulators and differentiated cytokines, and the survival and proliferation of B cells can be controlled by regulating the expression of pro-apoptotic and anti-apoptotic proteins. BTK inhibitors inhibit B cell maturation and activation by targeting the BCR signaling pathway. Compared with other BTK inhibitors, orelabrutinib is highly selective. Previous studies showed that among 456 tested kinases, the inhibition rate of orelabrutinib only exceeded 90% at 1µM concentration, which is the BTK inhibitor with the highest kinase selectivity reported so far. It has shown a good safe treatment window in animal models, and its pharmacokinetic properties are far superior to those of ibrutinib. In the Phase I dose exploration study of orelabrutinib in Australia, the single dose was from 20mg/ day to 400mg/ day, and the continuous dose was from 100mg/ day to 200mg/ day. No serious adverse events related to the drug occurred, and no dosion-limiting toxicity was found. The main adverse reactions were headache, intubation pain, fatigue, etc. Most of them were mild and generally well tolerated, providing a reference for the selection of subsequent clinical drug dosage. Phase I/II clinical trials of orelabrutinib for MCL and CLL/SLL have been conducted in more than 20 centers across the country. Based on preliminary results observed in Phase I, obrutinib has demonstrated excellent safety and tolerability in patients with relapsed refractory MCL and CLL/SLL. Most of the adverse reactions were grade 1-2. Good results have been observed early on in patients. Good pharmacokinetic/pharmacokinetic properties. Several studies have shown that ibrutinib combined with lenalidomide and rituximab improves survival in patients with relapsed refractory diffuse large B-cell lymphoma. In addition, ibrutinib combined with lenalidomide and rituximab has been included in the expert recommendation of multiple relapsed and refractory B-cell lymphomas in the 2021CSCO Lymphoma Guidelines. In conclusion, orelabrutinib and lenalidomide combined with rituximab demonstrated good efficacy and tolerability in the treatment of relapsed refractory B-cell lymphoma. Moreover,orelabrutinib has better selectivity than ibrutinib, so we believe that orelabrutinib combined with lenalidomide and rituximab (OR2) may have better efficacy in the treatment of relapsed and refractory B-cell lymphoma, and there is no research report on this regimen. The application of this regimen may bring new hope for relapsed refractory B-cell lymphoma.