Immunochemotherapy combined with novel agents for Richter syndrome: report of 3 cases

Abstract Objective Richter syndrome (RS) occurs in approximately 2–10% of chronic lymphocytic leukemia (CLL) patients, more often during the disease course than at diagnosis, with a diffuse large B-cell Lymphoma (DLBCL) histology in 95% of cases. Despite great advances in the treatment of CLL in recent years, RS also develops in patients treated with novel agents, as summarized in our case report and review. Methods We summarized 3 patients with RS treated with immunochemotherapy combined with BTK inhibitor (BTKi) or BCL2 inhibitor (BCL2i) and reviewed the literature. Results Three RS patients were summarized. Patient 1 was transformed into DLBCL during dose reductions in ibrutinib and achieved bone marrow (BM) minimal residual disease (MRD)-negative complete response (CR) after rituximab etoposide, dexamethasone, doxorubicin, cyclophosphamide, and vincristine (R-EDOCH) combined with BTKi treatment and sustained progression-free survival (PFS) for more than 2 years. Patient 2, who transformed at the time of diagnosis, progressed after being treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), followed by PD1 antibody combined with cytosine, arabinoside, cisplatin and dexamethasone (DHAP) treatment and PD1 antibody combined with ifosfamide, carboplatin, and etoposide (ICE) treatment. Patient 2 achieved CR after treatment with rituximab, gemcitabine, and oxaliplatin (R-GemOx) combined with BTKi. Patient 3, who transformed at the time of diagnosis with CARD11, TP53, and ATM mutations, progressed after being treated with R-EDOCH combined with BTKi and achieved MRD-negative CR after treatment with R-GemOx and venetoclax, which has continued for 3 months. We summarized new protocols utilizing targeted therapy, such as BTKi acalabrutinib, and checkpoint inhibition, and the potential role of precision medicine in future trials of RS treatment. The efficacy of these protocols as single agents or in combination with immunochemotherapy is currently being evaluated. Conclusion In our study, immunochemotherapy combined with BTKi or BCL2i achieved favorable efficacy in the treatment of RS. The treatments should be optimized by the combination of both chemotherapies and targeted therapy to develop a specific individual approach for each patient, according to previous treatment and biological characteristics.