Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma. While 50-60% of patients are cured with the standard R-CHOP chemotherapy, only 10-20% of patients who fail R-CHOP experience improvements and long-term remission with other therapies. Current treatments options for DLBCL after R-CHOP include high-dose chemotherapy or autologous stem cell transplant (ASCT). However, patients are often ineligible to receive these treatments due to their advanced age or other health problems. Younger patients with relapsed DLBCL may not be able to move onto transplant due to refractory disease. This highlights the unmet medical need to explore additional treatment options for high risk patients whose DLBCL is refractory or relapsed (R/R) within 12 months of diagnosis.
Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which has shown clinical activity as a single agent in R/R DLBCL, particularly in the non-germinal center B-cell–like (non-GCB) subtype. Lenalidomide is an immunomodulatory agent that is active in combination with rituximab (RTX) in R/R DLBCL. The combination ibrutinib and lenalidomide, plus rituximab, has been evaluated in a multicenter, open-label, phase 1b/2 study in pts with R/R DLBCL . The preliminary results of the phase 1b portion of the study has been reported in a podium presentation at the 2016 American Society of Hematology annual meeting in San Diego.
The primary objective of this Phase 1b trial was to determine the maximum tolerated dose of and/or recommended phase 2 dose of ibrutinib in combination with lenalidomide and rituximab. A total of 37 patients were enrolled in the trial. Their median age was 63 and they had a median of 3 prior treatment regimens, and were refractory to their last treatment. The most serious side effects were grade 3/4 neutropenia (32%), thrombocytopenia (14%), and maculopapular rash (11%). On the 15mg dose level of lenalidomide, the overall response rate for patients was 44%, including 3 complete responses and 5 partial responses. Response evaluation is ongoing for 20 mg lenalidomide dose level.
Based on the safety data from this phase 1B study, the phase 2 portion of the study is currently being initiated with lenalidomide at 20 mg dose level and ibrutinib at 560 mg. Despite the small number of patients involved in this trial the results are encouraging for the treatment of high-risk refractory DLBCL. The combination of ibrutinib + lenalidomide/rituximab offers a potentially promising novel option.