Ibrutinib in Combination with Lenalidomide and Rituximab Displays Improvement for Patients with Relapsed or Refractory DLBCL

Dr. Jia Ruan

By Jia Ruan, M.D., Ph.D.

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.

Ibrutinib Plus Palbociclib in Patients with Previously Treated Mantle Cell Lymphoma

Picture1By Peter Martin, M.D.

Data from three pooled clinical trials suggest that, by itself, ibrutinib works to keep mantle cell lymphoma (MCL) at bay for about one year. For reasons that we have previously discussed on this blog, these results are both impressive and discouraging. For people with MCL, ibrutinib is singular in its ability to produce durable remissions with minimal toxicity. Unfortunately, roughly one third of patients do not respond, while all responding patients eventually experience relapse or progression.

Data from the Chen-Kiang laboratory at Weill Cornell Medicine suggested that palbociclib, an oral inhibitor of CDK4/6, could prevent MCL cells from growing and dividing. Moreover, these arrested MCL cells become even more sensitive to the effects of ibrutinib, essentially overcoming some of the more common mechanisms of ibrutinib resistance and laying the groundwork for a clinical trial.

With the support of the National Cancer Institute, doctors at Weill Cornell Medicine, Ohio State University, Washington University, and the University of North Carolina initiated a phase I clinical trial designed to evaluate the safety and activity of ibrutinib plus palbociclib in people with previously treated MCL. I presented the results of the trial at the 2016 Annual Meeting of the American Society of Hematology. The early results of the trial appear promising, with 70% of patients responding including 45% of study patients experiencing a complete response. More interesting is the observation that only one responding patient has experienced lymphoma progression, corroborating the Chen-Kiang laboratory data that the combination might overcome some mechanisms of ibrutinib resistance. So far, the all-oral regimen appears well tolerated, with low blood counts being the primary side effect.

Although these data appear promising, the number of patients treated so far is relatively small and the follow up time is relatively short. A large, multicenter phase II trial is being planned and will likely open in early 2017. Details regarding that study will be available on this blog and clinicaltrials.gov as soon as they become available.