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.

Weill Cornell Researchers Unlock Potential New Target for Relapsed/Refractory DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma in adults. While DLBCL is potentially curable, patients with relapsed or refractory DLBCL cannot be cured with chemotherapy due to the aggressive nature of their disease and their tumors lack of response to chemotherapy. Therefore treating this subset of DLBCL patients requires new treatment options. Recently researchers from Dr. Leandro Cerchietti’s lab published a paper on a potential new target for DLBCL.

DLBCL tumor cells grow because malignant cancer cells disturb cell processes like DNA methylation and histone acetylation that are two key parts of the “epigenomic” machinery. Researchers in Dr. Leandro Cerchietti’s lab have previously reported that inhibiting one of these epigenomic pathways by using DNA methyltransferase inhibitors (DNMTI), makes tumors more susceptible to chemotherapy treatments. His group hypothesized that inhibiting both epigenomic pathways by combining DNMTI with a histone deacetylase inhibitor (HDI) could be a potential treatment option for DLBCL patients that relapsed after chemotherapy or never responded to chemotherapy.

Leandro Cerchietti, MD
Leandro Cerchietti, MD

Researchers decided to evaluate the effectiveness of combining the HDI, vorinost with the DNMTI’s, azacitidine or decitabine in pre-clinical models to determine the feasibility of beginning phase I human trials. Researchers found no significant toxicity increase in initial laboratory and animal trials. In the ensuing trial 18 patients with a median of 3 prior therapies were treated with 4 different dose levels of azacitidine and vorinostat. The most common side effects were manageable and included hematological, gastrointestinal, and metabolic toxicities.

The clinical benefit to the combined epigenetic treatment was low as only one patient experienced a partial response. However, 2 of the 7 patients, who received chemotherapy after the study achieved a complete response, while 3 others patients derived a significant clinical benefit. This suggests that the proposed epigenetic combination could make tumors more susceptible to chemotherapy treatments.

Further research in pre-clinical models confirmed that DNMTI is the most important drugs in the combination to achieve chemosensitization, which makes tumors more susceptible to chemotherapy treatment. The data supports the strategy of using DNMTI in relapsed and refractory DLBCL patients to overcome disease resistance and improve their outcomes. This treatment could potentially be a new option for patients with relapsed or refractory DLBCL.

New Clinical Trial: Phase 2B Open-label, Randomized Two-arm Study of Selinexor with Low Dose Dexamethasone in Patients with Relapsed/Refractory DLBCL

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The study sponsor is Karyopharm, and the principal investigator at Weill Cornell is Peter Martin, M.D.. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older
  • Pathologically confirmed DLBCL whose disease is relapsed and/or refractory with documented evidence of disease progression after the most recently administered chemotherapy regimen and who in the opinion of the investigator are not candidates for high-dose chemotherapy with stem cell rescue
  • Patients must have received at least 2 but no more than 4 prior multi-agent therapies
  • Detailed eligibility reviewed when you contact the study team

Study Details

This clinical trial is for men and women with Diffuse Large B-Cell Lymphoma (DLBCL) and were previously treated for this disease.

For patients who are not cured with front-line therapy, DLBCL is a very difficult disease to manage with only limited treatment options. Selinexor has demonstrated anti-tumor activity in heavily pretreated patients with various subtypes of DLBCL. This study is designed to confirm selinexor activity with relapse and/or refractory DLBCL in patients who have had at least two but no more than four prior multi-agent therapies and are not eligible for high dose chemotherapy with stem cell rescue at the time of study entry.

This is a randomized, two-arm, multicenter, open-label Phase 2b study of the selinexor high (100 mg) and selinexor low (60 mg) doses with low dose dexamethasone given orally to patients with relapsed/refractory DLBCL who have no therapeutic options of demonstrated clinical benefit. Two hundred patients (100 per arm) with relapsed/refractory DLBCL who meet eligibility criteria will be enrolled and randomized in a 1:1 ratio of high (100 mg) to low (60 mg) selinexor doses.