Novel Three-Drug Combination of Ibrutinib plus Lenalidomide and Rituximab Shows Promising Anti-Lymphoma Activity in Relapsed/Refractory DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, rising in incidence among older populations. The standard of care for the approximate one-third of DLBCL patients who do not achieve remission with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) is salvage high-dose chemotherapy followed by consolidative autologous stem cell transplant, which leads to long-term disease-free survival for only 10-20 percent of relapsed/refractory patients. Patients who relapse within a year of initial therapy, those who relapse after transplant, and those who are ineligible for transplant due to age or comorbidities face the most significant unmet treatment need.

With an eye toward improving therapeutic options and outcomes for this patient population, the Lymphoma Program team, led by Dr. Jia Ruan, collaborated with colleagues nationwide and contributed significantly to a study examining the maximum tolerated dose and preliminary safety and activity of a novel three-drug combination – ibrutinib plus lenalidomide and rituximab – in treatment of relapsed/refractory DLBCL. The team’s encouraging findings were published in the American Society of Hematology’s Blood journal.

The study population consisted of 45 transplant-ineligible DLBCL patients whose disease returned after at least one prior therapy. Patients received oral ibrutinib daily, intravenous rituximab on every first day of six 28-day cycles, and oral lenalidomide on the first 21 days of each cycle. The treatment was provided as continuous chronic therapy in an outpatient clinic setting for as long as patients could derive benefit.

Forty-four percent of patients responded to the triplet, and 28 percent achieved a complete response. The combination performed particularly well (ORR: 65%, CR: 41%) in patients with non-germinal center b cell (non-GCB) DLBCL, a molecular subtype based on disease cell of origin that is not typically associated with favorable prognosis. Common treatment side effects included gastrointestinal complications, fatigue, myelosuppression (reduced blood cell production), hypokalemia (low blood potassium), peripheral edema and skin rash. Side effects could be monitored and mitigated by dose adjustment in the outpatient setting.

Dr. Jia Ruan

“This novel treatment consists of two oral agents typically used to treat B-cell lymphoma, plus the anti-CD20 antibody rituximab, and can be easily administered in the clinic or patient’s home,” said Dr. Jia Ruan. “This effective low-intensity approach makes it very appealing to a broad range of R/R DLBCL patients in need of treatment.”


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.

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