The combination of lenalidomide and rituximab may represent a reasonable alternative to chemotherapy for some people with previously untreated follicular lymphoma (FL), according to a study led by Dr. Peter Martin, chief of the Weill Cornell Medicine and NewYork-Presbyterian Hospital (WCM/NYP) Lymphoma Program.
Dr. Martin collaborated with the Lymphoma Program’s Drs. Jia Ruan and John Leonard, along with experts from academic medical centers across the country, to evaluate the non-chemotherapy drug combination in a phase II trial known as CALGB 50803, the results of which were recently published in the Annals of Oncology. The formalized collaboration was made possible by the Alliance for Clinical Trials in Oncology, a cooperative group sponsored by the National Cancer Institute (NCI).
Lenalidomide plus rituximab was administered over twelve 28-day cycles to 65 adults with previously untreated follicular lymphoma. Seventy-two percent of patients achieved a complete response. At five years, the overall survival rate was 100 percent, and 70 percent of patients remained free from disease progression. Rates are comparable with those typically produced by standard chemotherapy.
The study also demonstrated low rates of hematologic toxicity, such as neutropenia (low white blood cell count), lymphopenia (low lymphocyte levels) and thrombocytopenia (low platelet count), but low-grade side effects like fatigue, constipation, diarrhea and rash were commonly reported.
The results of the CALGB 50803 study do not definitively establish whether lenalidomide-rituximab is more or less toxic or more or less effective than a standard chemotherapy regimen; such insights will be clearer following completion of the randomized phase III RELEVANCE trial, which compares lenalidomide-rituximab to chemotherapy plus rituximab.
Optimal use of chemotherapy requires a careful balance of anti-tumor activity with tolerability. WCM/NYP is proud to be a leader in the discovery and development of therapies that are both active against cancer and well tolerated.
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.
Recently Dr. John Leonard was interviewed by the Lymphoma Research Foundation and answered questions about the current state of treatment for patients with mantle cell lymphoma (MCL). Specifically, they discussed how results from the 2015, New England Journal of Medicine published study, “Lenalidomide plus Rituximab as Initial Treatment for Mantle Cell Lymphoma” has improved the treatment options for MCL patients. This multi-center phase 2 study showed that a combination therapy, lacking many of the typical debilitating effects of traditional cancer treatment could effectively manage MCL by inducing remissions in the vast majority of patients.
Dr. Leonard, the study’s senior author, described the potential impact of this research and how it could improve our understanding of MCL and treatment as follows,
“This research provides an additional option for patients with MCL and represents the first study of a non-chemotherapy approach that is generally of lower intensity than usual initial treatment. The fact that the majority of patients had durable disease control, with good quality of life, suggests that this approach may have value for some patients. Ongoing research will better assess the longer term outcomes with this approach, and how it either compares with or can be combined with other treatments. This study demonstrates the value of potentially using newer agents as part of initial treatment in MCL, rather than holding off until the disease recurs later.”
In April 2016 the study was nominated by the Clinical Research Forum as one of their Top 10 Clinical Research Achievement Awards of 2016. The 10 winning papers were chosen based on their degree of innovation from a pool of more than 40 nominations from 30 research and academic health centers nationwide.
In the video below you can watch the study’s lead author Dr. Jia Ruan describe the importance of her team’s findings.