The combination of rituximab and lenalidomide shows evidence of effectively managing mantle cell lymphoma (MCL), generally considered incurable, while avoiding the side effects associated with more intensive treatments, according to a study in The New England Journal of Medicine (2015;373:1835-1844).
While studies of lenalidomide and rituximab in refractory MCL have demonstrated clinical responses, “the efficacy of the combination in the first-line setting, when provided as induction and maintenance treatment, was beyond our expectations,” said the lead author, Jia Ruan, MD, PhD, Associate Professor of Clinical Medicine at Weill Cornell Medicine.
“Because of the ease of administering this outpatient, fairly low-intensity treatment, it may be a useful option for MCL patients, particularly for those who would otherwise not tolerate or would like to avoid a more intensive approach,” said Ruan, who receives clinical research funding from Celgene, the maker of lenalidomide (Revlimid) and the sponsor of the study.
“Lenalidomide and rituximab are approved for MCL in the relapsed/refractory, setting, so we knew this combination was active,” commented Paul Barr, MD, Associate Professor of Medicine and Director of the Clinical Trials Office for the Wilmot Cancer Institute of the University of Rochester Medical Center. “What warrants publication in The New England Journal of Medicine was how efficacious this combination looks given as first-line therapy. It does look incredibly active.”
Still, said Andre Goy, MD, MS, Chairman and Director of the John Theurer Cancer Center and Chief of the Division of Lymphoma at Hackensack University Medical Center, who was also asked for his perspective, although the data presented on the combination of lenalidomide and rituximab as frontline therapy appears very promising, the number of patients was relatively small and the follow-up is still short.
For the Phase II study of 38 patients, researchers at four medical centers—Weill Cornell Medicine/NewYork Presbyterian, Moffitt Cancer Center, the University of Pennsylvania Abramson Cancer Center, and the University of Chicago Medical Center—conducted the study between July 2011 and April 2014. Patients had a median age of 65, and at baseline, 34 percent had low-risk disease, 34 percent had intermediate-risk, and 32 percent had high-risk disease.
For the induction phase, physicians gave oral lenalidomide at 20 mg daily, for 21 days of a 28-day cycle, for 12 cycles. If patients had no dose-limiting adverse events, the dose was raised to 25 mg after the first cycle. For the induction phase, participants also received four weekly infusions of rituximab, given at a dose of 375 mg per square meter of body surface, and received subsequent infusions every two months.
After 12 months, participants transitioned to a maintenance phase, the duration of which was for as long as they wanted to continue treatment while receiving benefit, up to a maximum of five years. Lenalidomide was reduced to 15 mg daily during the maintenance phase and the rituximab infusions remained the same.
Of the 36 patients who could be evaluated after a median follow-up time of 30 months, the overall response was 92 percent, while the complete response was 64 percent. At 30 months, median progression-free survival had not been reached.
The two-year progression-free survival rate was 85 percent, and two-year overall survival was 97 percent. Progression-free survival, which is an endpoint often evaluated in Phase II studies, appears better with rituximab-lenalidomide than with R-CHOP or with bendamustine plus rituximab, Barr noted. “However, it's not completely fair to compare against other studies.”
Side Effects Manageable
The investigators reported that half of patients experienced grade 3 or 4 neutropenia,13 percent had thrombocytopenia, and 11 percent experienced inflammatory syndrome. Anemia occurred in 11 percent of patients, serum sickness was reported in eight percent, and fatigue was also reported in eight percent of patients; there were also seven secondary cancers in the patients in the study.
Overall, the side effects experienced by patients were expected and manageable, Ruan said. For example, cytopenias were managed with lenalidomide dose adjustments.
Goy said that even though this was an early follow-up, there were a significant number of secondary cancers, including skin cancer, pancreatic cancer, and Merkel-cell carcinoma in a small population of patients who had not been previously treated: “This obviously needs more follow-up and observation and a larger group of patients,” he said.
While the side effects of rituximab are well known and very manageable, adding lenalidomide may result in additional adverse events, and the long-term effects in younger patients are not yet known, commented Leo I. Gordon, MD, the Abby and John Friend Professor of Cancer Research at Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine.
Ruan said that in addition to manageable side effects, how well patients were responding to treatment and whether their symptoms were subsiding were measured on study and showed that patients appeared to either maintain their quality of life or improve through the induction and maintenance phases.
Role Yet to Be Determined
Gordon said that while the study is well done, it remains to be determined where the drugs fit in in terms of aggressive chemo-immunotherapy, ibrutinib, and stem cell transplant. The study demonstrates that the drug combination may be an option for patients who are older and may not tolerate high-dose chemotherapy, although long-term follow-up is still needed.
And although treatment of MCL is still debated, there is clear evidence that high-dose chemotherapy, with or without autologous stem cell transplantation, leads to a very high and early complete response rate and molecular complete response, which translates into long-term clinical benefit and a survival advantage, Goy said.
In addition, the median age of people diagnosed with MCL is in the mid to late 60s, sometimes making intensive strategies difficult to use. Bendamustine plus rituximab has become the treatment backbone for patients who cannot receive these intensive regimens, but the complete response and progression-free survival rates are much shorter that intensive strategies.
“I don't think that with these [NEJM] data we are ready to abandon chemotherapy,” Goy continued. This is especially true in younger patients who can tolerate high-dose therapy. However, having non-chemotherapy options for elderly patients is appealing, and using lenalidomide and rituximab could be one such approach, he said.
Several studies incorporating lenalidomide and rituximab are ongoing, Barr noted. For example, a national clinical trial being led by the Eastern Cooperative Oncology Group (E1411) uses the bendamustine rituximab backbone to treat previously untreated MCL patients and incorporates randomizations to study the effect of adding bortezomib to the induction phase and lenalidomide to the maintenance phase—“This is another strategy of incorporating these novel agents into the first-line setting,” he said.
Ruan and her colleagues hope this Phase II study generates enough interest in lenalidomide combined with rituximab to support larger clinical trials with longer follow-up, including the E1411 trial. She said they would like to see studies that compare this combination with treatment options such as chemotherapy, stem cell transplant, and other biologics.
Ibrutinib is another important second-line therapy in MCL that may also prove to be an excellent first-line treatment, Gordon said, adding that combinations of lenalidomide, rituximab, and ibrutinib could also be tested.
Ruan said the team hopes the pilot study leads to further research, with an increased interest in novel approaches among patients and physicians both in the academic and community settings.
We really need to think about clinical trials for all of our patients, especially those with MCL,” Barr said. “Performing studies like this is the only way we advance knowledge about disease and treatment. This manuscript is a good example of multiple centers working together to answer important questions.”