Led by Dr. Jia Ruan, clinical investigators at four medical centers across the United States launched a phase two clinical trial in 2011 to evaluate the novel biological pairing of lenalidomide plus rituximab as induction (initial) and maintenance (relapse prevention) therapy. The team’s treatment goals were to provide disease control and extend survival, while maintaining quality of life.
Of 36 evaluable patients, about 92 percent responded to treatment, with 64 percent achieving complete remission. At five-year follow-up, 77 percent of participants were alive and well, and 64 percent remained free of disease progression.
To determine how well the lenalidomide plus rituximab combination works, the team also measured the status of minimal residual disease (MRD) – the small amount of cancer cells that may be left after treatment that have the potential to lead to relapse. Eight out of a subset of ten evaluable patients tested MRD-negative.
Overall, the chemotherapy-free drug combination has produced durable remission rates with potential to achieve MRD-negative remissions. Chronic maintenance therapy with lenalidomide and rituximab has manageable side effects, including infections, cytopenias (low blood count), and some expected secondary primary malignancies.
This outcome represents a major stride in treatment and care of the MCL patient population, who harbor a rare and generally incurable disease where intensive chemotherapy regimens do not necessarily translate to cure and may not be tolerated by all patients.
“The introduction of novel agents – including the immunomodulatory agent lenalidomide and Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib, which are FDA-approved for MCL – is poised to transform MCL management by making effective ‘chemo-free’ treatment accessible to all patients in both relapsed/refractory and frontline settings,” says Jia Ruan, MD, PhD.
Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma that occurs primarily in older adults. The disease is typically managed in the initial treatment setting with a combination of chemotherapy and immunotherapy, which tends not to be curative and may impart toxic side effects in some patients.
In search of an effective, less toxic treatment option for those afflicted by MCL, Dr. Jia Ruan and colleagues explored an alternative regimen free of conventional chemotherapy – lenalidomide plus rituximab – to be used in the initial treatment setting. Their multi-center phase II clinical trial of the novel biological pairing was the first-ever study of a non-chemotherapy first-line MCL treatment approach.
Thirty-eight MCL patients enrolled in the trial from July 2011 to April 2014. They received lenalidomide on days 1-21 of a 28-day cycle, and rituximab was administered four times per week during the first cycle, then once every other cycle. The first 12-cycle treatment was considered induction, or initial therapy, and was followed by a maintenance phase, in which therapy is provided to prevent relapse. Treatment was continuous until disease progression, and patients had the option to cease therapy after three years if in remission.
At the 2017 American Society of Hematology Annual Meeting, the researchers examined the long-term outcomes of the trial in a 5-year follow-up analysis to reveal that the drug combination shows promise for effective management of MCL, with the majority of trial participants doing well and maintaining good quality of life. About 90 percent of patients responded to the therapy, and over 60 percent remain in remission.
The research team also measured minimal residual disease (MRD) in patients’ blood, the small number of cancer cells that may be left after treatment that have the potential to grow and cause the patient to relapse. In the small subset of patients with available tumor tissues for MRD analysis, about 80 percent of patients were found to be MRD negative, further demonstrating the novel treatment regimen’s activity and feasibility as an additional therapeutic option for people with MCL.
“We are encouraged by the quality and durability of the responses with the biologic doublet of lenalidomide plus rituximab as initial therapy for mantle cell lymphoma,” said Dr. Ruan. “We hope to bring this active combination to larger studies where it can be combined with other agents and compared to conventional chemotherapy.”
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.