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.”
Ribavirin, a drug that has been approved by the Food and Drug Administration (FDA) to treat hepatitis C, as well as some viral respiratory infections and viral hemorrhagic fevers, has shown promising activity against some types of lymphoma. There is a growing movement to repurpose older drugs that might have mechanisms of action that could benefit cancer patients.
Dr. Leandro Cerchietti
Based on preclinical work performed in the laboratory of Dr. Leandro Cerchietti, the Weill Cornell Medicine and NewYork-Presbyterian Lymphoma Program is planning a clinical trial examining the oral antiviral drug ribavirin in patients with two non-Hodgkin lymphoma subtypes, slow growing follicular lymphoma and mantle cell lymphoma. This clinical trial will be led by principal investigator Dr. Sarah Rutherford.
Previously, physicians and scientists in the Weill Cornell Medicine Lymphoma Program have demonstrated that ribavirin may be able to inhibit lymphoma cell growth. Dr. Cerchietti’s laboratory research has shown that the eukaryotic translation initiation factor 4E (eiF4E) is blocked by ribavirin in B-cell lymphoma cell lines, as well as in patient-derived xenograft (PDX) models, which more closely resemble the way cancer behaves in the human body. Blocking eiF4E ultimately leads to decreases in key proteins (MYC, BCL2, and BCL6) which are crucial for lymphoma cells’ survival.
Additionally, Dr. Rutherford conducted a retrospective review of patients with lymphoma who underwent stem cell transplants at NewYork-Presbyterian Hospital/Weill Cornell Medicine. Patients who were treated with ribavirin for viral infections just before or after their stem cell transplant had better lymphoma-related outcomes compared to what was expected based on their disease risk profiles.
This clinical trial, run by Dr. Rutherford and Dr. Cerchietti, will enroll patients with follicular lymphoma and mantle cell lymphoma, and they will receive 3-6 months of oral ribavirin. Using a blood test, Dr. Rutherford and Dr. Cerchietti will monitor for the presence of a marker of lymphoma in the blood to confirm that ribavirin has the intended anti-lymphoma effect.
“We are excited about opening this clinical trial and aim to conduct additional trials in the future that combine ribavirin with other drugs,” said Dr. Rutherford. “Our goal is to ultimately develop a well-tolerated, targeted oral regimen to control lymphomas.”
This preclinical research is supported by a Translational Research Program from the Leukemia and Lymphoma Society (LLS) awarded to Dr. Cerchietti.
Citing a pattern of intensive mantle cell lymphoma (MCL) treatment regimens, Dr. Peter Martin – who co-chaired the OncLive State of the Science Summit on May 4, 2017, along with Dr. John Leonard – proposed that physician-researchers become more mindful of patient preferences when determining treatment regimens. He noted that some patients might prefer to receive more broadly accessible treatments and that those decisions may not significantly impact outcomes.
High-dose cytarabine followed by an autologous stem cell transplant, for example, is an effective treatment regimen for patients with MCL, at times inducing remission durations of 10 years. But people with MCL, who tend to be in their mid-sixties, are rarely keen to take the requisite six months away from work in order to receive treatment. Because fewer than 25 percent of MCL patients are eligible for intensive regimens, more practical treatment strategies are needed.
Dr. Martin also stressed the need to find a way to help patients who are destined to have poorer outcomes due to the presence of multiple risk factors as defined in the combined Mantle Cell Lymphoma International Prognostic Index (MIPIc). These factors include: age, white blood cell count, performance status, lactate dehydrogenase (LDH), and Ki67, a marker of tumor cell proliferation.
In a comparison of two clinical trials from the European Mantle Cell Lymphoma Network, one in which patients less than 65 years of age were treated intensively with an autologous stem cell transplant, and another wherein a set of older patients received R-CHOP or fludarabine-based therapy followed by rituximab maintenance, Dr. Martin pointed out that patients with similar MIPIc scores had similar outcomes no matter their treatment regimen.
Dr. Martin highlighted that multiple clinical trials are underway to determine the best drug to combine with the MCL treatment backbone of bendamustine rituximab, to investigate ibrutinib combinations in the relapsed setting, and to evaluate the necessity of intensive treatments like stem cell transplantation.
Watch this OncLive clip for more of Dr. Martin’s thoughts on patient preference: