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.
On January 19, 2017, the United States Food and Drug Administration (FDA) approved ibrutinib to treat patients that have received at least one line of prior therapy for marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma (NHL).
MZL is an indolent B-cell lymphoma that accounts for 5-10% of all lymphomas and lacks a standard of care. Current MZL treatments include anti-CD-20 antibody therapy (e.g. rituximab) or chemotherapy. However, ibrutinib is the first-ever treatment to specifically be approved for MZL.
Ibrutinib works by inhibiting Bruton’s tyrosine kinase (BTK), an enzyme responsible for transmitting pro-growth and survival signals from the surface of a cell to its nucleus. In this way, ibrutinib may interfere with chronic stimulation arising from inflammation in the tumor microenvironment; thus slowing the growth of B-cells.
The Weill Cornell Lymphoma Program is proud to have played a role in the phase 2 trial — the largest trial to date for people with previously treated MZL of all subtypes —leading to FDA approval for ibrutinib. Roughly half of all patients had a significant response to ibrutinib, with some degree of tumor shrinkage observed in almost 80% of all patients in the trial. Roughly one-third remained on treatment 18 months after beginning treatment.
The most common side effects included fatigue, diarrhea, and anemia. These side effects were manageable, and consistent with previous research, although some cases required the discontinuation of treatment with ibrutinib.
Results from this study support the use of ibrutinib as an effective well tolerated chemotherapy-free option for the treatment of previously treated MZL. However, some questions remain. MZL is a heterogeneous group of lymphomas, and it is unclear which subtypes might respond best to ibrutinib. With only half of all previously treated MZL patients responding to ibrutinib, improvements might be realized by combining ibrutinib with other drugs and/or using it earlier in the treatment of MZL.
Click on the graphic above to watch this interview from the 2016 annual meeting of the American Society of Hematology, Lymphoma Program Director, Dr. John Leonard discusses results from the recently completed GALLIUM trial. In this trial researchers compared the safety and efficacy of either rituximab or obinutuzumab with chemotherapy followed by maintenance with the same agent as first-line therapy for patients with previously untreated follicular lymphoma.