FDA-Approved Drug to Treat Viral Infections Shows Promise Against Lymphomas

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.

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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.

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Dr. Sarah Rutherford

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.

Dr. Sarah Rutherford Sheds Light on Double-Hit, Double-Expressor Lymphomas

Diffuse large B-cell lymphoma (DLBCL), a fast-growing cancer of abnormal B lymphocyte cells that ordinarily help to fight infection and inflammation in the body, is the most common type of lymphoma. Approximately two-thirds of DLBCL patients are cured by six cycles of the chemotherapy drug combination rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) that serves as a standard treatment, but chromosomal changes involving MYC, BCL-2, and BCL-6 have been linked to more aggressive disease that is harder to cure.

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Normally, MYC plays a role in cell growth, protein synthesis, metabolism, DNA replication, and blood vessel formation (known as angiogenesis), while BCL-2 regulates the natural death of cells when they are no longer needed in the body (known as apoptosis), and BCL-6 helps regulate genes that suppress tumor growth.

At the OncLive State of the Science Summit on Hematologic Malignancies, Dr. Sarah Rutherford provided an overview of two aggressive variations of B-cell lymphoma involving MYC and BCL-2 or BCL-6 that are characterized by resistance to chemotherapy: double-hit lymphoma and double protein-expressor lymphoma.

Double-hit lymphoma occurs due to alterations in two chromosomes involving MYC, BCL-2, and/or BCL-6, with the majority of cases involving MYC and BCL-2. This variant is fairly uncommon and has an incidence rate estimated at 5-10 percent of DLBCL cases, which can include instances in which patients’ follicular lymphoma transformed into DLBCL. Many double-hit lymphomas also tend to infiltrate sites outside the lymph nodes, such as the bone marrow and central nervous system.

According to Dr. Rutherford, outcomes for double-hit lymphomas are poor, even when intensive therapies like autologous stem cell transplant are added to treatment. Overall survival (OS) for double-hit lymphoma patients ranges between 5-24 months when treated with six cycles of R-CHOP, but dose-adjusted chemotherapy drug combination etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) has become the standard frontline therapy for double-hit cases. DA-EPOCH-R is more intensive than the R-CHOP approach and appears to have improved outcomes, but data is still limited and new strategies are being planned to increase response rates in the double-hit patient population.

Double protein-expressor lymphomas have increased protein expression of MYC and BCL-2 or BCL-6 in the absence of the chromosomal changes seen in double-hit lymphomas. This variant is more common than double-hit lymphoma, with an incidence rate of about 30-40 percent of DLBCL cases, but it is not as difficult to cure. It is, however, more aggressive and has less favorable outcomes than classical DLBCL cases (those without changes in MYC, BCL-2, and BCL-6). The standard treatment for double protein-expressor lymphomas is six cycles of R-CHOP.

Dr. Rutherford said that the Lymphoma Program at Weill Cornell Medicine/NewYork-Presbyterian Hospital – along with other institutions, including Massachusetts General Hospital – is working hard to develop novel strategies that will improve outcomes for these patients. For example, the team currently has a multi-center investigator-initiated clinical trial open to determine the maximum tolerated dose of BCL-2 inhibitor venetoclax combined with DA-EPOCH-R. The goal is to then open a second clinical trial with an objective of evaluating the efficacy of this promising combination in the double-hit and double-expressor lymphoma population.

Watch Dr. Rutherford speak with OncLive about the discrepancy between double-hit and double protein-expressor lymphoma here: