Weill Cornell Investigator Highlights Pilot Study of Ribavirin in Follicular Lymphoma

Sarah Rutherford, MD

Sarah Rutherford, MD

Ribavirin, an antiviral oral medication that has been approved by the FDA for hepatitis C and respiratory syncytial virus (RSV), is being investigated in a pilot study at Weill Cornell Medicine as a treatment for patients with follicular lymphoma (FL).

Based on preclinical data from Leandro Cerchietti, MD, associate professor of medicine at Weill Cornell Medicine, the trial aims to inhibit eukaryotic translation initiation factor 4E (eIF4E), a protein that facilitates the growth of B-cell lymphoma cells. With previous approvals in various viral infections, investigators are comfortable with the side effects that have been seen with ribavirin, which has generally been well-tolerated.

“[FL] is a disease that is really ideal for clinical trials,” said lead investigator Sarah Rutherford, MD. “[FL] tends to be a good disease to be used in clinical trials at any point during a patient’s disease, whether it may be newly diagnosed or relapsed/refractory patients.”

The pilot study is currently accruing patients with FL and mantle cell lymphoma (MCL). In addition, correlative studies are actively investigating blood samples to determine if the agent is having the intended effect in these patients.

In an interview withTargeted Oncology,Rutherford, assistant professor of medicine in the division of hematology/oncology at Weill Cornell Medicine, discussed this trial accruing patients with FL. She also described the current treatment landscape for this patient population and shared advice for community oncologists.

TARGETED ONCOLOGY:Can you discuss the rationale for conducting the pilot study of ribavirin?

Rutherford:I work closely in combination with basic and translational scientists here at Weill Cornell, which is something that’s really unique. Actually today, I was meeting with my collaborator, Leandro Cerchietti, MD. He’s also a hematologist by training but focuses on laboratory research, so he often uses novel strategies. Leandro has been working for a number of years here and in conjunction with a group at the University of Montreal where they have been working on a mechanism called eIF4E inhibition. It stands for the eukaryotic translation initiation factor 4E. Essentially, this is a protein that works in both the nucleus and the cytoplasm of B-cell lymphomas, and it helps to facilitate the growth of these lymphoma cells. This drug, ribavirin, is actually an FDA-approved oral drug that is available and used to treat certain viral infections in humans, primarily hepatitis C and a respiratory virus called RSV, so it’s a drug that we already have a level of comfort with and know the types of side effects, and it is generally a well-tolerated drug. Leandro has been working on this preclinical model to show that this drug used in these lymphomas is actually able to inhibit the eIF4E. He’s done a number of elegant studies showing the effects of that. He and I were working for a couple of years to plan this study, and it’s been open since 2018 now here in Weill Cornell looking at people with forward growing versions of FL and MCL.

I mentioned earlier in our discussion that some people with these diseases don’t need aggressive therapy and can be even monitored or given a less intense therapy, so we are typically looking in that patient population that doesn’t really have an aggressive disease that requires treatment right now. For people that have slower growing disease, we assess the feasibility of treating them with ribavirin for 6 months, and it’s a continuous oral treatment course that patients come in to see us once a month throughout the course of the therapy. We’re assessing if patients can tolerate it for that period of time, and we are also doing a number of correlative studies where we are drawing blood when they come in for appointments and Leandro’s lab is assessing whether the ribavirin is having the intended effect of eIF4E inhibition. We use the term bench-to-bedside sometimes in cancer therapy and clinical trials, and this really is an example of the type of research that started in a lab and moved into the clinic. We’re seeing promising results so far, and we are happy to continue on enrolling in this trial.

TARGETED ONCOLOGY:Are there any other ongoing trials for FL at Weill Cornell that you would like to highlight?

Rutherford:What I want to mention is that here at Weill Cornell, we have a wide portfolio of different trials for patients with lymphoma, and our goal is to have a trial available for any patient in any different scenario along their disease. For FL, for example, we’d ideally like to have a trial for the newly diagnosed patient who needs treatment, and we’d like to have 1 for a person who has their disease come back after treatment. For the ribavirin trial, anyone is eligible if they have that diagnosis of FL or MCL and meets certain other criteria, but they can have had previous treatment. The point I want to make is we often have representation across different types of trials. The one I’m describing is called an investigator-initiated trial. That’s 1 we have conceived here and are carrying out, in this case only at Weill Cornell but in some cases, we are able to open these investigator-initiated trials up at other sites. We also work really closely with the Alliance for Clinical Trials, which is the clinical trial consortium, and that is a group of a number of hospitals throughout the United States that work together to create and carry out trials. We have a number of them that are represented through that group. Then we also have industry-sponsored trials as well.

TARGETED ONCOLOGY:What does the current treatment landscape look like for patients with FL?

Rutherford:FL can be managed in a number of different ways. There are some diseases that we treat that have a really clear-cut, exact right way to manage, but in this disease, it really depends on the individual patient. The treatment should really be tailored to that person, so for example, there are many patients who may be diagnosed with FL based on an incidental finding. They may have a breast mammogram done and be found to have lymph nodes under their arms, have it biopsied, and have it be FL. But they are feeling well, their blood counts are normal, and there isn’t any particular indication to treat. For those people, we would do what we call an active surveillance approach; we monitor them carefully and may not do treatment at that point because we don’t have evidence that aggressive treatment upfront is going to make them live longer. Our goal would be to keep them feeling well and try to minimize side effects for as long as possible, really put off treatment until they really are symptomatic of the disease. For those who are symptomatic from the disease, some people have a lower burden amount of FL that we may consider using the drug rituximab by itself to be adequate. When we do that, it tends to be 4 weekly doses in a row and then watch them carefully after that. That doesn’t work quite as quickly as some of the other treatment options. For someone who is quite symptomatic from the disease, you would want to incorporate something more than just rituximab. The most standard treatment would be bendamustine and rituximab combination. That is usually given for 6 months once a month, bendamustine given 2 days in a row and then rituximab for 1 day every 4 weeks for 6 months. That’s a common treatment that we use for someone who we think is symptomatic and needs a faster response to treatment for FL.

An emerging treatment over the past year, too, has been lenalidomide in combination with rituximab. There’s also another monoclonal antibody called obinutuzumab, an antibody against CD20 that is expressed on the B cells. That’s another option to be incorporated at different points along the treatment. Lenalidomide is desirable for some patients because it can be administered orally, so it is usually given 3 weeks on, 1 week off, often in combination with rituximab and that has definitely emerged in recent years as an alternative to chemotherapy.

This other class of drugs that has some drugs FDA-approved and some in trials, is the PI3K inhibitors. That is certainly another line, typically more of a third-line or later option.

Also, FL is a disease that is really ideal for clinical trials. When we put people on clinical trials, they generally have to be well enough to wait a couple weeks to run different tests that are required by clinical trials. People with FL can have symptoms, but they tend to be less symptomatic than some patients with other more aggressive lymphomas. It tends to be a good disease to be used in clinical trials at any point during a patient’s disease, whether it may be newly diagnosed or relapsed/refractory patients. This way, patients can get access to promising, novel therapies that they might not be able to get otherwise.

TARGETED ONCOLOGY:What are some of the biggest challenges in treating these patients?

Rutherford:In general, non-Hodgkin lymphoma tends to be diagnosed in older patients. I believe the median age of diagnosis for FL is around 60, so many patients are older and may have other comorbidities that make it difficult for them to tolerate chemotherapy or other drugs that may have side effects that may interfere with their other medical problems. That is a challenge for many different lymphoma patients of many different subtypes.

On the flipside, we do have some younger patients, and it can be less clear how aggressively to treat some of them because our goal is for them to live their normal lifespan. There is some rationale for treating some people more aggressively upfront with the concept that they may have a number of years needing more therapy. I think in general, treating people with FL at the very younger ages and the very older ages is probably more difficult than people in their 50s or 60s, which may be a little more straight-forward to manage.

The other issue that could come up is FL can transform into a faster growing lymphoma like diffuse large B-cell lymphoma (DLBCL). In this case, it can become challenging to diagnose that. If that were to be found, the standard treatment would be R-CHOP, a multi-agent chemotherapy regimen. A lot of times, we base the work up on PET scan results. We usually do something called a PET/CT scan, a combination of PET and CT scans, so we can see the size of lymph nodes as well as the activity of lymph nodes. Those with higher activity can be concerning for transformation for the lymphoma changing into a faster-growing DLBCL, along with patient symptoms like fever, chills, night-sweats. What would we do in this case would be to try to biopsy the most active lymph node or other area of involvement to really assess whether the patient really has just FL or if they have a transformation to be a more aggressive lymphoma. That can sometimes be a challenge because we want to give the patient the most appropriate treatment, and if we suspect the transformation, it can sometimes be difficult to prove that it’s actually happening.

TARGETED ONCOLOGY:What advice would you give to a community oncologist who is treating a patient with FL?

Rutherford:One would be what I talked about with the possibility of transformation. I know community oncologists are aware of transformation as a possibility in these patients, but when the diagnosis is made, I would want to make sure that the patient had a biopsy that represents the disease as a whole. For example, if the patient had a PET scan and the biopsy that showed FL was not particularly active on the scan, but there is another lymph node that we think is very active, I would consider doing a second biopsy if that is feasible. Sometimes it is hard to do another biopsy because some of these lymph nodes may not be so accessible. However, if it’s possible, I would want to make sure the lymph nodes or another area of disease is biopsied to confirm the patient does indeed have only FL and not one turning into DLBCL.

I would also say that I wouldn’t back away from the concept of active surveillance for people who don’t have symptoms or other indications for treatment. I know a lot of times the patients have a hard time wrapping their mind around this concept of active surveillance when they’re diagnosed with a cancer. They’ll often want to go forward and start treating it immediately. In this disease, we really don’t have evidence that treating really aggressively upfront would make the patient live longer. Our goal is to keep them living for many years with minimizing treatment side effects, so I encourage community oncologists to really think through the case carefully and if the patient doesn’t really have an indication for treatment, it’s okay to watch them. We watch them carefully by having them come to clinic every 3 months or so and to call in between visits if any new issues come up that may be concerning that the disease is growing. I think for many patients, it’s a very valid management strategy.

Finally, for me specifically, I’m always happy to see patients treated in the community or followed in the community and get to follow along with the community oncologist. There are certainly times when a clinical trial or other treatments may be available at an academic center, but we also manage patients in conjunction with community oncologists. If it is helpful for them to feel reassured on some of these cases that are a little less straight forward with regards to management, I’m happy, myself and my colleagues, to be a resource for other doctors out there who may have questions. Even if they just want to run by cases, we are always happy to help out.