Ivanhoe Broadcast News Interview with
Jonathan Friedberg, M.D., Hematologist/Oncologist,
University of Rochester Medical Center, Rochester, New York,
TOPIC: Healing Lymphoma

What is non-Hodgkin's lymphoma, and how common is it?

Dr. Friedberg: Non-Hodgkin's lymphoma is a name we give to a number of diseases, and if you take all of non-Hodgkin lymphoma, it's about the fifth most common cancer in the United States. There are approximately 60,000 diagnosed cases per year of non-Hodgkin's lymphoma. One issue of interest in non-Hodgkin's lymphoma is that the incidents are increasing significantly. Over the last 30 years, the incidences of this disease have nearly doubled, and it's one of only two or three cancers in which incidences are going up. Most of the major cancers like breast cancer and prostate cancer are actually declining because of screening and appropriate health changes and so forth. We really have no idea of the etiology, or cause, of non-Hodgkin's lymphoma. For whatever reason, it's increasing significantly in incidents.

Is there anything that puts a person at greater risk for the disease?

Dr. Friedberg: There have been a large number of studies, and we really don't know. There have been subtle links to things like pesticides and various other exposures. There are theories viruses may contribute to non-Hodgkin's lymphoma. There is also a small group of patients on certain medications that suppress the immune system that appear to be at higher risk of lymphoma, but the vast majority of patients who have non-Hodgkin's really do not understand the cause.

So it's not necessarily more common in men or women, old or young?

Dr. Friedberg: There are more men that are inflicted with the disease than women, but pretty much all ethnic groups and all ages of patients as well can be affected by non-Hodgkin's lymphoma. You really have to divide non-Hodgkin's lymphomas into major categories, and I would at least divide them into two categories, indolent or relatively slow going lymphomas, and then more aggressive lymphomas.

The more aggressive lymphomas are potentially curable diseases. They are usually treated with combinations of chemotherapy and antibody therapy as well as occasionally radiation therapy. The indolent lymphomas are diseases that, in general, are not curable, however, they are highly treatable. We have a number of ways to treat those, including chemotherapy, pills, or intravenous medications. Antibody treatments, radiation, and then occasionally more aggressive treatments like bone marrow transplants are used.

They are slow growing or not as aggressive, but they are not curable?

Dr. Friedberg: The chemotherapy we give tends to affect dividing cells. Cells that are dividing quickly, as in aggressive lymphomas, are more susceptible to chemotherapy. Therefore, we think they are curable. Just because I say these diseases are incurable does not mean people cannot live for a very long time with the diseases. In fact, it is not uncommon for patients to live decades with the indolent or slow growing lymphomas, only requiring treatments on occasions.

Would it be continuous treatment?

Dr. Friedberg: No. Usually the natural history of that disease is that you become symptomatic in some way, by swelling lymph nodes, fatigue, or other symptoms developing near the lymphoma. You get treated, and the disease sort of goes away. It's what we call remission. At times, remission can last years and the disease will come back. Each time it comes back, it might be a little harder to treat. In general, remissions get shorter and shorter. Occasionally, the disease can transform or become more aggressive, so we use the same treatments we would use for aggressive lymphoma.

Can you tell me about this new drug, bendamustine?

Dr. Friedberg: The drug of interest, bendamustine, is actually what I'll call a new old drug. The history of this drug is quite interesting. The drug was initially developed in the early 1970s in communist Germany. At that time, physicians and scientists and the communist block were not readily speaking with the people in the West and for years they actually used this drug in communist Germany. When the Berlin Wall fell and there was some unification of the medical system in Germany in the early 90's, West German physicians started to use this drug and realized that it had some very interesting properties. Subsequently, there has been a great deal of interest in looking at the science and chemical structure of this drug as to how it works. There have been formal clinical trials. They were never done in the communist era. The drug is now under development in the United States for an indication in non-Hodgkin's lymphoma.

When it was developed in communist Germany, was it developed to treat lymphoma?

Dr. Friedberg: They used it for a variety of different cancers, including breast cancers, leukemia, lymphomas, and multiple myeloma.

And now it is being used for non-Hodgkin's?

Dr. Friedberg: That is what they are developing it for initially.

What were the results from the study you were involved in?

Dr. Friedberg: As part of this development plan, what we are studying is a very unique group of patients, and I think that is the first thing to really emphasize. Probably the biggest advance in the indolent non-Hodgkin's lymphoma over the last 20 or 30 years is a development of an antibody called rituximab. Rituxan is the brand name. It is an agent that clearly works very well for the treatment of these lymphomas. Most patients now get rituximab either alone or in combination with chemotherapy. The trouble is that over time we are learning that, like many of the treatments in oncology, lymphomas sort of figure out how to overcome rituximab therapy and patients eventually become resistant to Rituximab treatment. There have not been studies of chemotherapy in the setting of rituximab resistance. So what we did in this study was use a new chemotherapy drug, bendamustine, and require that patients be resistant to rituximab to be eligible for this study. Therefore, we were studying a population of patients that really hasn't existed before because the rituximab is relatively new, and this population of patients clearly needs a new option. We were surprised and happy to learn that this drug had great activity in that group of patients; more than 70 percent had good responses to the treatment, meaning shrinkage in lymph nodes or resolution of symptoms.

Did they already go into remission?

Dr. Friedberg: Yes. So that is the number of patients who obtain some sort of a remission. There is a smaller group of patients that have what I would call a durable response that lasted well over one year. Keep in mind that many of these patients have received many, many prior regimens of treatment. In fact, the median number of prior therapies was about four. So there were patients who received as many as 9 or 10 prior rounds of chemotherapy because this disease can have a very long natural history.

If they are resistant to rituximab and this drug were available, what would then happen?

Dr. Friedberg: There are other drugs that can be tried, but the thing is, in reality, in this country, when you are resistant to rituximab you are also often resistant to other chemotherapy drugs since they are often given together. So not only does this indicate this drug is useful in patients who do not respond to rituximab, but there is also evidence that this drug may be useful where other chemotherapy drugs do not work. In fact, this drug is in a class that we would call alkylating agents, and a subset of the patients in this study were also previously resistant to other alkylating agents that are available over-the-counter or as prescription, and the patients still responded to the bendamustine, suggesting that it really has some novel mechanisms of action.

What makes this one different?

Dr. Friedberg: Well, if you look at the crystal structure of this drug, there are components of this drug that appear like a classic alkylating agent, and there are other components that look like a different class of drugs. A certainly reasonable theory is this drug might work more than one way in to kill lymphoma cells. It is very hard to study inside a person to know exactly how a drug is working, so that certainly is a theory. Clearly, though, this drug does have unique properties, and it also has a unique toxicity profile. For example, none of the patients in our clinical trial lost their hair, which is a common side effect of other chemotherapy drugs in the alkylating agent class.

Were there any new side effects?

Dr. Friedberg: There is a syndrome some patients get that includes rash as well as some nausea and vomiting that is usually very well controlled. Of course, there are some expected side effects including a low blood cell count, which is common in any patient with lymphoma. There were not any surprising side effects that emerged.

How surprised were you about the effectiveness of this?

Dr. Friedberg: We had no idea what we needed to expect in a group of patients who are refractory of the rituximab. I was very, very pleased to see how many patients responded. I think there still may be some room to improve those responses based on changing the schedule of how the drug is given or potentially giving the drug for a longer period of time. Those studies are going on. However, it clearly suggests that this is a highly active agent, and I'm very optimistic that the agent will eventually become available to patients.

What has been the response of your patients?

Dr. Friedberg: Well, I think that we are fortunate as a regional program. We do have patients that drive a long way to see us and are looking for something new when standard treatments are not working. We had a couple of patients that I can remember by name. Some of them were my patients who were pleased, in the middle of winter, to drive to Rochester, New York, to get this agent, because they saw it was working when other agents were not working. It is a very satisfying part of conducting clinical research. So, I think there are a lot of opportunities. The way drugs are developed in lymphoma as well as other oncology areas is that initially they are studied in patients that do not have a lot of other options or have exhausted standard options. I think in general what may happen in the future is these drugs can be combined with standard treatments and used earlier in the course of the disease with the hope that this drug might be superior to some of our standard chemotherapy agents and could be used as initial therapy of the disease. In fact, in Germany right now there is a trial comparing a standard chemotherapy regimen called CHOP in combination with the Rituxan, comparing that regimen to bendamustine and Rituxan. This might become, over time, more of a standard approach used in this country as well.

What is the next step for this?

Dr. Friedberg: Right now there is a phase III trial going on, which is not too different from the trial we conducted, but it narrows the patient population a little bit just to try to learn a little more about toxicity and confirm the favorable results. This is enrolling patients at a number of centers across the United States. We are about two-thirds of the way completed with that. Once that happens, if data continues to look good, there will be a filing at the Food and Drug Administration. The hope may be that within about a year to 18 months the drug would become approved and available for use.

Have you enrolled all the patients now?

Dr. Friedberg: In the current study, we are close to enrolling all the patients of the anticipated accrual with about 20 centers across the United States participating. We are heavily involved and we meet with the company sponsoring the study very frequently to get updates on the results. I think with lymphoma, this has been an incredibly exciting time. Lymphoma may not get the press that breast cancer and some of the more common cancers seem to get, but there have been a tremendous number of new insights into lymphoma care in the last five to seven years. These include insights coming from studies on the biology of lymphoma and many, many new agents that are in development. As a clinical researcher, I am in the enviable position of having more clinical trials than patients. We are able to choose some very exciting agents to give to patients and I am certain the outcomes of lymphoma, including indolent lymphomas, will change for the better in the next five to ten years.

How is the drug administered?

Dr. Friedberg: This is a drug that, right now, is given intravenously. The schedule that was used in our study and is being used in the phase III study as well, is giving it two days in a row every three weeks. Other schedules have been explored with this drug. In Germany, there are some studies that, if given the drug daily for five days, other schedules might extend the period of time to every four weeks. It is a relatively short infusion time; it takes about an hour to give in the clinic and, as I said, usually we give a little bit of medicine to help prevent nausea before administering the drug.

And the drug is administered with a chemo drip bag?

Dr. Friedberg: That is right.

Is there anything you want to add?

Dr. Friedberg: Those are the main features. I think that it's probably worth noting that you never know exactly what to expect when you are participating in a clinical trial as a patient, but I think this is an example of a promising agent that actually had outcomes that were probably better than what most people expected. I always try to encourage people to consider clinical trials. For people suffering from lymphoma, seek a referral center offering these cutting edge studies. There are many new things being developed. It's important to answer these questions so patients have access to cutting edge care, and so the future patients will gain from the experience learned in the current era.

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