BRETT SCOTT: I'm Brett Scott in Orlando, Florida, where this year's American Society of Hematology meeting is currently underway. Rituxan was approved several years ago for the treatment of lymphoma but its use in therapy continues to evolve as new combinations of Rituxan and other medications are tested. Experts at the conference presented new data on this strategy and I had the chance to talk to them about their findings.
Dr. Goldstone, Rituxan was initially approved as a therapy to be used on its own. Why now is it also being used in combination with chemotherapy?
ANTHONY GOLDSTONE, MD: Like all other drugs they are looking at the initial effects of it come from its use as a single agent. It was shown to be active in lymphoma in a considerable number of patients, probably over half. But for some of them the effect wore off in due time, probably mostly over a few months or so.
Chemotherapy we know is traditionally effective in many types of lymphoma. And it's possible to add the two together for two reasons. First of all, they work in different ways. The antibodies in a different way from the chemotherapy so that patients not responding to one may respond to the other. Secondly, because there is no great toxicity from the antibody in terms of what it does to the hemopoietic system, that is the blood count.
BRETT SCOTT: What are the main differences between the addition of CHOP chemotherapy vs. the addition of fludarabine?
ANTHONY GOLDSTONE, MD: Well, CHOP and fludarabine are alternative regimens for the treatment of non-Hodgkin's lymphoma, particularly low-grade lymphoma. CHOP is a four-drug regimen and fludarabine is a single-agent regimen.
CHOP causes side effects in terms of toxicity to the patient -- sometimes a little bit of nausea and very rarely vomiting. And it's very aggressive on the blood count.
While fludarabine is a much more benign drug to take with few side effects, but it produces problems with the patient in terms of predisposing them perhaps to infection.
Now if you add Rituxan to the CHOP, you're not adding any extra toxicity because any of the toxicity comes from the CHOP. And hopefully, the problems with the blood count will be no more difficult than using CHOP alone.
If you add Rituxan to the fludarabine, you're adding a nontoxic agent to another nontoxic agent so the patient doesn't experience any difficulty. However, both those drugs, fludarabine and Rituxan lower the effects of the immune system. So one of the problems you may have is although you may improve the treatment of the lymphoma, those patients may be more susceptible to infection than with either drug alone.
BRETT SCOTT: Are these combination treatments suitable for all patients or all types of lymphoma?
ANTHONY GOLDSTONE, MD: Well, basically the CHOP regimen is suitable for patients with high-grade lymphoma and usually a second-line therapy for low-grade lymphoma. Fludarabine is only usually used for low-grade non-Hodgkin's lymphoma. The combinations with Rituxan will then be suitable for the same groups.
BRETT SCOTT: Dr. Goldstone, how is success measured in these studies and is there hope that these combinations may improve the cure rate?
ANTHONY GOLDSTONE, MD: Well, we measure success by looking at a randomized trial where half the patients get the chemotherapy and the antibody and the other half of the patients only get the chemotherapy so that we can see from the difference in the two groups of patients how much the antibody is adding.
And we look at two things. We look at the time to progression which means how long does it take from the end of that chemotherapy with antibody for the disease to progress. And we also look at how long the patient lives. This is what we call the overall survival. That's the time from the end of treatment til the time the patient perishes either from the lymphoma or for some other reason.
Now we have real data at the moment -- just on the combination of CHOP and Rituxan and just in a group of elderly patients over the age of 60 who have a subgroup of non-Hodgkin's lymphoma called high-grade lymphoma. And in the only randomized study which is through, which has come from France at the moment. There is quite clearly an improvement in the time to progression and in the overall survival if you get the antibody.
We would be hopeful that these combinations in old patients can be translated to the younger patients with the same beneficial result. And combinations of Rituxan with other forms of chemotherapy also seem possible to produce a beneficial result as well.
BRETT SCOTT: If a patient goes into remission following combination therapy, how would you retreat that patient.
ANTHONY GOLDSTONE, MD: Well, depending upon the individual situation, how fragile or not the patient is and whether they can tolerate more chemotherapy. You may consider, first of all, giving them antibody alone in some groups of patients. Secondly, salvage chemotherapy with or without antibody. And some of the younger patients who now go on after salvage therapy to this treatment we called the stem cell transplant. I think would still be eligible for it.
So in essence, you're not burning your bridges by giving the chemotherapy with the antibody and I think the options for other treatments remain open.
BRETT SCOTT: Dr. Goldstone, are the two regimens actually taken together or one after the other?
ANTHONY GOLDSTONE, MD: They are given together. That is, the antibody is given at the same time as the chemotherapy so that throughout the whole of the treatment you're getting both of the agents.
BRETT SCOTT: How do you see monoclonal antibody therapy such as Rituxan used in the future?
ANTHONY GOLDSTONE, MD: Well, I think in the moment, we're only just touching the surface of the potential uses of Rituxan and allied or closely related forms of antibody. Since we know that many patients -- 40% or more -- will respond to that agent a second time, it seems quite likely we will be devising schedules in the future where the drug may be repeated with chemotherapy over several different forms of chemotherapy over a number of years. So we may well be using more.
Also, the studies to be done would include those in which the antibody is used as maintenance therapy in patients who have remitted and have no evidence of disease, but in whom there is a considerable probability of relapse. In other words, we'll give the antibody because it's nontoxic on a regular basis to try and keep the disease away. And again, properly structured studies need to be thought out to decide on what the best way to do that is.
And I think thirdly, there are certainly a group of patients who will benefit from the use of antibody alone. They would be patients with low-grade lymphoma perhaps who have had a lot of chemotherapy over many courses over a number of years. Clearly don't have a very good prognosis because they've failed several regimens but in whom the antibody may still have some effect.
There are those who have the strongest form of treatment, which is some form of stem cell transplant, and then fail unfortunately or relapse from that afterwards. So many of them aggressive chemotherapy again after the transplant is really not helpful and they can't tolerate it. They don't want it and the outlook is not very good. So then there is also evidence that you can get a response with antibody alone and therefore, it may have a use in that situation as well.
BRETT SCOTT: Dr. Goldstone, any closing message for the viewers of this webcast?
ANTHONY GOLDSTONE, MD: The closing message should be an optimistic one. That we're looking at in non-Hodgkin's lymphoma at a new type of treatment which is nontoxic mostly, which is working in a different way from chemotherapy with fewer side effects, which can sometimes be on its own to produce a reasonable or decent effect. But which in most cases will be added to chemotherapy and produce an additive or an additional effect.
BRETT SCOTT: Dr. Goldstone, thank you for your insights. And thank you for watching. I'm Brett Scott.
Dr. Goldstone, Rituxan was initially approved as a therapy to be used on its own. Why now is it also being used in combination with chemotherapy?
ANTHONY GOLDSTONE, MD: Like all other drugs they are looking at the initial effects of it come from its use as a single agent. It was shown to be active in lymphoma in a considerable number of patients, probably over half. But for some of them the effect wore off in due time, probably mostly over a few months or so.
Chemotherapy we know is traditionally effective in many types of lymphoma. And it's possible to add the two together for two reasons. First of all, they work in different ways. The antibodies in a different way from the chemotherapy so that patients not responding to one may respond to the other. Secondly, because there is no great toxicity from the antibody in terms of what it does to the hemopoietic system, that is the blood count.
BRETT SCOTT: What are the main differences between the addition of CHOP chemotherapy vs. the addition of fludarabine?
ANTHONY GOLDSTONE, MD: Well, CHOP and fludarabine are alternative regimens for the treatment of non-Hodgkin's lymphoma, particularly low-grade lymphoma. CHOP is a four-drug regimen and fludarabine is a single-agent regimen.
CHOP causes side effects in terms of toxicity to the patient -- sometimes a little bit of nausea and very rarely vomiting. And it's very aggressive on the blood count.
While fludarabine is a much more benign drug to take with few side effects, but it produces problems with the patient in terms of predisposing them perhaps to infection.
Now if you add Rituxan to the CHOP, you're not adding any extra toxicity because any of the toxicity comes from the CHOP. And hopefully, the problems with the blood count will be no more difficult than using CHOP alone.
If you add Rituxan to the fludarabine, you're adding a nontoxic agent to another nontoxic agent so the patient doesn't experience any difficulty. However, both those drugs, fludarabine and Rituxan lower the effects of the immune system. So one of the problems you may have is although you may improve the treatment of the lymphoma, those patients may be more susceptible to infection than with either drug alone.
BRETT SCOTT: Are these combination treatments suitable for all patients or all types of lymphoma?
ANTHONY GOLDSTONE, MD: Well, basically the CHOP regimen is suitable for patients with high-grade lymphoma and usually a second-line therapy for low-grade lymphoma. Fludarabine is only usually used for low-grade non-Hodgkin's lymphoma. The combinations with Rituxan will then be suitable for the same groups.
BRETT SCOTT: Dr. Goldstone, how is success measured in these studies and is there hope that these combinations may improve the cure rate?
ANTHONY GOLDSTONE, MD: Well, we measure success by looking at a randomized trial where half the patients get the chemotherapy and the antibody and the other half of the patients only get the chemotherapy so that we can see from the difference in the two groups of patients how much the antibody is adding.
And we look at two things. We look at the time to progression which means how long does it take from the end of that chemotherapy with antibody for the disease to progress. And we also look at how long the patient lives. This is what we call the overall survival. That's the time from the end of treatment til the time the patient perishes either from the lymphoma or for some other reason.
Now we have real data at the moment -- just on the combination of CHOP and Rituxan and just in a group of elderly patients over the age of 60 who have a subgroup of non-Hodgkin's lymphoma called high-grade lymphoma. And in the only randomized study which is through, which has come from France at the moment. There is quite clearly an improvement in the time to progression and in the overall survival if you get the antibody.
We would be hopeful that these combinations in old patients can be translated to the younger patients with the same beneficial result. And combinations of Rituxan with other forms of chemotherapy also seem possible to produce a beneficial result as well.
BRETT SCOTT: If a patient goes into remission following combination therapy, how would you retreat that patient.
ANTHONY GOLDSTONE, MD: Well, depending upon the individual situation, how fragile or not the patient is and whether they can tolerate more chemotherapy. You may consider, first of all, giving them antibody alone in some groups of patients. Secondly, salvage chemotherapy with or without antibody. And some of the younger patients who now go on after salvage therapy to this treatment we called the stem cell transplant. I think would still be eligible for it.
So in essence, you're not burning your bridges by giving the chemotherapy with the antibody and I think the options for other treatments remain open.
BRETT SCOTT: Dr. Goldstone, are the two regimens actually taken together or one after the other?
ANTHONY GOLDSTONE, MD: They are given together. That is, the antibody is given at the same time as the chemotherapy so that throughout the whole of the treatment you're getting both of the agents.
BRETT SCOTT: How do you see monoclonal antibody therapy such as Rituxan used in the future?
ANTHONY GOLDSTONE, MD: Well, I think in the moment, we're only just touching the surface of the potential uses of Rituxan and allied or closely related forms of antibody. Since we know that many patients -- 40% or more -- will respond to that agent a second time, it seems quite likely we will be devising schedules in the future where the drug may be repeated with chemotherapy over several different forms of chemotherapy over a number of years. So we may well be using more.
Also, the studies to be done would include those in which the antibody is used as maintenance therapy in patients who have remitted and have no evidence of disease, but in whom there is a considerable probability of relapse. In other words, we'll give the antibody because it's nontoxic on a regular basis to try and keep the disease away. And again, properly structured studies need to be thought out to decide on what the best way to do that is.
And I think thirdly, there are certainly a group of patients who will benefit from the use of antibody alone. They would be patients with low-grade lymphoma perhaps who have had a lot of chemotherapy over many courses over a number of years. Clearly don't have a very good prognosis because they've failed several regimens but in whom the antibody may still have some effect.
There are those who have the strongest form of treatment, which is some form of stem cell transplant, and then fail unfortunately or relapse from that afterwards. So many of them aggressive chemotherapy again after the transplant is really not helpful and they can't tolerate it. They don't want it and the outlook is not very good. So then there is also evidence that you can get a response with antibody alone and therefore, it may have a use in that situation as well.
BRETT SCOTT: Dr. Goldstone, any closing message for the viewers of this webcast?
ANTHONY GOLDSTONE, MD: The closing message should be an optimistic one. That we're looking at in non-Hodgkin's lymphoma at a new type of treatment which is nontoxic mostly, which is working in a different way from chemotherapy with fewer side effects, which can sometimes be on its own to produce a reasonable or decent effect. But which in most cases will be added to chemotherapy and produce an additive or an additional effect.
BRETT SCOTT: Dr. Goldstone, thank you for your insights. And thank you for watching. I'm Brett Scott.