DR C FARBER: I treated her on a clinical trial that was somewhat novel at that time (2.2). She received six cycles of R-CHOP followed by two years of maintenance rituximab, a la Hainsworth, with four consecutive weekly infusions every six months for two years.

After the initial R-CHOP, she achieved a complete remission with resolution of her adenopathy. I did a bone marrow biopsy after the sixth cycle and, although the large cells were cleared, she had some residual small cleaved cells. She’s remained in remission since that point in time.

Over the last three and a half years, with close follow-up, she has not had any clinical recurrence. I have not repeated any bone marrow biopsies, but her CBC has remained in good range.

What’s the significance of the residual small cells? If you read the long-term data in low grade lymphoma, whether or not they have involvement is not prognostic; patients tend to have the same survival.

DR LEONARD: The one scenario in which residual small cells may be an issue — relative to the prognostic issue — is collecting her stem cells. It becomes more difficult to collect stem cells if you want to “bank them for a rainy day.” It’s debatable whether you need to do that, but certainly it’s worth doing if the insurance companies will allow it.

The prognostic significance of a CR versus a PR in a population-based study evaluating hundreds of patients is that the CR patients do better. For an individual patient, I’m not sure that’s the make-or-break thing.

Another thing to consider is that it’s not rare to see lymphoid aggregates in the marrow after rituximab treatment — these may be residual T cells. I have had debates with our pathologist over this issue because often what appear to be apoptotic B cells are actually T cells, so it doesn’t necessarily represent lymphoma. If there is any question, it is worth performing a CD-3 stain to ensure that it’s not a residual T cell.

I would continue observing her at this point. I agree with this management in that you treated her on a trial, which is appropriate, and she received more treatment, rather than less, on this trial. Patients in this situation often want to do as little as possible. Some trials and regimens offer less, rather than more treatment. With this patient I would err toward more, as you did, rather than less.

DR MALHOTRA: Considering that her marrow is positive, if you want to collect her stem cells, would you think about doing any purging?

DR LEONARD: My understanding is that the benefits of purging are debatable. The CUP trial, which is a randomized trial evaluating autologous transplant in follicular lymphoma, did not show a difference between purging and not purging; however, that was a different situation and the study was underpowered to evaluate that outcome.

Intuitively, purging makes a lot of sense. Even though you have marrow involvement, you can still mobilize stem cells that are free of tumor. I would not necessarily rule out a stem cell collection, and I would probably offer purging if it were readily available.

DR SMITH: Can I clarify whether the positive bone marrow biopsy was at the end of the R-CHOP or the end of the two years of maintenance rituximab?

DR C FARBER: It was at the end of the RCHOP, not at the end of the maintenance rituximab.

DR SMITH: So it’s possible that the additional rituximab has cleared her marrow. In low grade lymphomas, we don’t know where the response rate improves over time. Perhaps she’s negative now in terms of her small cell component. That should not impact management now, but it might be of interest in the event she needs a transplant. R-CHOP was designed to take care of the large and small cells. The small cells can continue to survive after they’re damaged and don’t die until much later.

DR LOVE: What do we know about long-term outcome for patients like this, Dr Smith?

DR SMITH: In this patient, you have the benefit of time. I suspect her large cell component is not likely to come back; however, her low grade small cell component is likely to come back. If her disease progresses, she needs to undergo biopsy to verify the histology and be treated for low grade lymphoma at that point.

DR C FARBER: This patient was treated on a study, so her maintenance was predicated and known. How would you manage her off study? Would you have endorsed maintenance therapy and, if so, would you have followed the Swiss approach or the Hainsworth approach? What duration of maintenance would you advocate?

DR SMITH: In low grade lymphoma, data indicates that rituximab either as a single agent or with CVP is beneficial when administered as prolonged maintenance or scheduled re-treatment. In contrast, we have little data regarding treatment of large cell lymphoma. The ECOG E-4494 trial suggested that if a patient received rituximab with CHOP, then maintenance rituximab did not add any benefit to the treatment of large cell lymphoma; however, that trial was a two-by-two-design not a four-arm trial.

When treating patients, I tend to use the Swiss 1-3-5-7-9 regimen, which has now been adopted by ECOG in their up-front trial for low tumor-burden disease, into an every three-month schedule. We see patients every three months, which makes it easier to give them their treatment; therefore, I find it technically easier. I think the Hainsworth schedule certainly has a lot of support, and I don’t have a strong feeling as to which one is better. I think it is whichever one is easier.

DR LOVE: Dr Leonard, if it turns out that all we are dealing with is progression-free survival as a benefit of maintenance rituximab, do you think that this is a positive benefit-to-risk ratio?

DR LEONARD: That is a difficult question. In indolent lymphoma, patients can have disease that putters on a long time before becoming symptomatic. Even if you’re not extending survival, having prettier CAT scans may be psychologically meaningful for some people. For other people, it’s not a big deal. From my perspective, if that’s the only benefit of maintenance versus re-treatment with rituximab at progression, then it’s an individualized decision.

I believe some patients like to come back to be treated because it is a security blanket, while others prefer to stay away as long as possible. Relatively few of the diseases we encounter offer us the luxury of leaving these decisions up to the patient and allowing us to tailor the treatment to their preferences and comfort levels.

DR VOGEL: If you were a medical director of an insurance company, what would you say? You have to pay a certain amount of money for treatment. How are you going to advise the physicians who call you in terms of the efficacy of maintenance rituximab?

DR SMITH: Dr Hainsworth’s trial evaluating scheduled maintenance versus re-treatment at relapse resulted in only about a 20 percent difference in total drug delivered. It wasn’t a huge difference, and that difference may be counteracted by fewer scans and tests. I don’t think the cost is as much an issue as some people first thought. You might think, “Oh, this is a huge difference, giving scheduled maintenance, and we’re going to use so much more drug that an insurance company would never want to do it.” However, if you evaluate the numbers, it’s not a huge difference.

DR LOVE: Fifteen years ago, a similar question was on the table in breast cancer. We thought that tamoxifen was only going to delay progression-free survival. At that point, we were saying, “The side effects and toxicity of tamoxifen are not much of a price to pay to delay progression.” Dr Farber, how does it play out in terms of rituximab?

DR C FARBER: I believe patients enjoy receiving maintenance therapy because it gives them a significant degree of reassurance. They feel they’re being proactive with their treatment. I explain to them up front that it’s a two-year commitment and it doesn’t go beyond that, but deep down inside I wonder if maybe it should be extended beyond two years. I realize that it’s a tremendous financial cost and no data exist to support it.

DR LEONARD: The bottom line is your comfort level. It parallels using five years of tamoxifen for breast cancer before we knew whether or not it made a difference. The fear is that, as soon as you stop whatever you’re doing, the patient may relapse.

They probably would have relapsed regardless of whether or not you were continuing your maintenance therapy, but it just makes everybody feel lousy about stopping the drug. It’s reasonable to have these discussions with the patient and say, “We don’t have the data.”

If the patient is comfortable continuing with the therapy, great, and if they’re not, then stop. On some level we like to participate in clinical trials. I presume that eventually trials will evaluate rituximab beyond two years; however, I think you have to evaluate the patient’s situation.

On one hand, if the patient has done well for two years and everything’s quiet, on some level you don’t want to rock the boat. On the other hand, it’s been two years and they haven’t progressed. If the patient progresses after two years of maintenance rituximab, I would expect they’d have a beautiful response to rituximab when they relapse, so in my opinion you probably haven’t lost a whole lot. I’ve given a longwinded answer, but the bottom line is that I don’t think a right answer exists — either way is reasonable.

DR LOVE: Dr Smith, I’m guessing we aren’t going to have randomized trial data on two versus five years of rituximab. Do you offer the option of continuing beyond two years?

DR SMITH: Again, without any data, that involves a long discussion with the patient. If you evaluate what Dr Hainsworth has presented from their trials with patients who have been on rituximab for two years and then stopped, what strikes me is that the patients with follicular lymphoma who are doing well at that point seem to do well for another couple of years.

The patients with the small, lymphocytic lymphomas don’t do as well in the relapse setting, and they seem to fall off a lot faster. I would be more hesitant about stopping rituximab in someone who has a small lymphocytic lymphoma and has done well for two years, because I am concerned that they will progress. Perhaps we are just holding them in check and haven’t addressed the disease as well as we have with the follicular lymphoma.

Right now, looking at the curves, that’s sort of where I’m leaning. In patients with follicular lymphomas, I tend to stop and say, “Why don’t we give you a break and when you relapse you’ll probably respond well.” If a patient has a small lymphocytic lymphoma, I’m a little more concerned and lean toward continuing treatment.

DR RADER: You’re involved in research in this field every day. Why do you think clinical trials are not evaluating five years versus two years of rituximab?

DR SMITH: When Dr Hainsworth first proposed his two-year maintenance trial, people thought he was crazy for giving that much rituximab. Now they say, “Why did you stop?” I think we’re just beginning to realize that we should ask that question. However, you’d have to be in your first year as an assistant professor to design that trial, launch it and expect an answer in your lifetime. No pharmaceutical company wants to do that either. I think it’s difficult to take on such long-term projects.

DR LEONARD: I think that question will be obsolete by the time it is answered. We probably will no longer be giving maintenance rituximab as we are now. We’ll be giving it in combination, using receptor polymorphisms to subset patients. I think five years down the line — which would be the earliest that we could answer that question — we’ll be way ahead of that result with other drugs, regimens and subclassification of patients.

DR LOVE: It’s fascinating to see these oncologic issues discussed across tumor lines. In breast cancer, bevacizumab is going to be evaluated in adjuvant clinical trials. How long do you use that therapy in that setting? In evaluating the aromatase inhibitors, we picked five years because of tamoxifen, yet bevacizumab utilizes a much different mechanism.

DR KAPLAN: The problem is the median survival of these patients is eight or 10 years. If you design a trial, you’re going to be dead or retired before the trial is finished, so we’re doing this purely by feel.

I don’t use maintenance rituximab because I’m not convinced that it makes any difference over the long term. No data exist either way. However, I think that if you are going to give maintenance rituximab, you ought to continue indefinitely. These tumors are not like breast cancer, in which you are going to eradicate the tumor. With lymphoma, you’re sitting on it, and if you’re going to sit on it, you have to continue the maintenance therapy — if that’s your philosophy. I can understand that philosophy, but I don’t believe in it; however, I can’t understand why you would stop at two years.

DR LOVE: If we are only going to focus on the endpoint of overall survival, trials like this probably aren’t going to be done, or by the time we learn the answer we’ll be on to something else. Dr Leonard, what other endpoints should we be evaluating? Progression-free survival is obviously an option, but will anything else give us a quicker answer?

DR LEONARD: Trying to come up with a surrogate for survival is challenging. Certainly, progression-free survival is an objective endpoint. We can design criteria and evaluate the same patient and say, “Yes, that person has progressed.”

I think the problem is that when the patient progresses, he or she can go another two months, two years or sometimes longer, feeling fine and not needing any clinical treatment. To me, that is the “Catch 22.” If progression meant the patient was sick or needed treatment, then I believe we would agree it is a meaningful endpoint. In most tumors, that is the case. That is why progression is a valid endpoint; however, in indolent lymphoma, progression is not necessarily a bad thing.

We’ve tried to evaluate time to next treatment, which is a nice endpoint. The problem is that everyone sitting around this table could evaluate the same patient and have different opinions, or have two different patients with the exact same clinical scenario and not agree on whether the patient needed treatment. Because progression is a subjective issue, it may not be a valid endpoint.

The psychology of indolent lymphoma and the use of rituximab are fascinating. It’s a unique situation in oncology when a patient wants to come back for more treatment even though it may not necessarily be helpful in the long run. You have to think that a psychological benefit occurs for some people.

Chuck put the hammer on the nail’s head. For some patients, being proactive helps their quality of life because they feel like they’re doing something; however, we need some objective scales. Whether it’s variations on the quality of life or the psychology of the stress of these chronic disorders in which the patient has a tumor sitting there like a time bomb. I think it’s a pretty unique situation in oncology.

DR SCHER: I have a quick question. In the past, we were concerned about the infusion reactions with rituximab, especially up front. After a discussion with Mitchell, we started using dexamethasone 20 mg right before each rituximab dose. Since then we haven’t seen any toxicity. I think a lot of controversy exists about whether that’s bad or good. I was wondering what your input would be about that now.

DR SMITH: Steroids were prohibited in the original trials, because they would have confounded the interpretation of responses. I think the theoretic concern is that you’re immunosuppressing the patient, regardless of how rituximab works, whether it’s ADCC or complement activation or direct apoptosis.

A dose of steroids with each infusion is probably not detrimental given the long half-life of the antibody. I believe it reduces the incidence of infusion-related toxicity; therefore, I do it in most patients.

DR LOVE: Len, how does the issue of patient age relate to the decision to use maintenance rituximab? One of the fascinating developments in breast cancer is the Adjuvant! online model. You input patient characteristics and can then obtain quantitative estimates on the effects of therapy.

One of the most interesting things about that model is when you put in the patient’s age and you start to factor in co-morbidities. In NHL, we sort of do this by the seat of our pants. When we use Adjuvant! in breast cancer, the numbers are right in front of us. How does age factor into the decision to use maintenance rituximab?

DR L FARBER: I think age relates to the decision in two ways. One is the difficulty older patients may have with transportation to the office. If you have a treatment that is not clearly beneficial in the patient, and the patient’s son has to take a day off from work once a week for four weeks, then you’re not necessarily going to be as inclined to recommend this option as you would in another scenario. If the patient is retired and has an open schedule and transportation, it’s not as big an issue. I think the practicalities of frequent office visits affect the decision.

While the data for maintenance rituximab is less clear and, in fact, does not exist in large cell lymphoma, intuitively part of me says, “Well, gee, that’s a scenario in which I might be more inclined to use it, despite negative data.”

Again, I’m not advocating the use because there are no supporting data. However, the consequences of a relapse for a patient with large cell lymphoma, who may not be a candidate for intensive treatment or transplant, certainly make the concept of maintenance particularly more attractive as an effort to avoid or delay a toxic treatment. I believe that’s the psychology some physicians follow when using rituximab in that setting despite the lack of data.

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