Edited excerpt from the discussion:

DR HAINSWORTH: This is an asymptomatic patient with high-stage disease, extranodal sites and minimal adenopathy who has bone marrow and bone involvement and a subcutaneous nodule.

He’s elderly, but otherwise in good health. This patient would be in a relatively lowrisk group according to either the IPI or the FLIPI index. This is a patient for whom you could predict a relatively indolent course despite having Stage IV disease and bone involvement in L-4.

DR LOVE: Dr Cabanillas, what are some evidence-based options that you might have presented to this patient, and how do you think you would have sorted through that?

DR CABANILLAS: I’m concerned about the presentation of this patient. Having three extranodal sites is unusual for a patient with low grade lymphoma. This patient presents with bone marrow involvement and the PET scan showed bone involvement.

He also has a soft-tissue lesion in the scalp. One of the first things I would like to clarify before giving this patient my opinion is that he doesn’t have transformed lymphoma, or what we call “divergent histologies,” which is probably a better term.

Some patients with low grade lymphoma could have had the disease for years and it might have been undiagnosed. At some point, it might have evolved into a large cell lymphoma.

When I see extranodal areas that are not common as a presentation for low grade lymphoma, I consider the possibility of a transformation.

You mentioned that the scalp lesion was biopsied and it showed the same diagnosis. I assume that it was called small cleaved cell lymphoma?

DR SCHER: Yes, the scalp lesion had the same diagnosis.

DR CABANILLAS: That’s a bit unusual. Even if it’s low grade lymphoma in those areas, having three extranodal sites is an adverse feature.

The patient’s flow cytometry was positive for CD20 and CD10 and negative for CD5. That indicates a follicular lymphoma, perhaps Grade I.

I would like to know about the PET scan in this patient. I pay a lot of attention to the PET scan because it not only tells you where the disease might be located, but it gives you something that no other test will give you, which is an idea about how avid the various lesions are for fluorodeoxyglucose (FDG), which is a manifestation of the metabolic rate of that tumor.

Seeing an area like the one on the scalp, which has a low standard uptake value (SUV) — the method that nuclear medicine physicians use to calculate the amount of uptake in each tumor site — I would be convinced that the area is a low grade lymphoma. If other areas have a high SUV, then I would consider the possibility of transformation in those areas.

You could biopsy one of the areas that have a high SUV to ensure that the patient is not treated for a low grade lymphoma when he might actually have a more aggressive lymphoma. I would make that clarification before giving my opinion.

DR LOVE: What do we know about PET scan activity and disease type?

DR CABANILLAS: There are data indicating that low grade lymphomas have a lower SUV, and more aggressive lymphomas have a higher SUV. The complication is with the low grade lymphomas, which we always think of as one disease. For example, in follicular lymphomas, you can biopsy one node and find follicular small cleaved cell lymphoma; however, a biopsy from a different place might indicate that the patient has follicular large cell, follicular Grade II or even diffuse large cell lymphoma. Because we rely on one biopsy, I think we frequently miss those cases.

DR LOVE: John, is that something you’ve also observed in your patients — a correlation between activity on PET scan and transformation or disease activity?

DR HAINSWORTH: In general, the low grade lymphomas are less hot on PET than the large cell lymphomas. The pattern that would be worrisome in a patient like this is variation in intensity in different areas. If everything was uniform except that one area is much hotter than the others, that would be a tip-off that you might have a transformation, and should biopsy that area. I’m not aware of any data in low grade lymphomas that suggests that patients with hotter PET scans do worse.

DR CABANILLAS: No, it is not that they do worse, nor did I say that PET is a prognostic factor. What I said is that it correlates with the histology. If you treat patients with low grade lymphoma using R-CHOP, then you’re going to be covering the possibility of a transformation; however, other types of treatment, such as RFND, specifically target the low grade lymphomas.

We know that FND is not a good combination for large cell lymphoma, particularly diffuse large cell lymphoma, because fludarabine as a single agent did not exhibit much activity. In fact, it was a poor agent in diffuse large cell lymphoma. We don’t use FND in that situation. Whenever I use a combination that is primarily designed for low grade lymphoma, I want to be sure the patient doesn’t have transformation.

DR LOVE: John, how would you have approached therapy for this patient?

DR HAINSWORTH: A number of legitimate treatment options exist for this patient because he seems to be completely asymptomatic. One option would be to observe the patient. I might be a little worried about the vertebral body involvement, although usually when you see that in a low grade lymphoma and it’s a sclerotic-type lesion, it doesn’t correlate with future skeletal problems, so I’m not sure that is a reason to pursue treatment. Other options include single-agent rituximab or combination chemotherapy/rituximab. I think arguments can be made for each of those.

DR LOVE: Dr Cabanillas, what do you think would be your management in this situation?

DR CABANILLAS: When you’re treating a patient who is in his seventies, certainly watch-and-wait is a possibility, even though I have not been inclined to manage patients with a watch-and-wait approach. We put patients on clinical trials regardless of whether or not they have symptoms. A patient who is 72 and active might have a relatively long life expectancy if you can eradicate his disease.

I usually use the watch-and-wait approach only for patients who have a lot of comorbidity and whose life expectancy is not long. I let the patient decide, but you have to give the patient the necessary information to enable them to make the decision. The prognostic factors associated with outcome in low grade lymphoma play an important role in making that decision.

This can be done in various ways. The IPI (2.1), which was designed for aggressive lymphomas, has been applied to low grade lymphomas and it predicts the outcome. More recently, we have the follicular lymphoma IPI (2.1) that John mentioned, which gives you a better idea.

When I use the IPI, I always use the acronym APLES to remember the factors. The first consideration is A, which stands for age over 60. This patient scores one point for that. The P stands for performance status; this patient’s performance status appears to be adequate, so he doesn’t score a point for that. The L stands for LDH, which was normal. The E stands for the number of extranodal sites, and his was more than one (it was three), so he scores one point for that. The S stands for stage, and because he has Stage IV disease, he scores a point for that. His overall score is three factors out of five, which puts him in an intermediate category.

The FLIPI utilizes the acronym NoLASH. This patient had one nodal area involved and his LDH was okay, so he doesn’t score points in those areas. He scores one point for age and another point for stage, and the last consideration is hemoglobin level, which was normal.

So with the FLIPI he only scores two points out of the five, which does not place him in the best category, but not in the worst category, either.

One prognostic factor that has not been included in any of these methods is beta-2 microglobulin. I think the reason it’s not being used is because the investigators who supply the prognostic factors to the trial investigators did not have information on the serum beta-2 microglobulin; however, we have found that beta-2 microglobulin is a powerful prognostic factor, not only for large cell lymphoma but also for Hodgkin’s disease and low grade lymphoma. To me, beta-2 is as important, or maybe even more important, than LDH; therefore, I would like to know his beta-2 level. In our laboratory, the cutoff is 2.0, but we accept up to 3.0 for large cell lymphoma. As soon as it reaches 3.0 it is considered a poor or adverse factor.

In low grade lymphoma, we use 2.5 as the cutoff because the median beta-2 microglobulin for low grade lymphoma is lower than for large cell lymphoma.

This patient is active, his life expectancy is good, and he doesn’t have a lot of comorbidity, and although I’m a bit concerned that his prognostic factors are not excellent, I would be inclined to offer him treatment.

DR LOVE: I want to ask John first, and then I want some feedback from the group in terms of how you handle similar patients in your practice. John, of course you’d have to see the patient in person, but based on what you’ve heard, how do you think would likely manage this patient?

DR HAINSWORTH: I will say that I too am less and less enamored with watch-and-wait. As was just said, this patient is at low to intermediate risk, rather than high risk. It is possible that he’s going to do well for a while and continue to be asymptomatic.

In general, I have recently been recommending single-agent rituximab to older patients, rather than more intensive treatment up front. I’ve been using chemotherapy/ rituximab combinations in younger patients.

It is not a hard and fast rule, but you can predict that someone who is 72 and at relatively low risk is going to have a course that spans several years, and it would be nice to have him consistently feeling well during that time.

DR LOVE: If the man said to you, “Can you give me some numbers in terms of what to expect over the next five, 10 or 20 years, without any treatment or, say, following your plan of rituximab?” What would you say to him?

DR HAINSWORTH: Those numbers are probably easier to give him with regard to no treatment or with whatever has been standard in the past, rather than with rituximab. With an IPI or a FLIPI score such as his, the 10-year survival is probably between 50 and 75 percent, and that’s with traditional observation treating with sequential regimens designed to avoid toxicity.

With rituximab, I’m not sure that the bottom line is going to change but it allows you to treat someone with a minimally toxic regimen that also has a high chance of having a prolonged remission.

Many of these patients who receive rituximab first-line are either retreated or receive maintenance treatment. “Prolonged” means for several years without doing anything else.

DR LOVE: What schedule of rituximab would you use, and would you use maintenance therapy for this patient?

DR HAINSWORTH: I would start out with a standard four-week course and see whether the patient responded. I prefer to use maintenance, rather than to wait and use re-treatment, although I think either one of those options would be reasonable. I have the most experience with the once-every-six- month courses.

DR LOVE: How long do you continue it?

DR HAINSWORTH: I sort of arbitrarily stop at two years, so I don’t have much experience with longer, indefinite maintenance.

DR LOVE: Dr Cabanillas, how do you think this patient likely would have been managed in your practice?

DR CABANILLAS: I offer these patients a combination of FND and rituximab, primarily based on our study results (3.1) — it was a randomized trial for patients with Stage IV low grade lymphoma — in which half of the patients were randomly assigned to receive FND plus rituximab simultaneously, and the other half received FND first, and then one year later they received rituximab. We used molecular response as the major parameter.

Most of these patients have Bcl-2 rearrangement, which you can monitor for response in their blood and bone marrow. Attaining a molecular remission with traditional chemotherapy like CHOP is uncommon.

Approximately 10 to 15 percent of the cases with Stage IV will achieve a molecular remission with CHOP, yet with FND/rituximab, we had 90 percent molecular remissions; therefore, I believe this regimen is superior to CHOP.

Zinsani, in Italy, used fludarabine/mitoxantrone (FN) plus rituximab, without the dexamethasone, and he compared the results to CHOP.

He also found that FN plus rituximab has a higher molecular response rate, so I think it’s a powerful combination in indolent disease. The patients in whom we saw a molecular response have had an excellent failure-free survival. I’m more focused on failure-free survival because a good failure-free survival will result in superior survival.

I prefer that the patient continue with no evidence of disease, rather than survive seven or nine years having multiple relapses, because quality of life is compromised once they start relapsing and they have to go from one treatment to another. I think it’s more traumatic for the patient psychologically, but the fact that they have to change therapy and take chemotherapy also takes away from their quality of life.

DR LOVE: Dr Scher, can you follow up in terms of your discussions with this patient?

DR SCHER: I discussed the various options with him, including watch-and-wait and the Hainsworth data using rituximab that was available at that time.

He was not anxious to start therapy because he was completely asymptomatic. He was somewhat worried about the few times we occasionally see rituximab reactions.

He was mostly concerned, as I was, that we had no sense at all regarding the pace of his disease. His approach, which I was comfortable with, was to proceed with watch and wait. I saw him in three months and he was without symptoms.

I saw him six months after that initial visit and, at that point, I was a bit concerned, because he was complaining of left arm pain.

He was playing golf every day and was perfectly active, but he had developed pain in his left arm. I repeated the CT and PET scans at that time, and they revealed essentially the same thing we saw before, with two exceptions.

An area of uptake near the left internal carotid indicated a small lymph node that was visible on the PET scan, but not on the CT scan. Uptake in the C-2 vertebral body was also noted, which was not present previously. The other vertebral bodies were the same. An MRI of the cervical spine showed evidence of what was probably lymphoma in the C-2 vertebral body, but it was not compressing any nerve and we don’t believe it was contributing to his left arm pain.

His orthopedic surgeon believes his left arm pain was due to arthritis and not related to the disease. The lymph node in the left carotid region was so small that it couldn’t be seen, and it was unlikely to be the cause of his left arm pain. We are now in the process of trying to make a decision as to whether we should proceed with therapy.

DR LOVE: What kind of therapy are you considering?

DR SCHER: I discussed several therapies with him, including rituximab alone, which he was most comfortable with. The alternative treatment was CVP and rituximab based on the recently published data indicating high response rates and good tolerance with that regimen. He was most comfortable with rituximab alone.

Parenthetically, he has had no other disease recurrence. The small subcutaneous lesion on his scalp has not recurred. He has not developed adenopathy elsewhere, just in those unusual sites — the C-2 vertebral body and the bone lesions.

DR LOVE: John, if this patient had come to you for a second opinion at this point, as opposed to the initial point, how would you be thinking it through?

DR HAINSWORTH: Well, I think now you have the additional data of new things happening within a relatively short time. I’d now be more worried about his bone involvement. Certainly, C-2 is a bad area to be affected by a complication or a compression fracture. I would be more intent on treating him now than I was before. I would tell him that, at this point, continued watching and waiting is not what I would recommend.

DR LOVE: Would you be more likely to recommend rituximab alone or with chemotherapy?

DR HAINSWORTH: Either one of those options would be defensible and reasonable. I would still probably favor using the single agent.

DR LOVE: As you listen to this case, it sounds as though this patient is oriented toward not experiencing toxicity from treatment unless it’s absolutely necessary.

DR CABANILLAS: We see all variations in how people respond to this situation. Some patients want to be treated immediately and aggressively, while others, like this patient, are interested in minimizing toxicity from therapy. I tell my patients that they should not only consider the toxicity of the chemotherapy, but also the toxicity of the disease itself.

If a patient is developing pain and new bone lesions within six months, I don’t think it’s going to be a low grade lymphoma, and if it is a low grade lymphoma, I think it’s on the way to transformation.

I am concerned about this patient, and again, I would carefully evaluate the PET scan to determine whether any areas have more than seven SUV. Up to six is usually okay for low grade lymphoma. You start seeing more large cell lymphomas when the SUV is above six.

I think a needle biopsy of one of the high SUV areas might offer more information, but at this point I would not be inclined to use FND/rituximab, especially now that we know that the pace of the disease is more aggressive and that the patient is experiencing pain. Low-grade lymphomas usually don’t cause pain, and they usually don’t go to bone. When they do go to bone and start causing pain, that usually means something is wrong, and the patient’s disease is going to evolve more rapidly than the usual course of low grade lymphoma.

I think this six-month period of time is already telling you that the tempo of the disease is not going to be that of a low grade lymphoma. If I have to make a choice, I would be more inclined to use R-CHOP, or try to make a more informed decision, perhaps by performing a biopsy of the area that has the highest SUV.

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