Edited excerpt from the discussion:

DR LEONARD: We’re facing an older gentleman who’s had prior treatment. He has a combination of diffuse mixed cell and diffuse small cell lymphoma. His presentation is consistent with chronic lymphocytic leukemia (CLL). He may also have a leukemic spread of an indolent lymphoma, potentially follicular or mantle cell lymphoma.

My first question is: Are we sure of his diagnosis? Peripheral blood immunophenotyping might be helpful in that regard. My second question would be: Is his high white count the main issue? From what you have said, it sounds like the major problem is anemia and cytopenia, and not so much the nodes.

DR RADER: He also had constitutional symptoms — weight loss, but no fever or sweats. The flow cytometry was positive for CD20, CD5, CD19, CD23, CD38, CD45 and CD52. He was also noted to have some cytogenetic abnormalities — deletion of 11q and trisomy 12.

DR LEONARD: His presentation seems consistent with CLL. Are the nodes much of an issue right now or is it mainly the constitutional symptoms?

DR RADER: It’s mainly the constitutional symptoms.

DR LEONARD: The issue here is how we approach him, because he has an indolent lymphoproliferative disorder. The blood counts and the bone marrow are the main issue. He’s already had some pretty good treatment regimens. His last treatment was FCR, which he tolerated well. He’s had several years of remission with FCR, so you could potentially treat him with that again.

Another approach would be to treat him with alemtuzumab, which is approved in this population of patients. This agent is particularly effective in the blood and the bone marrow, and less effective for the nodes; therefore, if you are dealing with nodal disease, alemtuzumab might not be as effective.

I think that either of these options is quite reasonable. It’s a matter of balancing out how well he tolerated FCR, and the positive and negative aspects of the regimen. Toxicities occur with the FCR regimen and with alemtuzumab. I’m not certain that one approach is better than the other. I probably would lean toward alemtuzumab.

DR SMITH: I would also lean toward alemtuzumab, since he hasn’t had it yet. A number of regimens could be considered: FCR again; FR without C, which may be less toxic; or prednisone/cyclophosphamide/rituximab, which is another option.

I agree, it sounds as though this patient has CLL. He has trisomy 12, which is correlative and CD-38 positivity, which is a poor prognostic factor in general. One could also evaluate patients for ZAP-70, but that won’t change day-to-day treatment. These indicators put the patient in a favorable- or poor-risk group, and you still have to consider the pace of the disease.

DR RADER: We decided to enroll him in one of our active clinical trials, which offered a combination of fludarabine and rituximab (4.1). In the trial design, at the end of four months the patient would be restaged, and if there was no evidence of active disease, started on alemtuzumab.

He was started on fludarabine/rituximab as part of that study, and at the end of the fourth cycle, his white count was really low — in the range of about 1,000 to 1,500 — with a relatively low ANC. At that point, we evaluated his bone marrow. The marrow revealed erythroid hyperplasia and persistent evidence of small-cell lymphoma/CLL in the blood. At that point we elected to continue the protocol and put him on alemtuzumab.

After approximately a month and a half of the alemtuzumab, we became concerned because his white count never increased. It remained in the 1,000 to 1,800 range, with no evidence of infection.

A repeat bone marrow biopsy at that point revealed that his cytogenetic abnormalities had cleared. The 11q and trisomy 12 had disappeared and flow cytometry was normal.

Chromosome studies on bone marrow revealed no evidence of MDS. The patient has remained persistently leukopenic to this time, with an ANC of approximately 1,000 and total white count of approximately 1,500. He is afebrile, his hemoglobin is in the 11 to 12 range, and his hematocrit is 33. Computed tomography revealed marked resolution of his lymphadenopathy.

We had him on Bactrim prophylaxis, which we usually continue until the CD4 counts return to normal. Later on, we decided to stop the Bactrim. He’s currently chugging along with a mild anemia and is doing quite well. He actually had a cytogenetic remission as a result of the alemtuzumab treatment, which I thought was impressive.

DR LOVE: John, could you comment on the case?

DR LEONARD: It seems like he’s had a good response, but I think the real question is: Why is he persistently cytopenic? I think you’ve done a good job chasing after that. Obviously, residual lymphoma would be one possibility, and an autoimmune process could be another. The marrow is consistent with that, although it sounds like his biggest issue is his neutropenia more so than his erythroid lineage.

Myelodysplasia, which can be associated with the FCR regimen, is certainly in the differential diagnosis, but you have utilized cytogenetics to rule that out. The FCR regimen is obviously immunosuppressive, so it may be CMV or a related infectious process; however, it sounds like he’s not systemically ill. Perhaps he has low-level myelodysplasia that you’re not detecting, or profound cytopenia, which is occasionally evident after a fludarabine-based regimen.

DR GOLDBERG: One of the problems with fludarabine is that some patients become cytopenic. It is hard to predict which ones, but even after one treatment, they can be left with profound cytopenia that becomes problematic and prevents further therapies. Do you have any evidence of which patients might be at risk for this and how you deal with it?

DR SMITH: I don’t know that we have any a priori notion of whom it’s going to affect. I think it relates to the number of cycles. Clearly, when you combine fludarabine with other drugs — FC or FN — the combination is a lot more myelosuppressive than fludarabine alone, and it is cumulative.

This patient was initially treated with fludarabine for six months and then, three years later, was treated for another four months. The addition of rituximab seems to enhance the myelosuppression, so this patient has had a lot of fludarabine in combination with other agents. I believe that is one of the more predisposing factors in addition to age, prior therapy, etc. I don’t think we can predict it up front; however, I do see it more frequently with the fludarabine combinations.

DR VOGEL: Do you think pentostatin would have been a better choice here in terms of reducing bone marrow toxicity?

DR LEONARD: It’s hard to say. I’m not aware of any randomized studies comparing these regimens. From my perspective, the choice between these approaches is based on personal preference. We all tend to become familiar with a regimen — either one learned in training or one we have a lot of experience with — and we stick with it. I believe that it is probably more important to select a regimen that you’re comfortable with, rather than focus on the subtle differences between regimens.

DR LOVE: Mike, what are your concerns for the future for this patient?

DR RADER: My major concern is infection because of the low ANC. I can treat the red cell series with erythropoietin; however, I can’t justify putting him on chronic white cell growth factors because he is asymptomatic and I anticipate that his CD4 counts are going to rise.

We chose this treatment regimen because it was part of a clinical trial investigating the role of alemtuzumab in CLL, which I felt was important because of associated toxicities. I find it interesting how he didn’t respond initially to the repeat FR treatment, but subsequently responded to the alemtuzumab part of the trial. The trial is still accruing, so we don’t have the final results, but I was extremely impressed with the reversal of cytogenetics in this patient.

DR LOVE: Dr Leonard, how do you think you would approach this patient if he does have progressive disease and is still neutropenic?

DR LEONARD: I think it’s going to be very tough. I would probably re-evaluate his marrow and if he has progressive disease in the marrow I may be more inclined to treat him more intensively. Overall, I would reassess the marrow and focus on symptomatic treatment. If it were a nodal disease, perhaps I would consider radiation.

DR RADER: Now that we’ve had resolution of the cytogenetic abnormalities, do we have any data on how these patients do? Once again, he has poor prognostic markers. Does resolution of the cytogenetic abnormalities produce a longer-term response? What’s the data on that, looking at this over the long term?

DR SMITH: I’m not sure I can quote any specific data on that. It’s evident that the deeper your response, the better you do. Therefore, a patient who is PCR-negative would do better. I don’t know of any data with alemtuzumab that has a long enough follow-up to indicate that the patient is going to do better. With every other disease and every other marker, the increasingly smaller proportion of patients who have reached that definition of response clearly do better.

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