Session One: Nucleoside analogue drugs (Cladribine and Fludarabine) in the treatment of Waldenstrom's Macroglobulinemia
- Nucleoside analogue therapy in Waldenstrom's Macroglobulinemia, Meletios A. Dimopoulos, MD, Alexandra Hospital, University of Athens
Athens, Greece
- Fludaramine in Waldenstrom's Macroglobulinemia, Veronique Leblond, MD, Hospital Pitie Salpetriere, Paris, France
- Novel drug combinations with nucleoside analogues in the
treatment of Waldenstrom's macroglobulinemia, Donna Weber, MD, M. D. Anderson Cancer Center, Houston, TX

Nucleoside analogue therapy in Waldenstrom's Macroglobulinemia
Meletios A. Dimopoulos, MD, Alexandra Hospital, University of Athens
Athens, Greece

Patients with Waldenstrom's macroglobulinemia are generally treated when they exhibit one or more of the common symptoms of the disease - hyperviscosity of the blood; anemia; enlargement of the lymph nodes, liver or spleen; peripheral neuropathy or cryoglobulinemia (the presence of protein that settles out of the blood at lower temperatures).

Once the decision to treat has been made, several options are available, all of which provide a median survival in excess of five years. The standard treatment for about forty years has been the use of alkylating agents, such as chlorambucil, with or without prednisone(a steroid), either administered separately or in combinations like the so-called M2 protocol.

For about the last ten years, nucleoside analogues (2CdA and fludarabine) have been employed. They were found to be very useful in the treatment of CLL; multiple myeloma does not seem to be as readily ameliorated by them. In WM patients resistant to alkylating agents, the response rate has been found to be about forty percent (40%). Survival of such relapsed patients after nucleoside analogue treatment is between two and four years. It is today clear that either fludaribine or cladribine is the treatment of choice for patients who relapse after chlorambucil. They can also be used as first-line treatment. Among previously untreated symptomatic patients, the response rate runs about seventy-five percent (75%). Though the two compounds have not been directly compared as treatments for WM, these agents seem to be equivalent.

These compounds show some toxicity; therefore, patients under treatment require careful monitoring. White cell and platelet counts are usually suppressed. There is some interference with normal immune responses, so opportunistic infections may result unless prophylactic measures are taken. And in a few cases, myelodysplasia, a stem cell malignancy, may result.

We now have some long-term follow-up data. Cladribine (2CdA) was used as a primary treatment in sixteen (16) patients. Two seven-day treatments were given, four weeks apart. Fourteen (14) patients responded, with two showing a complete response (no measurable disease). Furthermore, the response was rapid. Patients responded in one to two months, as opposed to the usual six to twelve months in the case of alkylating agents. The median duration of remission was twenty-two (22) months. When relapse occurred, patients were retreated. Seven of nine responded, with a median remission of seventeen (17) months. Median overall survival was seventy (70) months.

We can therefore conclude that cladribine (2CdA) is highly active in Waldenstrom's macroglobulinemia, with a life expectancy after initial treatment of about six years.

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Fludarabine in Waldenstrom's Macroglobulinemia
Veronique Leblond, MD, Hospital Pitie Salpetriere, Paris, France

In Europe, fludarabine has primarily been used as second-line therapy in the treatment of CLL. It is currently given by infusion. But next year it will become much more readily administered, because it will be available there in pill form. The compound works by impeding the synthesis of RNA and DNA. It therefore has a greater effect on the more rapidly growing cancer cells than on the relatively stable normal cells in the body. We need to administer it carefully to avoid too much damage to non-cancer cells, and it is particularly necessary to be careful in patients with kidney impairment.

In WM, its first use was in previously treated patients. In this mode, it provided in a study I published in 1998 a thirty percent (30%) response rate as opposed to eleven percent (11%) in the control group using the more traditional alkylating therapy using a CAP regimen. There were no complete responses.

The results of fludarabine treatments given at first relapse were compared with those of patients given traditional CAP. As indicated, the responses were greater in number. They were also longer before re-treatment was required. Yet the use of fludarabine did not markedly increase overall survival time of the sample group.

But there are other factors besides survival time to consider, primarily quality of life. Those treated with fludarabine not only were able to obtain a longer treatment-free interval than those to whom CAP was given, nineteen (19) months as opposed to three; they also suffered fewer side effects.

When fludarabine was given to previously untreated patients, there was a much higher response rate; about eighty percent (80%) of the sample responded to treatment. The response was also much more rapid than with older treatments, though there were few complete responses among these patients. The five-year survival rate was about sixty percent (60%). It is not, therefore, clear whether fludarabine is the best primary treatment option. Studies to evaluate this element of the equation, particularly in comparison with chlorambucil, are now underway in Europe.

The current state of the matter, then, is this: fludarabine is a very good salvage agent. Given the variety of other possibilities, however, it is not clear whether it should be used as a patient's first treatment option. Multicenter clinical trials, comparing it, either alone or in combination with alkylating agents, with the standard regimens, are needed.

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Novel drug combinations with nucleoside analogues in the treatment of Waldenstrom's Macroglobulinemia
Donna Weber, MD, M.D. Anderson Cancer Center, Houston, TX

Unique criteria are needed for the proper study and evaluation of Waldenstrom's macroglobulinemia. The usual staging methods for lymphoma studies do not fit. But it does appear in different stages, and those stages may require differing treatment approaches for best control of the malady. We also must be clear as to what we really mean by response. A "partial" response means a fifty percent (50%) or greater reduction in tumor burden. A "complete" response implies that no discernible disease remains.

The traditional treatments, of course, are the various alkylating agents, used alone or in combination with each other and/or with the steroid prednisone. And their usefulness continues. The nucleoside analogues - Cladribine and fludarabine particularly - are more recent.

The usual regimens involve two to six courses of medication with one or the other of these, followed by a period in which no treatment is given.
Response can be seen primarily in the improvement of the hemoglobin level and the reduction of lymphocytes in the marrow. On the down side, there appears to be an increased occurrence of opportunistic infection, for which prophylactic treatment might be given. It is not a great increase, but in patients resistant to treatment more infections have been observed.

2CdA and fludarabine appear to be approximately equivalent. Experiments combining 2CdA with alkylating agents have given mixed results. Combination of 2CdA with prednisone, for example, seems to be less effective than 2CdA used alone. Cytoxan makes a better choice. So a new treatment regimen was tried, to see whether 2CdA would inhibit the repair of cancer cells on which we used cyclophosphamide to inflict damage. The addition of rituximab gave even better results, with about ninety percent (90%) of patients responding.

Why prednisone does not work well in combination with nucleoside analogues is not clear. The usual alkylating agents do. The most effective combination of all in our experience has been the threefold combination of 2CdA, Rituxan and Cytoxan. Responses, of course, vary, as does the time before relapse. The best predictor of response has proven to be the level of beta-2 microglobulin in the blood.

Question and answer session

Is there a reason to choose between 2CdA and fludarabine as the better nucleoside analogue to use?

There is no proof that one of them is better than the other. However, when fludarabine becomes available in oral form, the relative ease of administration might give it a distinct edge. In primary treatment we might guess 2CdA would be better. It appears, for example, that Cladribine (2CdA) gives positive results against hairy cell leukemia that fludarabine does not.

When should treatments begin?

Quality of life must be considered in making any decision about treatment. And in fact, there is still no evidence that currently available treatments should be begun as long as the symptoms of the disease can be controlled by plasmapheresis or other means. If treatment becomes the obvious best option, nucleoside analogues are better choices than alkylating agents because they work faster and the patient's symptoms disappear more rapidly, giving a better overall quality of life.

How can remissions be extended?

Several ideas have surfaced, none proven. One idea is to administer rituximab every three months. Another is to combine it with fludarabine or some other combination of agents. There is, of course, the possibility that over-treatment might result in myelodysplasia (abnormal blood cell creation), but the chance of this is small.

Is there any way of predicting negative reactions to treatment?

Unfortunately, the answer is "no." Some patients react violently to a given drug; others show no reaction at all. But care is needed. Perhaps, for example, particularly in older patients, we ought not automatically give the traditional six courses of fludarabine, but start with two, then wait and see what effect they have before deciding to continue.

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