First International Symposium on Waldenstrom’s Macroglobulinemia

Banff, Alberta, Canada, May 4, 2001

By Ben Rude, President

International Waldenstrom’s Macroglobulinemia Foundation

An important feature of the VIIIth International Myeloma Workshop was the Waldenstrom’s Symposium, organized by Dr. Steven Treon of Dana Farber Cancer Center. The audience consisted of 2-300 physicians, mostly from the U.S., Canada and Europe and perhaps a dozen or so IWMF members. Bert Visheau, of Hamilton, Ontario joined me in representing the IWMF and in making available our sponsorship of two $40,000 research grants to qualified attendees.

The program opened with welcoming remarks by Anne Mann, Executive Secretary of the Research Fund for Waldenstrom’s, a co-sponsor, with Genentech and Ortho Biotech, of this event, and Dr. Treon, chairman, who stressed three goals: collaboration on clinical studies, education of physicians, and recruitment of talent in the treatment of this rare malignancy.

The keynote presenter was Dr. Robert Kyle of Mayo Clinic, Chairman of the IWMF Scientific Advisory Committee, former colleague of Jan Waldenstrom, and renowned expert on WM. Dr. Kyle briefly reviewed the history of the disease since it was first described over half a century ago, described the associated symptoms (weakness, fatigue, weight loss, oral or nasal bleeding, blurred vision) and explained its relationship to myeloma, chronic lymphocytic leukemia, and non-Hodgkin’s lymphoma. Kyle defines three stages: monoclonal gammopathy of undetermined significance (MGUS), smoldering Waldenstrom’s (SW) and Waldenstrom’s Macroglobulinemia (WM). He suggests that the disease not be diagnosed as WM until the immunoglobulin M (IgM) exceeds 30 grams per liter and hemoglobin drops below 10. He further stressed that treatment should not begin in the absence of symptoms.

The second speaker, Dr. Pierre Morel, of Lens, France, reviewed his research into prognostic factors such as age, anemia, weight loss, platelet count, white blood count, to classify patients as low, intermediate, or high risk. I had met Dr. Morel previously, and caught him for a brief discussion, in the course of which he agreed that while prognostic data are useful for physicians, researchers, and insurance companies, the patients need to remember that they are not statistics, that statistics apply to broad populations, not to individuals.

The third speaker, Dr. Meletios Dimopoulos of the University of Athens, Greece, pioneered the use of 2CdA in the treatment of WM, and discussed his earlier research when he was at M.D. Anderson, in which they found that only 30 percent of patients who had become resistant to alkylating agents such as chlorambucil and cytoxin responded to 2CdA. Of 16 previously untreated patients, however, 12 achieved a partial response (50% or greater reduction) and 2 achieved a complete response (no measurable disease). On retreatment, 7 of 9 patients responded.

Dr. Dimopoulos also used thalidomide with 20 WM patients, giving it in gradually increasing dosages. Seven patients discontinued treatment because of the side effects (constipation, tiredness, mood changes, peripheral neuropathy) and five achieved partial response. He concludes that 2CdA is the most active agent for first-line treatment and that it has a survival value over chlorambucil, that thalidomide shows activity but is not well tolerated in high doses, and that it may have potential in combination with nucleoside analogs (2CdA and fludarabine) or Rituxan.

Dr. Donna Weber of M. D. Anderson also spoke of work she, Dr. Dimopoulos and others conducted with various combinations involving 2CdA with and without alkylating agents, prednisone, and Rituxan. They found that 2CdA plus prednisone was no more effective than 2CdA alone. With 2CdA and Cytoxan they recorded a 90% response, with a first remission of 37 months. Most recent work has involved patients on a combination of 2CdA, Cytoxan and Rituxan. All twelve patients have responded. Duration of response has not yet been reached. Her conclusion is that 2CdA is the treatment of choice, either alone or in combination with alkylating agents and/or Rituxan.

Dr. Steven Treon discussed serotherapy strategies in the treatment of WM. The first such compound is Rituxan, also known as Rituximab, a monoclonal antibody composed of 10% mouse and 90% human antibodies. Rituxan targets specifically the CD20 antigen, expressed on B-cells of patients with various hematological malignancies (low grade lymphoma, chronic lymphocytic leukemia, multiple myeloma, Waldenstrom’s Macroglobulinemia). However its effectiveness is unpredictable. We don’t know precisely how it works or why it will not be effective in two patients who express CD20 equally. With WM, for example, 30 to 60% of patients respond, whereas with myeloma, the rate is only 5 to 15%. In a retrospective study of 30 patients, 8 had a partial response, 10, a minor response, and 9 remained stable. The median time to treatment failure was 8 months. Prior to treatment 7 patients were transfusion- or erythropoietin-dependent, whereas following treatment only one was.

Treon believes that Rituxan sensitizes cells to Fludarabine, and that a combination of the two appears promising. [My note: Clinical trials with this combination are now underway; Dr. Treon is the principal investigator.] He also believes that some of the conjugated antibodies, not yet available, such as Zevilan, Bexxar, and Campath might show promise in the treatment of WM.

The final speaker was Dr. Nikhil Munshi of the University of Arkansas for Medical Sciences, whose topic was the role of high-dose therapy (HDT) for Waldenstrom’s. This treatment involves very high doses of an alkylating agent, commonly melphalan, which destroys malignant cells and requires infusion of stem cells or bone marrow, either from the patient (autologous transplant) or donor (allogeneic transplant). He believes that HDT is the next logical step to achieve higher response rates and improve survival.

Perhaps the most important point made was the difficulty in harvesting stem cells from patients who have been previously treated, particularly with a purine analog such as 2CdA or Fludarabine. [My note: Insurance companies will usually not pay for stem cell collection prior to need, at which time the patient’s cells may be depleted from prior therapy. Dr. Bart Barlogie, during the question and answer session, stressed the importance of advocacy groups in influencing change in this policy.]

During the question-and-answer period, Dr. Kyle commented that plasmapheresis is often effective in treating peripheral neuropathy (PN) as is chlorambucil. He recommends 3 pheresis treatments per week for 3 weeks, then 1-2 per week. He also stated that pheresis may be used as long-term maintenance for patients who no longer respond to other treatments, but it is costly. Dr. Dimopoulos indicated that Rituxan was also sometimes effective in alleviating PN.

Dr. Treon is to be congratulated for initiating the idea, planning the program, recruiting the speakers, and generating the funding for this first International Symposium on Waldenstrom’s Macroglobulinemia. We are proud that four of the six speakers (Dimopoulos, Kyle, Treon, and Weber) are members of our Scientific Advisory Committee.