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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.


Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.

WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 6)

PROGNOSIS

Waldenström’s macroglobulinemia typically presents as an indolent disease though considerable variability in prognosis can be seen. The median survival reported in several large series has ranged from 5 to 10 years98-104, though in a recent followup of 436 consecutive patients diagnosed with WM, the median overall survival from time of diagnosis was in excess of 10 years105. The presence of 6q deletions have been suggested to have prognostic significance in one study, though others have reported no such association in WM20,21. Age is consistently an important prognostic factor (>60-70 years)98,99,101,104, but this factor is often impacted by unrelated morbidities. Anemia which reflects both marrow involvement and the serum level of the IgM monoclonal protein (due to the impact of IgM on intravascular fluid retention) has emerged as a strong adverse prognostic factor with hemoglobin levels of <9-12 g/dL associated with decreased survival in several series98-101,104. Cytopenias have also been regularly identified as a significant predictor of survival99. However, the precise level of cytopenias with prognostic significance remains to be determined101. Some series have identified a platelet count of <100-150 x 109/L and a granulocyte count of <1.5 x 109/L as independent prognostic factors98,99,101,104. The number of cytopenias in a given patient has been proposed as a strong prognostic factor99. Serum albumin levels have also correlated with survival in WM patients in certain but not all studies using multivariate analyses99,101,102. High beta-2 microglobulin levels (>3-3.5 g/dL) were shown in several studies100,101,102,103,104, a high serum IgM M-protein (>7 g/dL)104 as well as a low serum IgM M-protein (<4 g/dL)102 and the presence of cryoglobulins98 as adverse factors. A few scoring systems have been proposed based on these analyses (Table 3).

TREATMENT OF WALDENSTRÖM’S MACROGLOBULINEMIA

As part of the 2nd International Workshops on Waldenström’s macroglobulinemia, a consensus panel was organized to recommend criteria for the initiation of therapy in patients with WM.101 The panel recommended that initiation of therapy should not be based on the IgM level per se, since this may not correlate with the clinical manifestations of WM. The consensus panel, however, agreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as recurrent fever, night sweats, fatigue due to anemia, or weight loss. The presence of progressive symptomatic lymphadenopathy or splenomegaly provides additional reasons to begin therapy. The presence of anemia with a hemoglobin value of <10 g/dL or a platelet count <100 x 109/L owing to marrow infiltration also justifies treatment. Certain complications, such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia, may also be indications for therapy.101

FRONTLINE THERAPY

While a precise therapeutic algorithm for therapy of WM remains to be defined given the paucity of randomized clinical trials, consensus panels composed of experts who treat WM were organized as part of the International Workshops on Waldenström’s macroglobulinemia and have formulated recommendations for both frontline and salvage therapy of WM based on the best available clinical trials evidence. Among frontline options, the panels considered alkylator agents (e.g. chlorambucil), nucleoside analogues (cladribine or fludarabine), the monoclonal antibody rituximab as well as combinations thereof as reasonable choices for the upfront therapy of WM.106-108 Importantly, the panel felt that individual patient considerations, including the presence of cytopenias, need for more rapid disease control, age, and candidacy for autologous transplant therapy, should be taken into account in making the choice of a first-line agent. For patients who are candidates for autologous transplant therapy, which typically is reserved for those patients <70 years of age, the panel recommended that exposure to alkylator or nucleoside analogue therapy should be limited. The use of nucleoside analogues should be approached cautiously in patients with WM since there appears to be an increased risk for the development of disease transformation as well as myelodysplasia and acute myelogenous leukemia.

Alkylator-based therapy

Oral alkylating drugs, alone and in combination therapy with steroids, have been extensively evaluated in the upfront treatment of WM. The greatest experience with oral alkylator therapy has been with chlorambucil, which has been administered on both a continuous (i.e. daily dose schedule) as well as an intermittent schedule. Patients receiving chlorambucil on a continuous schedule typically receive 0.1 mg/kg per day, whilst on the intermittent schedule patients will typically receive 0.3 mg/kg for 7 days, every 6 weeks. In a prospective randomized study, Kyle et al.109 reported no significant difference in the overall response rate between these schedules, although interestingly the median response duration was greater for patients receiving intermittent versus continuously dosed chlorambucil (46 vs. 26 months). Despite the favorable median response duration in this study for use of the intermittent schedule, no difference in the median overall survival was observed. Moreover, an increased incidence for development of myelodysplasia and acute myelogenous leukemia with the intermittent (3 of 22 patients) versus the continuous (0 of 24 patients) chlorambucil schedule prompted the authors of this study to express preference for use of continuous chlorambucil dosing. The use of steroids in combination with alkylator therapy has also been explored. Dimopoulos and Alexanian110 evaluated chlorambucil (8 mg/m2) along with prednisone (40 mg/m2) given orally for 10 days, every 6 weeks, and reported a major response (i.e. reduction of IgM by greater than 50%) in 72% of patients. Non-chlorambucil-based alkylator regimens employing melphalan and cyclophosphamide in combination with steroids have also been examined by Petrucci et al.111 and Case et al.112 producing slightly higher overall response rates and response durations, although the benefit of these more complex regimens over chlorambucil remains to be demonstrated. Facon et al.113 have evaluated parameters predicting for response to alkylator therapy. Their studies in patients receiving single-agent chlorambucil demonstrated that age 60, male sex, symptomatic status, and cytopenias (but, interestingly, not high tumor burden and serum IgM levels) were associated with poor response to alkylator therapy. Additional factors to be taken into account in considering alkylator therapy for patients with WM include necessity for more rapid disease control given the slow nature of response to alkylator therapy, as well as consideration for preserving stem cells in patients who are candidates for autologous transplant therapy.

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