Treatment of Waldenstrom's Macroglobulinemia with the Combination of Fludarabine and Cyclophosphamide

Fludarabine is an active agent for the treatment of Waldenstrom's macroglobulinemia (WM) and its combination with cyclophosphamide has been effective in many patients with low-grade lymphoma and chronic lymphocytic leukemia. Based on these data, we administered the combination of fludarabine (25 mg/m2 i.v. day 1-3) and cyclophosphamide (250 mg/m2 i.v. day 1-3,) to 11 patients with WM. Most patients had features indicating poor prognosis including median age of 73 years (range 60-84 years), hemoglobin <100 g/l in 73%, B2-microglobulin >3 mg/l in 64%, symptomatic hyperviscosity in 55% of patients. Only 2 patients were previously untreated, 7 were primary refractory and 2 were relapsing on treatment. The fludarabine-cyclophosphamide combination (FC) was administered every 4 weeks for a total of four courses. Partial response, defined by at least 50% reduction of serum monoclonal protein and of tumor infiltrate at all involved sites was documented in 6 patients (55%) (The median time to response was 4 months). Responding patients demonstrated resolution of disease-related symptoms and correction of anemia. Median time to progression for all patients was 24 months. With a mean follow-up of 28 months, two of six responding patients have progressed so far. The probability of 2-year survival is 70%. This regimen was relatively well tolerated. Complications included neutropenia grade 3 or 4 in 3 patients and thrombocytopenia grade 3 or 4 in 2 patients. There were five infectious episodes including two episodes of neutropenic fever. We conclude that the FC combination appears to be active in patients with WM most of whom were resistant to treatment and had poor prognostic factors. The addition of rituximab to FC requires further investigation.