8017 Background: Rituximab is active in Waldenstrom's macroglobulinemia (WM), producing response rates of 40–50%. Lower response rates are observed among patients with the FcγRIIIA-158 FF polymorphism; high B2M (≥3.0 mg/dL), and high serum IgM levels (≥6,000 mg/dL). Thalidomide enhances rituximab-mediated ADCC of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using thalidomide and rituximab in patients naïve to either agent. Methods: Intended therapy was: Weeks 1–52: Thalidomide (200 mg po qHS for 2 wks, then 400 mg po qHS) Weeks 2–5, 13- 16: Rituximab (375 mg/m2/wk) Twenty-five patients were enrolled, 20 of whom were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–80%), serum IgM of 3,670 (range 924–8,610 mg/dL), B2M of 2.6 (range 1.4–8.3 mg/L), Hct of 34.1 (range 23.6–42.6%). Results: Grade ≥2 toxicities to thalidomide included neuroparesthesias (n=11); somnolence (n=3); confusion (n=3); rash (n=2); tremors (n=2); bradycardia (n=2) and palpitations (n=1). Among patients experiencing neuroparesthesias, 10 demonstrated resolution to grade 1 (n=3) or complete resolution (n=7) at a median of 6.7 (range 0.4- 22.5 months). Dose reduction of thalidomide occurred in all patients and led to discontinuation in 11 patients. Twenty-three patients were evaluable. Responses among evaluable patients: CR (n=1); PR (n=15); MR (n=2); SD (n=1) for an overall and a major response rate of 78% and 70%, respectively. Median serum IgM decreased from 3,670 (924–8,610 mg/dL) to 1,590 (36–5,230 mg/dL) (p<0.001), while median hematocrit rose from 33.0 (23.6–42.6%) to 37.6 (29.3–44.3%) (p=0.004) at best response. With a median follow-up of 42+ months, the median TTP for all evaluable patients on study was 35 months, and 38+ months for responders. Overall response was associated with median cumulative thalidomide dose: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Overall responses were unaffected by FcγRIIIA-158 polymorphism status (81% vs. 71% for VV/FV vs. FF); serum IgM (78% vs. 80% for <6,000 vs. ≥6,000 mg/dL); and B2M levels (71% vs. 89% for <3 vs. ≥3 g/dL); p=NS. Conclusions: Thalidomide in combination with rituximab is highly active and produces long- term responses in patients with WM. No significant financial relationships to disclose.
Monocytosis and high serum macrophage colony-stimulating factor in Waldenstrom's macroglobulinemia [letter]