Thalidomide in Combination with Rituximab Is Active in Waldenström’s Macroglobulinemia and May Overcome Poor Response Determinants Associated with Rituximab Monotherapy.

INTRODUCTION: Rituximab is active in Waldenstrom’s macroglobulinemia (WM), producing major (CR + PR) response rates of 40–50% using an extended dose schedule. Lower response rates though are observed among patients with the FcgRIIIA-158 F/F polymorphism (JCO 23:474) and higher serum IgM levels (>6,000 mg/dL) (Ann Oncol 16:132). Thalidomide enhances rituximab mediated ADCC killing of lymphoplasmacytic cells and produces response rates of 25% in WM. As such, we conducted this phase II study using combination thalidomide and rituximab in patients naïve to either agent.

METHODS: Intended therapy was as follows: Weeks 1–52 Thalidomide (200 mg po qHS for 2 weeks, then 400 mg po qHS);Weeks 2–5, 13–16 Rituximab (375 mg/m²/week). Twenty-five patients were enrolled, 20 of who were previously untreated, with a baseline median age of 62 (range 44–86 yrs), BM involvement of 40 (range 5–90%), serum IgM of 3670 (range 924–8610 mg/dL), B₂M of 2.6 (range 1.4–7.8 mg/L), Hct of 33.0 (range 24.5–37.7%).

RESULTS: Grade 3/4 toxicities to thalidomide included paresthesia (n=10); somnolence (n=8); rash (n=7); neuropathic pain (n=6); confusion (n=4); tremors (n=2); and bradycardia (n=2). Dose reduction occurred in all patients and led to premature discontinuation in 11 patients. All evaluable patients received the intended rituximab therapy. Paradoxical IgM spikes following rituximab occurred during both courses of therapy and were observed in 12 patients. Two patients succumbed, unrelated to therapy, and were unevaluable. Responses were as follows: 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, among evaluable patients. Four patients had no response to therapy. With a median follow-up of 19 months, 6 patients have progressed. The median duration of response was 19.6+ months (range 7 to 26+ months) Overall response was associated with median cumulative dosed thalidomide: CR/PR/MR (29,275 mg) vs. SD/NR (7,400 mg); p=0.004. Importantly, overall responses were unaffected by FcgRIIIA-158 polymorphism status (75% vs. 71% for VV/FV vs. FF); serum IgM (83% vs. 80% for <6,000 vs. >6,000 mg/dL); and B₂M levels (86% vs. 78% for <3 vs. ≥ 3 g/dL); p=NS. Lastly, following completion of therapy, 15/18 responding patients reported improvements in quality of life.

CONCLUSION: These studies demonstrate that thalidomide in combination with rituximab is highly active in WM, though additional studies are warranted to determine the ideal dose and schedule for thalidomide in view of toxicities. Moreover, thalidomide in combination with rituximab may overcome unfavorable prognostic determinants previously reported with rituximab monotherapy in WM.