Imatinib Mesylate (Gleevec®) Produces Responses in Patients with Relapsed/Refractory Waldenstrom's Macroglobulinemia.

Abstract

Waldenstrom's macroglobulinemia is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells (LPC) in the bone marrow (BM), along with an IgM monoclonal gammopathy. Characteristic of WM is an increased number of mast cells (MC) which are found in association with LPC, and stimulate LPC growth through several TNF-family members including CD40L, APRIL and BLYS (Ann Oncol 17:1275; Blood 104:917A). As such, we have targeted MC in WM. One important growth and survival factor for MC is stem cell factor (SCF), which signals through CD117. Imatinib mesylate blocks SCF signaling through CD117, and induces apoptosis of WM BM MC and LPC, both of which highly express CD117 (Blood 2004; 104:314b). As such, we performed this Phase II study of imatinib mesylate in patients with relapsed and refractory WM. Intended therapy consisted of imatinib mesylate which was initiated at 400 mg po qD over the first month, and subsequently dose escalated to 600 mg po qD for up to 2 years. Dose de-escalation to 300 mg po qD was permitted for toxicity. Twenty-eight patients were enrolled, 27 of whom are eligible for evaluation at final analysis. Median age was 61 (range 33–80 years), and median prior therapies was 2 (range 1–5). Twenty-four and four patients had relapsed and refractory disease, respectively. With a median follow-up of 6.3 months for all evaluable patients, median serum IgM levels declined from 3,110 to 2,530 mg/dL at best response (p=0.002). On an evaluable basis, 7/27 (26%) and 2/27 (7%) of patients attained a ≥25% and ≥50% decrease in serum IgM, respectively. Responses were prompt, and occurred at a median of 2.1 months. The median time to progression for responding patients was 8.4 (range 2–15 months). Hematological toxicities were the most common feature and ≥grade 2 toxicities included anemia (n=12), leucopenia (n=5), edema (n=3), thrombocytopenia (n=2) and neutropenia (n=1). Tryptase levels, which measure mast cell burden, declined in all patients for whom pre- and post-serum was available from 6.7 (range 2.2–10 ng/ml) to 3 (range 1–5.5 ng/ml) (p<0.001) though did not predict response to therapy.The results of this study demonstrate that imatinib mesylate is an active salvage therapy for WM and is associated with decreases in mast cell burden in patients with WM.