We explored its use in combination with rituximab and observed higher ADCC activity in preliminary studies.24 However, its use in WM patients appears to be problematic because of the development of acute nonhemolytic anemia, signifying potential idiopathic toxicity for WM patients with this agent. serum IgM decreased from 3670 to 1590 mg/dL ( .001), whereas median hematocrit rose from 33.0% to 37.6% (= .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. RB Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalidomide in combination with rituximab is usually active and produces long-term responses in WM. Lower doses of thalidomide (ie, 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient populace. This trial is usually registered at www.clinicaltrials.gov as #”type”:”clinical-trial”,”attrs”:”text”:”NCT00142116″,”term_id”:”NCT00142116″NCT00142116. Introduction Monoclonal antibodies have been successfully used to treat patients with B-cell malignancies, including Waldenstrom macroglobulinemia (WM). Most of these efforts have focused on the use of rituximab, a chimeric human IgG1 monoclonal antibody, which targets CD20, which is usually widely expressed in WM.1,2 Studies using standard-dose rituximab therapy have demonstrated activity in WM, with overall response rates of 27% to 35% and median durations of response from 8 to 27+ months.2C7 More recently, the use of extended schedule rituximab has been evaluated wherein patients received 8 infusions of rituximab (375 mg/m2 per week) at weeks 1 to 4 GF 109203X and 12 to 16. Overall response rates of 44% to 48% were observed in these studies, with median durations of response from 16+ to 29+ months.8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM ( 6000 mg/dL) and beta-2 microglobulin (B2M; 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (FcRIIIA-158).8C10 Studies combining rituximab with chemotherapy have also been explored in WM.11 The combination of nucleoside analogs plus rituximab has yielded major response rates of 70% to 90%,12C15 whereas the combinations of CHOP-R (cyclophosphamide, adriamycin, vincristine, prednisone, rituximab) or DC-R (dexamethasone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%.16C18 Median time to progression (TTP) in excess of 3 years has been reported with these combinations. Although these combinations have produced more impressive responses, greater toxicity has also been reported in WM patients, with the use of nucleoside analogs causing prolonged neutropenia, stem cell damage, disease transformation, and secondary myelodysplasia/acute leukemia.11,12,19 In an effort to augment monoclonal antibody responses in WM patients while averting short- and long-term chemotherapy-induced toxicities, we sought the development of immunomodulatory agents for combination therapy with rituximab. Thalidomide is an immunomodulatory agent that induces the elaboration of immunostimulatory cytokines, including interleukin-2 and interferon-.20 Importantly, thalidomide induces the expansion of natural killer (NK) cells, which are important effectors of in vivo rituximab activity, as well as increased antibody-dependent, cell-mediated cytotoxicity (ADCC) induced by rituximab.20C24 As monotherapy, thalidomide has modest activity in WM patients, producing response rates of 25%, whereas the GF 109203X combination of thalidomide plus steroids and/or clarithromycin produces response rates of 40%.25C27 In view of these considerations, we carried out a phase 2 study of thalidomide and GF 109203X rituximab and here present outcome and long-term follow-up. Methods Patients with a clinicopathologic diagnosis of WM,28 who were naive to rituximab and thalidomide, who had CD20-positive disease as determined by previous bone marrow immunohistochemistry or flow cytometry, and who required therapy based on consensus guidelines29 were eligible for this study. A monoclonal IgM protein, a minimum IgM level more than or equal to 2 times the upper limit of normal, a baseline platelet count of more than or equal to 25?000/L, an absolute neutrophil count of more than or equal to 500/L, a serum creatinine of less than 2.5 mg/dL (unless nephropathy was attributable to their WM), a serum total bilirubin and serum glutamicoxalacetic transaminase of less than 2.5 times the upper limit of normal, and an Eastern Cooperative Oncology Group performance status of 0 to 2 were required for entry. No chemotherapy, steroid.