Thalidomide and rituximab in Waldenstrom macroglobulinemia

Abstract

Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Walden-strom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m 2 per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n 1), partial response (n 15), and major response (n 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalido-mide in combination with rituximab is 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 population. This trial is registered at www. clinicaltrials.gov as #NCT00142116. (Blood. 2008;112:4452-4457) Introduction Monoclonal antibodies have been successfully used to treat patients with B-cell malignancies, including Waldenstrom macroglobu-linemia (WM). Most of these efforts have focused on the use of rituximab, a chimeric human IgG 1 monoclonal antibody, which targets CD20, which is 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. 2-7 More recently, the use of extended schedule rituximab has been evaluated wherein patients received 8 infusions of rituximab (375 mg/m 2 per week) at weeks 1 to 4 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 (B 2 M; 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (FcRIIIA-158). 8-10 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%, 12-15 whereas the combinations of CHOP-R (cyclophosphamide, adria-mycin, vincristine, prednisone, rituximab) or DC-R (dexametha-sone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%. 16-18 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 toxi...

Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study

“…Although the exact mechanisms remain unclear, this is consistent with previous studies on patients with Waldenström macroglobulinemia treated with IMiDs, where no increased risk of venous thrombosis was observed. [34][35][36] Thus, our study and these prior observations suggest that there might be a biologic difference between IgG/IgA and IgM MGUSwith regard to risk of thromboembolism. In contrast to the study by For personal use only.…”

Interindividual Variability of Response to Rituximab: From Biological Origins to Individualized Therapies

“…Because FcgRIIIa is expressed only by monocytes/macrophages and NK cells (the main actors in ADCC), we have postulated that patients homozygous for FCGR3A-158V experience significantly better responses to rituximab because they have enhanced ADCC activity compared with FCGR3A-158F carriers. This was confirmed in other studies using rituximab (50,51) and for other IgG1 monoclonal antibodies, including trastuzumab (52) and cetuximab (53). It is important to note that some FcgRIIIa-158V homozygous patients can experience progression after rituximab treatment, whereas FcgRIIIa-158F homozygous patients can maintain a complete response, indicating that other factors may affect rituximab efficacy (49).…”

Clinical outcome of patients with follicular lymphoma receiving chemoimmunotherapy in the PRIMA study is not affected by FCGR3A and FCGR2A polymorphisms

“…12,13,[29][30][31] Considering specifically FL, 8 studies have previously examined these correlations. 12,13,15,[32][33][34][35][36] The first demonstration of the variability in the quality of response to rituximab treatment according to FCGR3A polymorphism was derived from analysis of a cohort of 49 patients with low tumor burden FL receiving 4 infusions of rituximab as first-line treatment.…”