Thalidomide-rituximab for Waldenstrom Macroglobulinemia

Abstract & Commentary

By William B. Ershler, MD

Synopsis: Thalidomide-rituximab was administered to 25 symptomatic patients (20 previously untreated) with Waldenstrom macroglobulinemia. The overall response rate was 72%, and the median time-to-progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event, occurring in 11 patients. Thus, thalidomide-rituximab is an active regimen, and may prove a less toxic alternative than combination chemotherapy when treatment is required for this disorder.

Source: Treon SP, et al. Thalidomide and rituximab in Waldenstrom macroglobulinemia. Blood. 2008;112:4452-4457.

Waldenstrom macroglobulinemia (WM) cells express CD201 and, accordingly, are suitable targets for rituximab, a therapeutic monoclonal antibody directed at the CD20 molecule. When used as a single agent at standard dose and schedule, rituximab induces an overall response rate of 27%-35% and median durations of response from 8-27 months.2,3 When used on a more extended schedule, response rates and durations of response are improved to a small degree.4 Factors that predict a less than optimal rituximab response include serum IgM level above 6,000 mg/dL and beta-2 microglobulin (B2M) greater than 3 mg/L.4 When combined with chemotherapy such as cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP-R), or with dexamethasone and cyclophosphamide (DC-R), response rates approach 90% and the median time-to-progression, in excess of three years, has been reported.5,6 Although impressive, these regimens are associated with prolonged neutropenia, occasional disease transformation, and the potential for secondary myelodysplasia and acute leukemia.

In an effort to avoid the complications of cytotoxic chemotherapy, the current phase II study was undertaken to assess the combination of rituximab with thalidomide. The rationale for this was based upon the observation that thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity.7,8 Patients with symptomatic WM who had not previously been treated with either rituximab or thalidomide were treated with daily thalidomide (200 mg for two weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m2 per week) administered on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom had been previously untreated. In total, one patient demonstrated a complete response, 16 patients achieved a major response, and two patients received a minor response, for overall and major response rates of 72% and 64%, respectively. Median serum IgM decreased from 3,670 to 1,590 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.


Thus, it is apparent that thalidomide, in combination with rituximab, is active, and produces long-term responses in WM. The combination was generally well tolerated, and the response rates and duration of responses were comparable to those seen with CHOP-R or DC-R. Additional study is warranted to determine whether lower doses of thalidomide (ie, < 200 mg/day) would be similarly efficacious in light of the relatively high frequency of treatment-related neuropathy in this patient population.

Two further clinical notes are worth mentioning. First, abrupt increases in serum IgM have been known to occur with the use of rituximab in patients with WM, and, although transient, this can aggravate hyperviscosity and contribute to hyperviscosity-related symptoms. In this study, six patients with very high pre-treatment serum viscosity (3.5 CP or higher) received prophylactic plasmapheresis. Of the remaining 17 patients, nine experienced a rise in serum IgM after rituximab infusion and five had a rise in IgM of greater than 25%. Of the 21 patients who received a second course of rituximab, one required pre-treatment plasmapheresis, seven had a rise in IgM after rituximab, but only one had a rise greater than 25%.

A second note is that, unlike multiple myeloma, for which the thalidomide analogue lenalidomide has proven very effective, and with considerably less neurotoxicity, its use in WM has been problematic. In a prior clinical trial from this same group of investigators with lenalidomide in combination with rituximab, there has been the unexpected and curious development of an acute, non-hemolytic anemia and, furthermore, response durations for those who tolerated the lenalidomide treatment were shorter than those described for thalidomide-rituximab (Clinical Cancer Research, in press). Thus, clinicians should resist the temptation to substitute lenalidomide for thalidomide when considering WM treatment. Perhaps, the exploration of newer thalidomide analogues will provide some clues as to why there is this unexpected difference in response to lenalidomide in WM patients.


1. Treon SP, et al. Expression of serotherapy target antigens in Waldenstrom's macroglobulinemia: therapeutic applications and considerations. Semin Oncol. 2003;30:248-252.

2. Dimopoulos MA, et al. Treatment of Waldenstrom's macroglobulinemia with rituximab. J Clin Oncol. 2002;20:2327-2333.

3. Gertz MA, et al. Multicenter phase 2 trial of rituximab for Waldenstrom macroglobulinemia (WM): an Eastern Cooperative Oncology Group Study (E3A98). Leuk Lymphoma. 2004;45:2047-2055.

4. Treon SP, et al. Extended rituximab therapy in Waldenstrom's macroglobulinemia. Ann Oncol. 2005; 16:132-138.

5. Dimopoulos MA, et al. Primary treatment of Waldenstrom macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25:3344-3349.

6. Treon SP, et al. CHOP plus rituximab therapy in Waldenstrom's macroglobulinemia. Clin Lymphoma. 2005;5:273-277.

7. Davies FE, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98:210-216.

8. Hayashi T, et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 2005;128:192-203.