Waldenstrom's Macroglobulinemia Program, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02116, USA
* Correspondence to: Dr S. P. Treon, Dana Farber Cancer Institute, LG102, 44 Binney Street, Boston, MA 02115, USA. Tel: +1-617-632-2681; Fax: +1-617-632-4862; Email: steven_treon{at}dfci.harvard.edu
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Abstract |
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Patients and methods: Eleven WM patients with CD20+ tumor cells who received rituximab at our Institution and had serum IgM levels measured within a 12-week period following start of therapy were evaluated. Therapy consisted of four weekly infusions of rituximab at 375 mg/m2. Pre- and post-therapy serum IgM levels were determined by nephelometry and corresponding serum viscosity levels were determined by viscometry.
Results: Ten of the 11 patients demonstrated an abrupt rise in serum IgM levels, with a >25% increase occurring in eight (73%) patients. Mean serum IgM levels for all 10 spiking patients rose from 4370 (range, 6557940) to a peak of 5865 (range, 87211 800) mg/dl (P=0.004), which occurred at a mean of 4 (range, 18) weeks following initiation of therapy. Mean serum viscosity levels also increased from 3.5 to 5.6 centipoise (CP) (P=0.09) in eight patients for whom pre- and post-therapy studies were obtained. A subdural hemorrhage occurred in one patient when serum IgM levels rose from 7530 to 11 800 mg/dl, and serum viscosity increased from 3.9 to 10.1 CP. Two other spiking patients with pre-therapy IgM levels of >5000 mg/dl experienced worsening headaches and/or epistaxis attributed to increasing serum viscosity.
Conclusions: Abrupt increases in serum IgM levels commonly occur following rituximab therapy in WM. Careful clinical and laboratory monitoring is warranted, particularly if patients have pre-therapy serum IgM levels of >5000 mg/dl. The mechanism of this effect is under active investigation, and may be related to CD20 signaling triggered by rituximab.
Key words: hyperviscosity, Rituximab, serum IgM, Waldenstrom's macroglobulinemia
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Introduction |
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With most of the above trials, responses which are based on serum IgM levels have typically been evaluated at 12 weeks following treatment with rituximab. Paradoxically, we have observed that serum IgM and viscosity levels can abruptly rise following initiation of rituximab therapy. In this report, we describe the outcome of 11 WM patients receiving rituximab who had serial IgM levels measured within a 12-week period following start of therapy.
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Patients and methods |
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Statistical analysis
Comparison of pre- and post-rituximab parameters was performed using a two-tailed Student's t-test on Microsoft ExcelTM software. A P value 0.05 was deemed to be significant.
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Results and discussion |
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Transient rises in serum IgM levels were also observed in several patients treated with extended rituximab therapy by Dimopoulos et al. [9]. Serum IgM levels also peaked on or about 30 days following initiation of rituximab treatment in this report. These studies, though, are the first to describe adverse effects coinciding with the abrupt increases in serum IgM and SV levels following rituximab in patients with WM. An important consideration is that these adverse effects occurred among those patients with the highest IgM levels in this study. All three patients had a pre-therapy IgM level of >5000 mg/dl, and a corresponding SV of >3.0 CP. More careful clinical and laboratory monitoring would therefore appear particularly warranted for those WM patients receiving rituximab therapy with pre-therapy IgM levels of >5000 mg/dl.
The mechanism by which rituximab induces IgM levels to rise in WM patients remains to be clarified. While it is tempting to speculate that rituximab-mediated tumor-cell death leads to intracellular IgM release, no appreciable change in disease burden as assessed by bone marrow biopsies and CT scans was observed for two patients who had abrupt increases in their IgM levels following rituximab therapy. These findings suggest that other mechanisms, including rituximab-induced signaling though CD20, may be responsible for the IgM surges observed in WM patients. In support of this hypothesis, modulation of cell surface IgM expression by the anti-CD20 monoclonal antibody B1 has been observed in normal B-lymphocytes and B-cell lines [14]. A signaling mechanism could also account for the abrupt serum IgM surge observed only hours after initiation of rituximab in the patient described above, since elimination of tumor cells in response to rituximab is typically delayed in WM [S. P. Treon, C. A. Emmanouilides, E. Kimby et al., submitted for publication]. Ongoing studies in our laboratory are addressing such signaling mechanisms by rituximab in WM.
In conclusion, these data suggest that paradoxical spikes in serum IgM levels commonly occur in WM patients following rituximab treatment. Careful clinical and laboratory monitoring is warranted, particularly if patients have pre-therapy IgM levels of >5000 mg/dl prior to initiation of rituximab therapy. The mechanism of this effect is under active investigation, and may be related to CD20 signaling triggered by rituximab.
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Acknowledgements |
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Received for publication May 25, 2004. Accepted for publication June 4, 2004.
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References |
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