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Flare in Neuropathy Following Rituximab Therapy for Waldenstrom’s Macroglobulinemia

Mid Valley Oncology and Hematology PC, Newburgh, NY

Thomas M. Fynan

Medical Oncology and Hematology, private practice, Hamden, CT

Thomas Duffy

Yale University School of Medicine, New Haven, CT

To the Editor:

Waldenstrom’s macroglobulinemia is a low-grade lymphoma characterized by a serum monoclonal immunoglobin M (IgM) protein spike and monoclonal lymphoplasmacytic cells present in the bone marrow. Approximately 5% to 10% of patients develop peripheral neuropathy, which may be immune-mediated as a result of paraprotein directed against myelin-associated glycoprotein (anti-MAG) or glycolipids. Therapy is challenging, with some success reported with steroids, chemotherapy, intravenous immunoglobin (IVIg), or plasma exchange. Recently, the monoclonal anti-CD20 antibody, rituximab, has been used, sometimes in combination with chemotherapy, with improvement in more than 80% of treated patients.^1,2 However, based on our experience, rituximab may initially paradoxically worsen neuropathy.

A 72-year-old man presented with a 5-month history of peripheral neuropathy manifested as calf pain and weakness. Serum protein electrophoresis demonstrated a monoclonal IgM spike of 1.1 g/dL, and his bone marrow revealed a scant monoclonal lymphoplasmacytic infiltrate, establishing the diagnosis of Waldenstrom’s macroglobulinemia with peripheral neuropathy. Therapy was initiated with prednisone 1 mg/kg daily and fludarabine chemotherapy in combination with rituximab. One day after the first cycle of therapy, he experienced worsening leg pain and numbness, which over a period of 3 to 4 days progressed stepwise to involve the legs, buttocks, lower back, and upper extremities. On admission to the hospital, he had decreased strength and sensation in both upper and lower extremities, lower greater than upper, distal greater than proximal, with no bulbar involvement. His serum IgM was 1,470 mg/dL, his spine magnetic resonance imaging and head computed tomography were both normal, and his CSF had an elevated protein level of 85 mg/dL with normal glucose and only three nucleated cells. Electromyography and nerve conduction studies revealed a predominantly demyelinating sensorimotor neuropathy. The clinical picture was thought to be consistent with acute inflammatory demyelinating polyneuropathy. Plasmapheresis was initiated but abandoned midway when the patient became acutely hypotensive with fever and flushing, suggesting autonomic involvement. He was transferred to the intensive care unit and started on intravenous immunoglobulins for treatment of the neuropathy. Respiratory paralysis prompted intubation and mechanical ventilation. After 5 days of intravenous immunoglulins, his strength improved allowing extubation. His polyneuropathy continued to improve and 8 days after admission, he was discharged to a rehabilitation facility. A month later, his neuropathy had improved and he has returned to his pretreatment baseline, which is stable as of this writing.

A paradoxical increase in IgM levels following rituximab therapy is well documented in Waldenstrom’s macroglobulinemia; it occurs in 30% to 70% of patients. The "flare" occurs immediately after completing the rituximab course, with IgM levels returning to baseline in about 4 months.³ The flare may create complications in addition to worsening neuropathy. The increased IgM paraprotein can lead to hyperviscosity, with severe consequences like intracranial hemorrhage, especially in patients with a pretherapy IgM level of more than 5,000 mg/dL.⁴ A case report by Buda-Okreglak et al⁵ describes the precipitation of acute inflammatory arthritis. The proposed mechanisms of this "flare" phenomenon include B-lymphocyte lysis with resultant release of intracellular paraprotein or CD-20 signaling induced by rituximab.

To our knowledge, this is the first report of a patient with Waldenstrom’s macroglobulinemia experiencing worsening neuropathy following rituximab therapy. Although our patient had pre-existing neuropathy, there was a dramatic worsening immediately after he received the drug, which was out of proportion to his pretherapy baseline, and he returned to baseline a month later. This phenomenon is important to recognize as it may be preventable, either by treating the patient with chemotherapy first to reduce the paraprotein burden or by administering concurrent immunosuppressive medication. Our patient was administered oral prednisone at 1 mg/kg, but his neuropathy progressed on this treatment. More aggressive immunosuppression may be warranted in the initial 3 to 4 months of rituximab therapy.

Authors’ Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Nobile-Orazio E: Treatment of dysimmune neuropathies. J Neurol 252:385-395, 2005[Medline]

2. Weide R, Heymanns J, Koppler H: The polyneuropathy associated with Waldenstrom’s macroglobulinaemia can be treated effectively with chemotherapy and the anti-CD20 monoclonal antibody rituximab. Br J Haematol 109:838-841, 2000[CrossRef][Medline]

3. Ghobrial IM, Fonseca R, Greipp PR, et al: Eastern Cooperative Oncology Group: Initial immunoglobulin M ‘flare’ after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia—An Eastern Cooperative Oncology Group study. Cancer 101:2593-2598, 2004[CrossRef][Medline]

4. Treon SP, Branagan AR, Hunter Z, et al: Paradoxical increases in serum IgM and viscosity levels following rituximab in Waldenstrom’s macroglobulinemia. Ann Oncol 15:1481-1483, 2004[Abstract/Free Full Text]

5. Buda-Okreglak EM, Drabick JJ, Delaney NR: Proinflammatory syndrome mimicking acute rheumatoid arthritis in a patient with Waldenstrom’s macroglobulinemia treated with rituximab. Ann Hematol 83:117-119, 2004[Medline]

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