Illustrative Case Series

Waldenström Macroglobulinemia with Hyperviscosity

A 57-year-old retail pharmacist presented to his primary care physician because of progressive headaches, blurry vision, hearing loss, and episodes of confusion. He had not had night sweats, fever, or weight loss. On physical examination he was found to be pale and there were ecchymoses over his upper and lower extremities that he reported occurred spontaneously over the past 3 months. He had attributed these to his current medications including both aspirin (81 mg/day) and clopidogrel (75 mg/day), although he had been taking these medications for more than 5 years without noticing ecchymoses in the past. He did not have palpable lymphadenopathy nor was there splenomegaly.

A complete blood count (CBC) revealed a white blood count of 3.1 K/cu mm with 57% lymphocytes, 23% neutrophils, 8% monocytes, and 3% eosinophils. Hemoglobin was 7.1 g/dL and the platelet count was 94 K/cu mm. Serum chemistries revealed sodium of 129 mg/dL and potassium of 3.9 mg/dL. Total serum protein was 9.8 g/dL with an albumin of 2.3 g/dL. Serum protein electrophoresis revealed the presence of a monoclonal protein that was identified as IgM/k by immunofixation. Serum viscosity was 4.2 cp. A bone marrow aspirate and biopsy revealed an expanded presence of lymphoplamacytic cells, which by flow cytometry demonstrated sIgM, CD19, CD20, and CD22.

Imaging studies, including an MRI of the brain and chest-abdomen-pelvis CT, were essentially within normal limits. A diagnosis of Waldenström macroglobulinemia (WM) was made and hematology/oncology was consulted for assistance in management.

Discussion

This patient presents with many symptoms attributable to Waldenström-associated hyperviscosity. WM is an indolent lymphoma characterized by the accumulation within the marrow of lypmphoplasmacytic cells that typically secrete pentameric IgM which by nature of size and chemical properties, expands plasma volume and increases serum viscosity.1,2 WM may present with constitutional signs/symptoms typical of indolent lymphoma (night sweats, weight loss) or more prominently as a result of organ damage created by the monoclonal IgM (e.g., painful neuropathy, amyloid) or by the consequences of increased viscosity.3 Typically, patients present with symptoms generally related to the triad of mucosal bleeding, visual changes, and neurologic symptoms.4 Constitutional symptoms and cardiorespiratory symptoms also contribute to the clinical presentation. The normal relative serum viscosity ranges from 1.4-1.8 units (reported as Centipoises). Symptoms usually are not seen at viscosities of less than four units, and the most dramatic presentations occur when the viscosity measures more than five units. However, there is considerable variability in response to hyperviscosity and some patients will be severely affected at levels as low as 3 cp.5

Initial Management

Once clinically recognized, hyperviscosity syndrome should be promptly treated so as to prevent the myriad of complications associated with reduced blood flow to critical organs. Plasmapheresis performed two to three times will reduce serum IgM by 30% to 60%.3 Each session should be calculated to perform one complete plasma exchange, using albumin as the replacement product. Such treatment should result in prompt resolution of viscosity-related symptoms but it is only a temporizing approach, as IgM levels will steadily rise and return to pretreatment levels within 4-5 weeks.

Patients with WM and hyperviscosity frequently will present with anemia and hyponatremia and clinicians need to keep in mind that much if not all of this is due to expanded plasma volume. Treatment with saline or packed red cells may expand whole blood volume further and have significant adverse consequences.

WM-directed Treatment

WM is a systemic illness, and, like other indolent lymphomas, there is a wide array of treatment choices. In patients requiring immediate treatment, the most rapid responses have been gained by combination chemotherapy. For example, bortezomib, dexamethasone, and rituximab (BDR) has been shown to be highly effective with an overall response rate of 96% and with 22% achieving complete response and 80% remaining progression free at 2 years.6 In this trial, the time to observation of at least minimal response was 1.1 months. A number of other combinations have been tested and most have been associated with reasonable responses. Cyclophosphamide-rituximab combinations have proven particularly effective,7 as have nucleoside analogues (e.g., fludarabine) in combination with rituximab, particularly in older patients.8 Thalidomid with rituximab has been a useful approach for some (particularly those presenting with significant myelosuppression),9 but lenalidomide has been associated with clinically significant anemia and thus is not recommended for patients with WM. A number of other agents, including bendamustine and everolimus, are currently under investigation, having exhibited demonstrable activity in early trials.

Recommendations for Presented Patient

The patient presented with symptoms and signs of hyperviscosity and was found to have WM. Once identified, the hyperviscosity should be treated promptly and most effectively by plasmapheresis, at least two or three sessions over the first week. Attention would then be directed to specific WM treatment, I would take into account his initial cytopenias, which may have resulted from marrow involvement with tumor or as a result of IgM-associated peripheral destruction. A careful review of the marrow and observation of CBC response to plasmapheresis would be helpful in defining the mechanism. In the absence of constitutional symptoms and attributing most of his symptoms to hyperviscosity, I would likely recommend a cyclophosphamide-based regimen (e.g., dexamethasone-cyclophosphamide-rituximab7), rather than more intensive approaches. I would avoid rituximab in the first one or two courses in light of the well-described IgM-flare that occurs with rituximab treatment, either when used alone or in combination.10 Such might transiently increase serum viscosity and associated symptoms. Upon remission, I would strongly consider maintenance rituximab at 3-month intervals for an additional 2 years, akin to what is currently standard care for other indolent lymphomas.

References

1. Harris NL, et al. Ann Oncol 1999;10:1419-1432.

2. Owen RG, et al. Semin Oncol 2003;30:110-115.

3. Treon SP. Blood 2009;114:2375-2385.

4. Adams BD, et al. Emerg Med Clin North Am 2009;27:459-476.

5. Menke MN, et al. Arch Ophthalmol 2006;124:1601-1606.

6. Treon SP, et al. J Clin Oncol 2009;27:3830-3835.

7. Dimopoulos MA, et al. J Clin Oncol 2007;25:3344-3349.

8. Treon SP, et al. Blood 2009;113:3673-3678.

9. Treon SP, et al. Blood 2008;112:4452-4457.

10. Ghobrial IM, et al. Cancer 2004;101:2593-2598.