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A 60-year-old woman presented to the emergency department with two weeks of worsening occipital headaches and blurry vision.

She had a history of atrial tachycardia for which she was prescribed daily diltiazem, and she required electrical cardioversion three years prior. One year ago, this patient was diagnosed with immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) during a rheumatology workup for bilateral knee pain. The remainder of the workup was unrevealing. Two weeks prior to presentation, the patient developed an intermittent headache that worsened in intensity in the past 72 hours. The night before, she developed blurred vision in both eyes. She denied associated fevers, night sweats, nausea, vomiting, chest pain, shortness of breath, cough, change in appetite, unintentional weight loss, or easy bruising or bleeding.

In the emergency department, vital signs were normal. Physical examination was notable for tender occipital and cervical lymphadenopathy, mild splenomegaly, and bilateral retinal hemorrhage on ophthalmologic examination. Brain and cervical spine MRI scans were normal. A serum electrolyte panel was also within normal limits, and the remainder of laboratory workup was notable as follows:

She was treated with intravenous fluids and acetaminophen with minimal improvement in headache and subjective worsening of visual symptoms.

What is the most appropriate next step in treating this patient?

1. Genetic testing for MYD88 and CXCR4 mutations
2. Rituximab monotherapy
3. Treatment with bortezomib, dexamethasone, and rituximab
4. Plasmapheresis
5. Treatment with ibrutinib

Answer: D. Plasmapheresis

Explanation:

This patient has symptomatic Waldenstrom macroglobulinemia (WM), a B-cell neoplasm characterized by clonal proliferation of IgM-secreting lymphoplasmacytic cells. Her presentation is complicated by hyperviscosity syndrome that is threatening her vision, and she should be treated with emergent plasmapheresis (choice D).

Morbidities associated with serum IgM deposition include organ dysfunction, type I cryoglobulinemia (Raynaud-like phenomenon, acrocyanosis, ulcers, purpura, cold urticaria), type II cryoglobulinemia (purpura, arthralgia, renal failure), peripheral neuropathy, and cold agglutinin (hemolytic anemia, livedo reticularis).¹ Particularly high-serum IgM levels can result in a hyperviscosity crisis characterized by headaches, blurred vision, epistaxis, retinal hemorrhage, intracranial hemorrhage, and altered mentation.

The diagnosis of WM requires the presence of IgM monoclonal protein and lymphoplasmacytic lymphoma infiltration of involved tissue (often bone marrow). There is no minimum serum IgM or bone marrow infiltration level required for diagnosis because patients can have symptomatic disease requiring treatment at a wide range of IgM levels. MYD88 is an early oncogenic driver in WM and is detected in more than 50 percent of patients with IgM MGUS and in more than 90 percent of patients with WM.² CXCR4 mutations are observed in 30 to 35 percent of patients with WM.³ Sequencing to detect these somatic mutations (choice A) is not required for diagnosis and would not change the need for immediate plasmapheresis in this patient.

Patients with disease-related anemia (Hgb < 10 g/dL), thrombocytopenia (Plt < 100 K/µL), or symptomatic disease should be considered for therapy. Though the decision to initiate therapy is not strictly based on serum IgM levels, most providers consider initiation of treatment for serum IgM greater than 6,000 mg/dL, even in asymptomatic patients, to prevent hyperviscosity-related injury.⁴ Symptomatic patients not requiring immediate disease control can be treated with rituximab monotherapy, rituximab in combination with alkylating agents (e.g., bendamustine), or ibrutinib. Rituximab monotherapy (choice B) should not be used in patients requiring immediate disease control owing to slow response rates and potential for rituximab-induced IgM flare, which occurs in 40 to 60 percent of patients with WM.^1,5 Proteasome inhibitor–containing regimens (choice C) can be used in patients with nonemergent paraprotein morbidity. Examples of these regimens include bortezomib, dexamethasone, and rituximab, and carfilzomib, rituximab, and dexamethasone. Ibrutinib (choice E) has a faster IgM reduction response than rituximab and does not have an IgM flare, making it a potentially attractive frontline option for symptomatic patients. However, plasmapheresis is still the superior choice for symptomatic hyperviscosity syndrome. Moreover, ibrutinib is avoided in patients with bleeding and history of tachyarrhythmia, and therefore would not be an appropriate initial choice for this patient.⁶

Case study submitted by Lachelle D. Weeks, MD, PhD, of Dana Farber Cancer Institute.

References

1. Treon SP . Blood. 2015 126:721-732.
2. Varettoni M, Arcaini L, Zibellini S, et al . Blood. 2013 121:2522-2528.
3. Poulain S, Roumier C, Doye E, et al . Blood. 2014 124:1627.
4. Kyle RA, Treon SP, Alexanian R, et al . Semin Oncol. 2003 30:116-120.
5. Treon SP, Branagan AR, Hunter Z, et al . Ann Oncol. 2004 1481-1483.
6. Treon SP, Tripsas CK, Meid K, et al . N Engl J Med. 2015 372:1430-1440.