I. What every physician needs to know.
Waldenstrom’s macroglobulinemia (WM) is a lymphoproliferative disorder characterized by bone marrow infiltration and clonal proliferation of B-lymphocytes that produce IgM.
II. Diagnostic Confirmation: Are you sure your patient has Waldenstrom's macroglobulinemia?
WM can be asymptomatic or symptomatic. To be diagnosed with the disease, there must be clonal proliferation of B lymphocytes producing IgM as well as bone marrow infiltration (10% or more). The B cells must express specific immunophenotypes consistent with WM (e.g., IgM+, CD20+).
A. History Part I: Pattern Recognition:
Some patients with WM are asymptomatic. Patients with symptomatic WM present with features related to tumor infiltration of tissues or due to high circulating IgM levels. Tumor infiltrates the lymph nodes, spleen and liver causing enlargement. The bone marrow is infiltrated leading to cytopenias (e.g., thrombocytopenia, anemia, and leukopenia). Symptoms related to circulating IgM levels include problems with hyperviscosity, one of the most serious and life-threatening complications of WM and occurs in 15% of the cases. Patients may report blurry vision, headaches, tinnitus, dizziness, mental slowing, or rarely present with symptoms of cerebral hypoperfusion (stroke or transient ischemic attacks). Hyperviscosity can precipitate heart failure that is exacerbated by concomitant anemia. Symptoms of hyperviscosity begin when serum viscosity is >4 centipoises (normal ≤1.8).
Patients may also present with neuropathy, predominantly of the lower extremities. Cryoglobulinemia and hemolytic anemia are also seen. Some patients present with bleeding/oozing from mucous membranes, a result of thrombocytopenia as well as due to IgM interfering with clotting factor function. Less common symptoms include intestinal malabsorption due to IgM deposition in the gastrointestinal tract. Renal failure can also occur as a result of IgM deposition and damage to the glomeruli.
B. History Part 2: Prevalence:
WM is a rare disorder with approximately 1400 new cases diagnosed in the US each year. The median age at diagnosis is 64 years. Most cases of WM are sporadic, though there may be a genetic predisposition in a subset of patients. People of Caucasian decent are at higher risk than those of Black or Mexican heritage. True risk factors for the disease are not fully understood given its relative rarity.
C. History Part 3: Competing diagnoses that can mimic Waldenstrom's macroglobulinemia.
WM can be confused with other lymphoproliferative disorders such as monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, chronic lymphocytic leukemia (CLL), and mantle cell lymphoma. Unlike multiple myeloma, patients with WM do not have concomitant hypercalcemia or lytic bone lesions. Furthermore, classical multiple myeloma with an IgM paraprotein is extremely rare.
D. Physical Examination Findings.
Physical findings associated with WM include organomegaly, lymphadenopathy, and neuropathy. Fundoscopic examination can reveal retinal vein engorgement (sausage link appearance).
E. What diagnostic tests should be performed?
To diagnose WM, the serum should be checked for IgM monoclonal gammopathy using both serum protein electrophoresis (SPEP) and quantitative IgM. Importantly, the presence of cryoglobulins can affect the results of the monoclonal protein studies. All patients must have a bone marrow aspirate to confirm the diagnosis as bone marrow involvement with plasmacytoid cells is a requirement for to distinguish WM from other monoclonal processes (e.g., MGUS). Immunohistochemistry and flow cytometry should be utilized to ensure the clonal cells have the immunophenotype typical of WM. Given the risks of hyperviscosity, all patients with suspected WM should have their serum viscosity measured. Since IgM can affect platelet function and clotting factor function, PT and PTT should be checked in all patients. Additional studies that may be useful, depending on patient presentation, include measurement of serum cryoglobulins, bone marrow or fat aspirate with Congo Red staining, lymph node biopsies and echocardiogram.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Consultation with a hematologist and/or hematopathologist is essential to interpreting the results of the bone marrow aspirate and immunohistochemistry/flow cytometry tests. The diagnosis of WM is made when the following criteria are met: the presence of IgM monoclonal gammopathy in the serum, involvement of bone marrow with 10% or more of lymphocytes that exhibit plasmacytoid or plasma cell differentiation, and the presence of typical immunophenotype (surface IgM+ etc.).
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
It is useful to obtain CT scan of the chest, abdomen, and pelvis to assess lymphadenopathy, spleen, and liver size. Bone survey should be obtained only if the patient has bone symptoms or in cases where there is a possibility of an IgM myeloma.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
III. Default Management.
The most important consideration in determining the best management for a patient with suspected or newly diagnosed WM is determining if the patient has symptoms related to the disease and how urgent these symptoms must be addressed. Many patients with WM are asymptomatic and can be observed for months or years after the diagnosis is established.
A. Immediate management.
If a patient has symptoms of hyperviscosity, including confusion, cerebral hypoperfusion, bleeding, or heart failure, steps taken to decrease the serum viscosity must be taken immediately. Since IgM is a large molecule and resides predominantly in the intravascular space, plasmapheresis can efficiently remove this molecule. Patients with life-threatening symptoms of hyperviscosity have a hematologic emergency and should undergo plasmapheresis immediately under the supervision of an experienced clinician. If possible, red blood cell transfusions should be avoided prior to plasmapheresis since they can increase serum viscosity. Once plasmapheresis is completed, patient should be started on chemotherapy to control the disease.
B. Physical Examination Tips to Guide Management.
Symptoms directly related to hyperviscosity should be followed clinically after plasmapheresis. Some patients will require ongoing plasmapheresis until more definitive cytotoxic therapy can be given or takes effect.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
Over the long-term, patients with WM should have serum IgM levels followed (using the same assay/method each time). Serum viscosity should also be followed for patients who develop symptoms related to hyperviscosity. Coagulation parameters may also be useful given the risk of a bleeding diathesis associated with high circulating levels of IgM.
D. Long-term management.
Patients with symptomatic WM require treatment. If symptoms of hyperviscosity are present, plasmapheresis should be considered first-line therapy for initial symptom management. However, plasmapheresis will not control the disease process – the clonal proliferation of B lymphocytes. Cytotoxic therapy is required to control the B lymphocyte expansion. There are no FDA approved drugs for WM, and clinical trials are ongoing to define the best treatment for this disease.
Since the B-lymphocytes in WM uniformly express CD20, a monoclonal antibody directed against CD20 (rituximab) has been used in the last decade for this disease and is recommended as first-line treatment for patients with mildly symptomatic disease. Other choices include alkylating agents, purine analogues, in sequence or in combination, as well as autologous peripheral stem cell transplant in eligible patients. Other novel therapies are being investigated.
E. Common Pitfalls and Side-Effects of Management.
Patients treated with rituximab can have a period of “rebound” or a paradoxical increase in serum IgM levels, persisting for several months after the start of treatment (“rituximab flare”). Patients with high monoclonal IgM should be considered for prophylactic plasmapheresis before treating with rituximab.
IV. Management with Co-Morbidities.
Chemotherapy and plasmapheresis to treat WM should be administered by an experienced hematologist.
A. Renal Insufficiency.
B. Liver Insufficiency.
C. Systolic and Diastolic Heart Failure.
D. Coronary Artery Disease or Peripheral Vascular Disease.
E. Diabetes or other Endocrine issues.
G. Immunosuppression (HIV, chronic steroids, etc.).
H. Primary Lung Disease (COPD, Asthma, ILD).
I. Gastrointestinal or Nutrition Issues.
J. Hematologic or Coagulation Issues.
K. Dementia or Psychiatric Illness/Treatment.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
Patients with WM are at risk for bleeding due to the interference of IgM with clotting factors and platelet function. Patients with WM are also at risk for hyperviscosity syndrome and associated symptoms of encephalopathy, malaise, dizziness and cerebral hypoperfusion.
B. Anticipated Length of Stay.
The length of stay for a patient with WM is related to how quickly plasmapheresis will control symptoms of hyperviscosity and the severity of the disease.
C. When is the Patient Ready for Discharge.
D. Arranging for Clinic Follow-up.
Patients should be seen routinely by an experienced hematologist.
1. When should clinic follow up be arranged and with whom.
Patients with asymptomatic WM should be seen regularly, perhaps every 3-6 months by an experienced hematologist.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
E. Placement Considerations.
Patients who require post-discharge care in a facility such as a nursing home or rehabilitation hospital require close follow up by an experienced hematologist and should be sent to a facility that can manage their unique concerns.
F. Prognosis and Patient Counseling.
Patients with asymptomatic (“smoldering”) WM can live without symptoms attributed to the disease for longer than 5 years. Although the outcomes of this disease are variable, the estimated median survival of symptomatic patients is 5-8 years. Poor prognostic factors include: older age, cytopenias, and an elevated beta-2 microglobulin level.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
Fonseca, R,, Hayman, S. “Waldenström macroglobulinaemia.”. Br J Haematol.. vol. 138. 2007. pp. 700-20.
Oza, A,, Rajkumar, S V. “Waldenstrom macroglobulinemia: prognosis and management.”. Blood Cancer J. vol. 6. 2016. pp. e391
Dimopoulos, MA,, Kastritis, E,, Ghobrial, IM. “Waldenström’s macroglobulinemia: a clinical perspective in the era of novel therapeutics.”. Ann Oncol.. vol. 27. 2016. pp. 233-40.
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
- Waldenstrom's macroglobulinemia
- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Waldenstrom's macroglobulinemia?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Waldenstrom's macroglobulinemia.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management.
- IV. Management with Co-Morbidities.
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure.
- D. Coronary Artery Disease or Peripheral Vascular Disease.
- E. Diabetes or other Endocrine issues.
- F. Malignancy.
- G. Immunosuppression (HIV, chronic steroids, etc.).
- H. Primary Lung Disease (COPD, Asthma, ILD).
- I. Gastrointestinal or Nutrition Issues.
- J. Hematologic or Coagulation Issues.
- K. Dementia or Psychiatric Illness/Treatment.
- V. Transitions of Care.
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up.
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures.
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.