Waldenström Macroglobulinemia: Definition and Clinical Overview
Waldenström macroglobulinemia (WM) is a rare B-cell lymphoproliferative disorder characterized by bone marrow infiltration with lymphoplasmacytic cells and the presence of monoclonal immunoglobulin M (IgM) protein in the serum. 1
Epidemiology and Pathophysiology
- Incidence: WM accounts for 1-2% of hematological neoplasms with an age-adjusted incidence rate of 3.4 per million in males and 1.7 per million in females in the United States 1
- Demographics:
- Predominantly affects the elderly (median age 63-75 years)
- Male predominance
- Higher prevalence among Caucasians than African-Americans 1
- Genetic factors:
Diagnostic Criteria
The diagnosis of WM requires both:
- Presence of monoclonal IgM protein in the serum (confirmed by immunofixation)
- Bone marrow infiltration by lymphoplasmacytic cells consistent with lymphoplasmacytic lymphoma (LPL) 1
Important diagnostic considerations:
- Monoclonal IgM without bone marrow LPL is not WM
- LPL without monoclonal IgM is not WM 1
Diagnostic Workup
Essential Tests:
- Complete blood count with differential
- Serum chemistry including LDH and albumin
- Serum protein electrophoresis with immunofixation
- IgM quantification
- Beta-2 microglobulin level (prognostic value)
- Bone marrow aspiration and biopsy with:
Additional Tests:
- Testing for cold agglutinins and cryoglobulins
- Coagulation parameters
- Coombs test (for hemolysis)
- CT imaging if clinically indicated or when considering therapy 1, 2
Clinical Manifestations
Common symptoms and complications include:
- Fatigue (often related to anemia)
- B symptoms (fever, night sweats, weight loss)
- Hyperviscosity syndrome (visual disturbances, headache, dizziness, bleeding)
- Peripheral neuropathy (often demyelinating, symmetrical sensory neuropathy)
- Organomegaly (hepatomegaly, splenomegaly)
- Lymphadenopathy
- Cryoglobulinemia (Raynaud-like symptoms, acrocyanosis)
- Cold agglutinin disease
- Amyloidosis (uncommon) 2
Indications for Treatment
Asymptomatic patients should be observed without therapy. Treatment is indicated for:
- Recurrent fever, night sweats, weight loss, fatigue
- Hyperviscosity syndrome
- Symptomatic or bulky lymphadenopathy (≥5 cm)
- Symptomatic hepatomegaly/splenomegaly
- Symptomatic organomegaly or tissue infiltration
- Peripheral neuropathy due to WM
- Cytopenias (hemoglobin <10 g/dL, platelets <100 × 10^9/L)
- Amyloidosis
- Symptomatic cryoglobulinemia
- Cold agglutinin disease 1, 2
Prognostic Factors
The International Prognostic Scoring System for WM (IPSSWM) stratifies patients into three risk groups based on:
- Age >65 years
- Hemoglobin ≤11.5 g/dL
- Platelets ≤100 × 10^9/L
- Beta-2 microglobulin >3 mg/L
- Serum monoclonal protein >70 g/L 1
Five-year survival rates:
- Low risk: 87%
- Intermediate risk: 68%
- High risk: 36% 1
Treatment Approaches
Treatment should be tailored based on:
- Need for rapid disease control
- Presence of specific complications
- Patient's age and comorbidities 3
First-line Treatment Options:
- Rituximab-based combinations are the mainstay of therapy:
- DRC (dexamethasone, rituximab, cyclophosphamide)
- BR (bendamustine, rituximab)
- BoRD (bortezomib, rituximab, dexamethasone) 4
Relapsed/Refractory Disease:
- BTK inhibitors (ibrutinib)
- Alternative rituximab combinations
- Purine nucleoside analogs
- Proteasome inhibitors
- Autologous stem cell transplantation in select cases 5, 4
Special Considerations:
- Hyperviscosity syndrome requires immediate plasmapheresis before initiating rituximab-containing regimens 2
- IgM flare can occur after rituximab treatment, potentially exacerbating hyperviscosity 2
- Peripheral neuropathy may require neurologist consultation and specialized treatment approaches 2
WM is an incurable but typically indolent disease with a median survival of several years. With appropriate management, many patients can achieve prolonged disease control and good quality of life.