Epidemiology

• Relatively rare accounting for approximately 2% of all haematological malignancies.
• The annual incidence is 6.1 per million in white males and 2.5 per million in white females.^[2]
• The incidence appears to be lower in non-Caucasians.
• The median age at presentation is 71 years and the median overall survival is 60 months.^[2]

Risk factors

• The cause is unknown.
• The potential role of viral agents such as the hepatitis C and human herpesvirus 8 remains controversial.^[2]
• Inherited genetic factors may play a role in a minority of patients.

Presentation

• The presentation is very variable, depending on the degree of tumour cell infiltration and the effects of IgM.
• A significant minority of patients are asymptomatic at presentation and are found to have an IgM paraprotein as a coincidental finding during clinical investigations.
• Some patients present with hyperviscosity syndrome, cryoglobulinaemia and autoimmune phenomena such as peripheral neuropathy and cold agglutinin disease.
• Usually presents with fatigue related to anaemia.
• Weight loss.
• Purpura, mucosal and gastrointestinal bleeding, and retinal haemorrhage: due to serum hyperviscosity causing engorged vessels and platelet dysfunction.
• Hepatosplenomegaly and lymphadenopathy.
• Neurological symptoms include altered consciousness, headache, dizziness, peripheral neuropathy, visual disturbance, nausea and vertigo.

Differential diagnosis^[3]

• Benign monoclonal gammopathy
• Chronic lymphocytic leukaemia
• Non-Hodgkin's lymphoma
• Multiple myeloma

Investigations

• Initial investigations should include FBC (anaemia - usually normochromic, normocytic but may be haemolytic; low platelet count), plasma viscosity (raised, marked rouleaux formation, raised erythrocyte sedimentation rate (ESR)), renal and hepatic function, direct antiglobulin test, cold agglutinin titre and cryoglobulins (IgM may cause cryoglobulinaemia), beta-2-microglobulin.
• Serum protein electrophoresis: monoclonal IgM spike in the beta- or gamma-globulin region. IgM paraproteins quantitated by densitometry. The concentration of serum IgG and IgA should be determined and urine analysis for free light chains is recommended. Bence-Jones' proteinuria is positive in approximately 10% of cases.
• Bone marrow examination (hypercellular and infiltrated by the plasmacytic lymphocytes):
  • Is essential to differentiate Waldenström's macroglobulinaemia (WM) confidently from other lymphoproliferative disorders in symptomatic patients.
  • The value of bone marrow examination in asymptomatic patients is less clear.
  • If bone marrow examination is required then trephine biopsy is preferred because the pattern of infiltration is important.
• Immunophenotypic studies are recommended in all cases.
• Cytogenetic analysis is of little value. Deletions of 6q appear to be the most common structural abnormality occurring in up to 50% of patients but their prognostic significance remains unclear.^[2]
• CT scan is advised as a baseline for all patients prior to chemotherapy but is not required in asymptomatic patients unless the result would influence the need for chemotherapy.
• Patients who present with peripheral neuropathy should have nerve conduction studies and anti-myelin-associated-glycoprotein (anti-MAG) serology.
• Additional serological investigations to assess for autoantibody specificity against other neural antigens such as gangliosides and sulphatide may be appropriate in those patients with severe neuropathy and negative MAG serology.^[2]

Management

• Supportive care: blood transfusions, antibiotics for infections. Hyperviscosity syndrome should be treated promptly by plasmapheresis.^[3]
• The usual criteria for starting active treatment consist of:
  • Clinical evidence of adverse effects of the paraprotein, eg hyperviscosity with neurological or ocular disturbance, peripheral neuropathy, nephropathy, amyloidosis, symptomatic cryoglobulinaemia.
  • Marrow suppression (haemoglobin less than 10 g/dL, or platelet count less than 100 x 10⁹/L).
  • Progression to high-grade lymphoma.
  • Development of constitutional symptoms.^[2]
• Drug treatment: when treatment is indicated, the three main choices for systemic treatment are chlorambucil, the nucleoside analogues fludarabine or cladribine and the monoclonal antibody rituximab.^[4][5]
• Alkylating agents:
  • Chlorambucil with or without prednisolone is frequently used as the initial therapy.
  • Cyclophosphamide alone or in combination is also effective but there are no comparative data with chlorambucil.
• Patients who are primarily refractory or acquire resistance to alkylating agents may be candidates for combination therapy, purine analogues or antibody therapy.^[2]
• Purine analogues: fludarabine and cladribine (2-chlorodeoxyadenosine (2-CDA)).
  • Both fludarabine and cladribine are effective therapy for patients who are primarily resistant or who relapse after alkylating agents.
  • Purine analogues and alkylating agents are known to be synergistic.
• Plasma exchange is indicated for the acute management of patients with severe problems due to a circulating paraprotein, eg hyperviscosity syndrome, peripheral neuropathy associated with an IgM paraprotein (evidence of benefit is weak) and cryoglobulinaemia, and for intractable congestive cardiac failure.
• The anti-CD20 monoclonal antibody rituximab is active in the treatment of Waldenström's macroglobulinaemia (WM). Response rates vary between 23% and 40% irrespective of whether patients have been previously exposed to chemotherapy.
• Thalidomide treatment has achieved response rates of 25%.^[2]
• Interferon alfa given for 6 months to a mixture of untreated and pretreated patients has produced a response rate of 50% with a median duration of response of 27 months.^[2]
• High-dose therapy with autologous stem-cell transplantation appears to be effective even in patients with advanced and resistant disease.^[6]

Complications

• Vision impairment.
• Gastrointestinal bleeding.
• Alterations in mental state, possibly progressing to coma.
• Congestive heart failure.

Prognosis

• Highly variable clinical outcome. A significant minority of patients remain asymptomatic and never require therapy while others have advanced lymphoma requiring therapy.
• Adverse prognosis is associated with:^[7]
  • Advanced age, male sex.
  • General symptoms (eg weight loss), lymphadenopathy, hepatomegaly.
  • Previous therapy, disease duration longer than 1 year.
  • Low haemoglobin, low white cell count, low platelets.
  • High beta-2-microglobulin; low serum IgM, low albumin, presence of cryoglobulinaemia, high ESR.