Waldenström's Macroglobulinaemia

Waldenström's macroglobulinaemia (WM) is a chronic, indolent, B-cell lymphoproliferative disorder characterised by an IgM monoclonal paraprotein and bone marrow infiltration by lymphoplasmacytic cells (lymphoplasmacytic lymphoma - LPL).^{[1, 2]}

The clinical manifestations are numerous and are caused by tumour infiltration of bone marrow and organs as well as the effects of the IgM paraprotein which can lead to hyperviscosity syndrome, amyloidosis and peripheral neuropathy.^[2]

Epidemiology

• WM is relatively rare, accounting for 1-2% of haematological neoplasms.^[3]
• Incidence rate is 0.55 per 100,000 per year in the UK.^[2]
• Males are affected more than females.^{[4, 5]}
• There is a lower incidence in non-white people.
• Median age at presentation is >70 years.^{[5, 6]}

Aetiology

• The exact cause is unknown.
• The potential role of viral agents such as the hepatitis C and human herpesvirus 8 remains controversial.
• An individual's risk is increased if there is a personal or family history of autoimmune, inflammatory or infective disorders.^[2]
• Particular association has been found with Sjögren's syndrome and autoimmune haemolytic anaemia, suggesting a possible shared susceptibility.^{[7, 8]}
• Relatives of people with WM and other B-cell disorders have an increased risk of developing WM.^{[9, 10]} However, the absolute risk for first-degree relatives remains low and systematic screening of family members is not indicated.^[2]

Presentation

The presentation is variable depending on:

1. The degree of bone marrow, spleen and lymph node infiltration by neoplastic lymphoplasmacytic cells. These cells may also (less commonly) infiltrate the liver, lungs, gastrointestinal tract, kidneys, skin, eyes, and central nervous system, causing various different symptoms.
2. The effects of the IgM which can lead to hyperviscosity syndrome, type I and type II cryoglobulinaemia, coagulation abnormalities, peripheral neuropathy, cold haemagglutinin disease (CHAD) and primary amyloidosis.

A significant minority of patients is asymptomatic at presentation. These patients are found to have an IgM paraprotein as a coincidental finding during clinical investigations.

Symptoms and signs may include:

• Fatigue and weakness.
• Weight loss.
• Fever.
• Purpura, mucosal and gastrointestinal bleeding, and visual disturbance due to hyperviscosity.
• Neurological symptoms including altered consciousness, headache, dizziness, peripheral neuropathy, Raynaud's phenomenon, nausea and vertigo.

Differential diagnosis

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

Investigations

According to the British Committee for Standards in Haematology (BCSH) guidelines, these may include:^[2]

Laboratory work-up

• FBC (with flow cytometry if lymphocytosis is present - confirms peripheral blood involvement).
• Plasma viscosity (may not be routinely available in all UK laboratories, in which case the diagnosis of high plasma viscosity remains a clinical one).
• Serum protein electrophoresis and immunofixation.
• Quantification of IgM paraprotein by densitometry.
• Quantification of IgG and IgA.
• Urea and creatinine.
• LFTs.
• Lactate dehydrogenase.
• Beta-2 microglobulin.
• Direct antiglobulin test.
• Hepatitis B and C status (because chemo-immunotherapy using rituximab can re-activate hepatitis B and/or hepatitis C virus infection).

And if the clinical picture dictates:

• Nerve conduction studies and anti-myelin-associated glycoprotein antibodies titre (if neuropathy is present).
• Cold agglutinins.
• Cryoglobulins.

The same method and same laboratory should be used for sequential paraprotein concentration assessment.

Bone marrow assessment

• Marrow infiltration by LPL gives a definitive diagnosis of WM.
• Bone marrow assessment should be performed in all symptomatic patients.
• It should also be considered in those who are asymptomatic with presence of an IgM paraprotein (a threshold of 10 g/L has been suggested by some guidelines).^[11] However, consider at lower IgM concentrations if there is suspicion of cytopenia, lymphadenopathy, splenomegaly or an IgM-related syndrome such as peripheral neuropathy or amyloidosis.^[2]
• Trephine biopsy as well as bone marrow aspirate cytology more accurately assesses the degree and pattern of infiltration.
• Immunophenotypic studies should be carried out in all cases.

Cytogenetic analysis^[1]

• This is not routinely needed for the diagnosis and assessment of WM.
• There are no disease-defining cytogenetic abnormalities.
• 50% of patients have deletion of chromosome 6q but its effect on survival outcome is unclear.^{[12, 13, 14]}
• Smaller numbers of WM patients have deletion of TP53 and they seem to have a poor outcome.^[14]
• Further research and clinical trials are needed to assess the prognostic significance of these two deletions.

Imaging

• Baseline CT of the chest, abdomen and pelvis are recommended in all symptomatic patients before starting chemotherapy.^[2]

Management

• Those who are asymptomatic at presentation can be observed and monitored at 3- to 6-monthly intervals - a 'watch and wait' approach.^[2]
• 59% will progress to symptomatic disease at five years.^[15]
• Indications for commencing treatment include:^[2]
• Constitutional symptoms.
• Symptomatic lymphadenopathy or splenomegaly.
• Hyperviscosity syndrome.
• Haematological suppression due to marrow infiltration.
• IgM-related syndromes - eg, peripheral neuropathy and cold haemagglutinin disease (CHAD).

Primary therapy^[2]

According to the BCSH guidelines:

• A rituximab-containing regimen should be used. The choice will depend on renal function, other comorbidities, suitability for stem cell transplantation, etc. Regimens may include:
• Dexamethasone + rituximab + cyclophosphamide (DRC).
• Bendamustine + rituximab (BR).
• Fludarabine + rituximab (FR).
• Fludarabine + cyclophosphamide + rituximab (FCR).
• Cladribine + rituximab (Clad-R).
• Chlorambucil is suitable treatment for elderly frail patients.
• All patients receiving rituximab should have sequential IgM monitoring because of the risk of IgM flare which can lead to hyperviscosity. They should have clinical assessment for hyperviscosity syndrome and monitoring of plasma viscosity if it is available.
• Rituximab should be deferred if IgM M-protein >40 g/L and/or plasma viscosity >4 centipose (cP).
• There is not enough evidence to support maintenance rituximab therapy.

Therapy at relapse^[2]

• Before any treatment is started, a repeat bone marrow aspirate and trephine assessment plus CT scanning should be carried out.
• If a person is asymptomatic despite serological evidence of progression, they can be observed, with no treatment initiated until symptoms occur.
• If CD20 is expressed, a rituximab-containing regimen should be started (as above).
• Re-treatment with the same primary therapy may be carried out.
• Regimens containing bortezomib can be used in relapse. Neurological toxicity is a risk with bi-weekly schedules, so weekly regimens are the preferred option. Herpes zoster virus prophylaxis is advised.
• Alemtuzumab may also be used in refractory disease. Monitoring for cytomegalovirus (CMV) reactivation is advised in this situation.

Transplantation^[2]

• Autologous stem cell transplantation may be an option for the treatment of relapse in young fit patients with aggressive disease. This can often lead to prolonged periods of disease control but not cure.^{[16, 17]}
• Allogenic stem cell transplantation may be an option for the treatment of relapse in selected young patients with aggressive disease.
• Stem cell transplantation should only be carried out in chemosensitive disease and when there is at least a partial response to re-induction therapy.

Supportive care^[2]

• Infective complications are common and so antimicrobial prophylaxis should be considered for those who develop recurrent bacterial infections.
• Immunoglobulin replacement therapy may be considered for those with hypogammaglobulinaemia and recurrent bacterial infections.
• Pneumocystis and herpes prophylaxis should also be considered depending on the treatment regimen being used.
• Vaccination against Streptococcus pneumoniae and Haemophilus influenzae type B is encouraged at time of diagnosis, as is annual vaccination against seasonal influenza.
• Live vaccines should be avoided.
• Any vaccination two weeks before, during and for six months after chemo-immunotherapy should be avoided.

Monitoring response to treatment

• Follow-up should include history, physical examination, FBC, routine chemistry and quantification of IgM.^[3]
• Clinical benefit may be experienced in some without a significant IgM response. Equally, reductions in IgM are not always associated with symptomatic improvement.^[2]
• Bone marrow assessment is recommended if IgM levels do not fall many months into treatment.
• There may be significant B-cell depletion in the bone marrow with poor IgM response in some cases and with some treatment regimens. The reverse may also be true.

Complications

Histological transformation

• Transformation to diffuse large B-cell lymphoma occurs in 5-10% of patients.
• It may be characterised by rapidly enlarging lymph nodes, extra-nodal disease and marked rise in serum lactate dehydrogenase.
• Tissue biopsy is needed for diagnosis.^[2]

Hyperviscosity syndrome

Caused by excessive levels of IgM.^[3] Symptoms include:

• Retinopathy leading to visual disturbance.
• Neurological symptoms.
• Skin and mucosal bleeding.
• Cardiac failure (rare).

Diagnosis

• Retinal haemorrhages and retinal venous engorgement ('sausaging') can be seen on fundoscopy.^[3]
• High IgM.
• High plasma viscosity (if available; hyperviscosity syndrome rarely occurs below 4 cP).

Treatment

• Plasma exchange.

Peripheral neuropathy

• Around 50% of patients will develop this.^[18]
• Can be attributable to activity of the monoclonal IgM to anti-myelin-associated glycoprotein (MAG).

Symptoms include^[19]

• Tremor.
• Unsteadiness.
• Vibratory sensory dysfunction but conservation of motor function.

Investigations

• Perform neurological examination in all patients with an IgM paraprotein.^[2]
• Nerve conduction studies show a characteristic demyelinating pattern.
• High serum anti-MAG antibodies are present.

Treatment^[2]

• Consider chemotherapy if there is disabling or rapidly progressing anti-MAG neuropathy.
• A rituximab regimen is appropriate.

Cold haemagglutinin disease (CHAD)

• This is a rare autoimmune haemolytic anaemia.
• It is due to a cold reactive autoantibody directed against I/i red cell antigens that agglutinates red cells at low temperatures.^[2]
• Most patients with CHAD will have an IgM paraprotein and fulfil the diagnostic criteria for WM.
• Clinical features include a chronic anaemia, Raynaud's phenomenon and other cold-induced symptoms.
• Rituximab-based therapy is recommended for those with symptomatic CHAD.^[2]
• If performance status and renal function allow, fludarabine treatment should also be considered in addition.^[2]

Cryoglobulinaemia

• Cryoglobulins are immunoglobulins that precipitate on cooling.
• 1% of people with monoclonal proteins will have cryoglobulins.^[20]
• Type I cryoglobulins do not usually have clinical consequences.
• Those with type II cryoglobulinaemia all have a clonal B-cell disorder with overt WM being present in a minority.^[2]
• Type II cryoglobulinaemia can cause purpura, skin ulceration, peripheral neuropathy, arthralgia and glomerulonephritis.^{[20, 21]}
• Underlying hepatitis C virus infection may be present in some people with type II cryoglobulinaemia and screening for it is therefore appropriate.^[2]
• Rituximab and corticosteroids show good disease control and can be used to treat type II cryoglobulinaemia.^[21]
• If overt WM is present, standard WM treatment may be used.^[2]

Primary amyloidosis

• This is a rare complication of IgM paraproteinaemia.^[2]
• Amyloidosis of the heart, liver, kidney, lungs and/or joints can occur.

Venous thromboembolism

• An increased risk has been shown in those with WM.
• Further research data are required before statements on prophylaxis can be made.^[2]

Prognosis

• Median survival is around 60 months.^{[5, 6]}
• The international prognostic scoring system for WM (ISSWM) should be recorded in all patients at presentation but there is no evidence that it should influence treatment decisions.^[2] It is based on five key adverse prognostic features:

• Age >65 years.
• Haemoglobin ≤115 g/L.
• Platelet count ≤100 x 10⁹/L.
• Beta-2-microglobulin >3 mg/L.
• Paraprotein concentration >70 g/L.
• Low-risk disease: 0-1 adverse features excluding age; five-year survival rate = 87%.
• Intermediate-risk disease: 2 adverse features or age; five-year survival rate = 68%.
• High-risk disease: >2 adverse features; five-year survival rate = 36%.