Waldenström Macroglobulinaemia (WM) (bsh 2014)

B and Plasma monotypic cells present.

Usually only B cells typed, as follows:

CD19+, CD20+, CD79a+, CD79b+, CD27+, CD52+

CD5+/-, CD23+/-

CD10-, BCL6-

definition

Waldenstrom Macroglobulinaemia (WM) is a B-cell lymphoproliferative disorder characterized by IgM monoclonal gammopathy and a lymphoplasmacytic lymphoma infiltrate in the bone marrow.

 

Epidemiology

0.5 per 100,000 per year in UK

Male > Female

Median age at diagnosis >70 y.o.

Median survival approx. 60 months

Relative risk for a first degree relative of patient with WM is 20. Absolute risk remains low.

 

Clinical features

Diverse signs and symptoms:

  • Disease burden – cytopenias, organomegaly, constitutional symptoms

  • IgM paraprotein  - hyperviscosity, amyloidosis

  • Autoantibodies – peripheral neuropathy, CHAD, acquired Von Willebrands

 

Classification of IgM Gammopathies

Waldenstroms.png

 IgM MGUS Diagnostic Criteria

Requires all three:

  1. Presence of an IgM paraprotein <30g/l

  2. No evidence of bone marrow infiltration

  3. Absence of signs or symptoms of WM

 

Investigations

Tailored to patient’s symptoms but broadly:

  • FBC, plasma viscosity, serum protein electrophoresis, SFLC

  • U&E, LFT, LDH

  • HIV, Hep B, Hep C

  • B2 microglobulin

  • Anti-myelin-associated glycoprotein titre (MAG antibodies)

  • Nerve conduction studies

  • DAT, Cold agglutinins, Cryoglobulins

  • BMAT + CT staging prior to treatment

 

Bone Marrow Biopsy

  • To demonstrate lymphoplasmacytic infiltrate – these are small lymphocytes showing morphologic differentiation in plasma cells (Immunophenotype = CD138+, MUM1+)

  • Dutcher / Russell Bodies (intranuclear / cytoplasmic Ig bodies)

  • Reactive mast cells may be present (CD117+)

 

ISSWM – International prognostic scoring system

1 point each for:

  • Age >65

  • Hb <115

  • Plt <100

  • B2 microglobulin >3

  • Paraprotein >70g/l

Scoring

  • Low risk: 0-1 excluding age     (87% 5-yr survival)

  • Intermediate risk: 2 factors      (68% 5-yr survival)

  • High risk: >2 factors                (35% 5-yr survival)

N.B. Provides prognostic information but should not guide treatment selection

 

Assessing response

Repeat bone marrow

Response may well be staggered

  • Alkylators, purine anologues and monoclonal antibodies will selectively deplete B cells rapidly with little change in IgM levels until later

  • Bortezomib may show excellent IgM response but persistence of B cells in the marrow.

 

Management

 

Indication to treat

  • Asymptomatic patients can be monitored 3-6 monthly

  • Risk of progression to symptomatic disease is 60% at five years

  • Indications to treat:

    • Constitutional symptoms

    • Symptomatic lymphadenopathy or splenomegaly

    • Hyperviscosity syndrome

    • Cytopenias

    • IgM-related syndromes (CHAD, periph neuropathy etc)

 

Primary Therapy

  • Lack of randomized trials

  • Patients usually elderly, need to weigh risk/benefit and tailor to patient

  • Bendamustine-Rituximab (BR), FR, FCR and Clad-R are all appropriate

  • Omit rituximab from first cycle if IgM >40 or PV >4 to avoid IgM flare

 

Relapse Therapy

  • Asymptomatic patients can be observed

  • Repeat BMAT and CT

  • If still CD20+ then use R-Chemo (can be same as primary therapy if good 1st remission)

  • Bortezomib valid alternative

  • Campath for refractory disease

 

Transplant

  • Maybe autograft in young, fit patients with aggressive disease

  • Maybe allograft in young, fit patients with relapsed aggressive disease (DLBCL transform)

 

Hyperviscosity Syndrome (HVS)

  • Skin/mucosal bleeding, visual disturbance, neurological symptoms, cardiac failure

  • Examine fundi for retinal haemorrhage, venous engorgement

  • No linear relationship between PV and IgM

  • Plasma exchange, 1-2 procedures exchanging 1-1.5 plasma volumes

  • May be indicated in asymptomatic patients if prev HVS and known trigger PV

 

 

IgM-Related Syndromes

 

Peripheral Neuropathy

  • 50% of WM patients

  • But be aware of co-morbidities, IgM may not be responsible

  • MAG peripheral neuropathy

    • Unsteadiness, tremor, vibratory sensory loss

    • Nerve conduction studies show demyelination

    • Anti-MAG antibodies detectable in serum

  • Treatment is with R-Chemo

 

Cold Haemagglutinin Disease (CHAD)

  • Anti-I or Anti-i cold reactive antibodies

  • It is considered a clonal B cell LPD and so most patients will meet criteria for WM

  • Symptoms: Chronic anaemia, Raynauds, acrocyanosis

  • Rituximab monotherapy may be sufficient

 

Cryoglobulinaemia

  • Type 1 almost entirely due to B cell LPDs.

  • Cryoglobulins found in 1% of patients with monoclonal proteins

  • Check for Hep C (Type II cryoglobulinaemia)

  • Rituximab and steroids, or R-Chemo if overt WM also present

 

Others

  • AL Amyloidosis – less common than in other B cell disorders

  • Autoimmune cytopenias – warm AIHA, red cell aplasia