Waldenström Macroglobulinaemia (2014)

B- and Plasma monotypic cells present.

Usually only B cells typed, as follows:

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

CD5+/-, CD23+/-

CD10-, BCL6-

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 of WM:

-       Diverse signs and symptoms:

o   Disease burden – cytopenias, organomegaly, constitutional symptoms

o   IgM paraprotein  - hyperviscosity, amyloidosis

o   Autoantibodies – peripheral neuropathy, CHAD, acquired Von Willebrands

 

Classification of IgM Gammopathies

waldens.png

 

IgM MGUS Diagnostic Criteria – need all three:

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

ii.              No evidence of bone marrow infiltration

iii.             Absence of signs or symptoms of WM

 

 

Investigations

-       Tailored to patient’s symptoms but broadly:

o   FBC, plasma viscosity, serum protein electrophoresis, SFLC

o   U&E, LFT, LDH

o   HIV, Hep B, Hep C

o   B2 microglobulin

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

o   Nerve conduction studies

o   DAT, Cold agglutinins, Cryoglobulins

o   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 for WM

-       1 point each for: Age >65, Hb <115, Plt <100, B2 microglobulin >3, Paraprotein >70g/l

-       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)

-       Provides prognostic information but should not guide treatment selection

 

Assessing response

-       Repeat bone marrow

-       Response may well be staggered

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

o   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:

o   Constitutional symptoms

o   Symptomatic lymphadenopathy or splenomegaly

o   Hyperviscosity syndrome

o   Cytopenias

o   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

o   Unsteadiness, tremor, vibratory sensory loss

o   Nerve conduction studies show demyelination

o   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