Waldenström Macroglobulinaemia (WM) (bsh 2014 / 2022)

B and Plasma monotypic cells present.

Usually only B cells typed, as follows:

CD19+, CD20+, CD22 weak+, CD25+, CD79a+, CD79b+, CD27+, CD52+

CD5+/-, CD23+/-

CD10-, BCL6-

MYD88 Mutation (>90% of cases)

definitions

Waldenstrom Macroglobulinaemia (WM) = 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. Family screening not recommended as absolute risk remains low.

Clinical features

Diverse signs and symptoms:

Disease burden – cytopenias, organomegaly, constitutional symptoms
IgM paraprotein - hyperviscosity, amyloidosis
Extramedullary - pleural effusions, renal, CNS
Autoantibodies – peripheral neuropathy, CHAD, acquired Von Willebrands

Classification of IgM Gammopathies

IgM MGUS Diagnostic Criteria

Requires all three:

Presence of an IgM paraprotein <30g/l
No evidence of bone marrow infiltration
Absence of signs or symptoms of WM

IgM MGUS carries a 1-2% per year risk of developing into WM. May also occur in presence of other LPD’s.

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
DAT, Cold agglutinins, Cryoglobulins
BMAT + CT staging prior to treatment

Symptom Specific investigations to consider:

Bleeding: Coag screen / Factor assays / VWF if bleeding symptoms
Periph neuropathy: Anti-myelin-associated glycoprotein titre (MAG antibodies)
?Neurological involvement (Bing-Neel): Lumbar puncture
?Amyloidosis: Congo red stains, biopsy of affected tissue
?POEMS: VEGF / Nerve conduction studies
?Schnitzler’s Syndrome: Skin biopsy of chronic urticarial rash

Bone Marrow Aspirate and Trephine

Aspirate for flow cytometry to identify B-cell phenotype

Trephine to demonstrate lymphoplasmacytic infiltrate – these are small lymphocytes showing variable morphological differentiation into plasma cells.
Dutcher / Russell Bodies (intranuclear / cytoplasmic Ig bodies)
Reactive mast cells may be present (CD117+)
N.B. The level of IgM pp correlates with the degree of plasma-cell differentiation more than it does the extent of overall marrow infiltration

Molecular Diagnostics

MYD88 mutation (L265P point mutation) present in 90-95% of cases. But not unique to WM.
CXCR4 mutation (30-40%)
TP53 mutations (10%)

ISSWM – International prognostic scoring system

N.B. Pre-dates modern treatments. May provides prognostic information but should not guide treatment decisions

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)

Assessing response

Repeat bone marrow

Depth of response may predict PFS but this may not be equal across different treatment regimens (discussed in detail in guideline)

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

Options listed below will often have to be balanced against patient fitness/frailty. In clinical trials, the mortality rate for non-WM related causes of death has repeatedly been seen to be high.

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)

Supportive Care

Hepcidin-related iron deficiency anaemia may occur - consider IV iron for anaemia with TSats <12% and otherwise low disease burden.
Aciclovir prophylaxis if on chemo
Co-trimoxazole prophylaxis if on BTKi
Offer seasonal flu and Covid vaccines
Offer pneumococcal vaccination - PCV13 followed by PPV23 at least 2 months later
Increased risk of VTE in WM patients. Evidence not sufficient for a definitive need for thromboprophylaxis but consider this increased risk at times of additional risk factors, e.g. surgery

Primary Therapy

Lack of randomized trials
Patients usually elderly, need to weigh risk/benefit and tailor to patient
Options
- Bendamustine-Rituximab (BR) & Dex/Cyclo/Ritux (DCR) are two most common UK choices
- Rituximab monotherapy, Chlorambucil
- (Detailed data on outcomes are in the guideline)
- (Bortezomib-based and BTKi regimens not necessarily funded in UK first line)
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
Options
- BTK inhibitors - Zanubrutinib expected to be approved by NICE shortly (as of sept 2022) for patients who have received one prior line of treatment AND who would also be fit for R-Bendamustine.
- R-Chemo (can be same as primary therapy if good 1st remission)
- Bortezomib (or other proteosome inhibitors) valid alternative
- Campath for refractory disease
- Novel agents under investigation - venetoclax, pembrolizumab, daratunumab

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)

Consider if plasma viscosity >3mPas (Prev. cut off of >4 missed half of patients)
Rare to occur if IgM pp <30g/l, but no linear relationship between PV and IgM
Skin/mucosal bleeding, visual disturbance, neurological symptoms, cardiac failure
Examine fundi for retinal haemorrhage, venous engorgement
Plasma exchange, 1-3 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

bing-neel syndrome (BJH 2019)

Intro

Infiltration of the CNS with WM cells, causing neurological deficits
1% of WM patients

History

First described in 1936 by Jens Bing and Axel von Neel, 8 yrs prior to Jan Waldenstrom’s 1st case report.

Clinical Features

Can occur at any time – presenting feature / in absence of systemic disease / during treatment
Balance & gait abnormalities most common deficit (approx. 50% of patients)
Cranial nerve deficits, cognitive impairment, sensory deficit, headache, back/limb pain, limb motor deficits, altered mental status.

Prognosis

Limited data – 5-year OS 70% in a 2015 review

Diagnosis

Radiology – MRI brain+spine - leptomeningeal disease seen in majority of patients
CSF – flow cytometry, PCR (for MYD88 mutation +/- IGH gene rearrangement)
Brain biopsy if appropriate

Treatment

No standardized treatment protocol, the authors of the BJH review favour ibrutinib 1st line
Traditional CNS penetrating drugs – fludarabine, methotrexate, cytarabine, bendamustine
Newer CNS penetrating agents – ibrutinib
?Future treatments to watch out for – marizomib, zanubrutinib, venetoclax, dastinib