Véronique Leblond

Hôpital Pitié-Salpêtrière Paris

France

Management of IgM-related

diseases UKMF Spring Day London, March 19th

M-component-related diseases “Dangerous  small  B-cell  clones”    

Merlini G , and Stone M J Blood 2006;108:2520-2530 ©2006 by American Society of Hematology

2nd  International  Workshop  on  Waldenström’s  Macroglobulinemia,  Athens  2002

Classification of WM and related disorders

Monoclonal Bone marrow Symptoms Symptoms due IgM protein 1 infiltration 2 due to IgM 3 to lymphoma 4 Symptomatic WM + + + + Asymptomatic WM + + - -

IgM-related + - + - disorders

MGUS + - - -

1 IgM concentration rarely>3 g/dl in MGUS. 2 Unequivocal diagnosis of lymphoplasmacytic lymphoma according to the WHO classification. Patient with equivocal evidence (eg, clonal B cells detected by PCR or flow cytometry with no morphological evidence of lymphoma) should be classified as MGUS until further data will become available). 3 eg, hyperviscosity, symptomatic crioglobulinemia, amyloidosis, cold agglutinin disease, peripheral neuropathy. 4 eg, B-symptoms, cytopenias, organomegaly.

Owen et al, Semin Oncol 2003

IgM- related manifestations MEDIATED BY THE IMMUNOLOGICAL EFFECTS OF IGM

Type II Cryoglobulinemia

Cold Agglutinin disease

Peripheral Neuropathies

MEDIATED BY THE PHYSICOCHEMICAL PROPERTIES OF IGM

Type I cryoglobulinemia Systemic deposition of monoclonal IgM (skin, kidney) Interaction with circulating proteins (acquired VW syndrome) Amyloidosis Hyperviscosity syndrome

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Cryoglobulinemias (Brouet JC Am J Med 1974)

Cryoglobulins: Immunoglobulins that precipate or gel at temperature below 37°C and re-dissolve at

37°C Type I: physicochemical properties of IgM

(20%)

Type II: Mixed cryoglobulimemia Immune complexes IgM-IgG

monoclonal IgM anti-IgG (80%)

Type III: polyclonal

Type I cryoglobulinemia (Terrier B et al Medicine 2013)

Type II cryoglobulinemia (Terrier B et al Blood 2012)

• Fatigue • Skin ( purpura, ulcers, necrosis ,

acrocyanosis etc..) • Joint arthralgia • Neuropathy • Kidney manifestations

Clinical Manifestations

Raynaud phenomenon acrocyanosis

Type I : Cold sensitivity

livedo

Skin manifestations

Skin manifestations: purpura, ulcers

Skin manifestations: purpura, necrosis

Histopathologic examination of a cutaneous lesion showing a perivascular inflammatory infiltrate, composed mainly of polymorphonuclear neutrophils, associated with fibrinoid necrosis of the vascular wall and leukocytoclasia Hyalin thrombi in the vessels occluding small vessels

CRYOGLOBULINEMIA Kidney manifestations

30% of the patients proteinuria with microscopic hematuria

Cryoglobulinemic Glomerulonephritis: membranoproliferative glomerulonephritis

Renal-Biopsy Specimen. Glomeruli have pseudothrombi (arrows), swollen endothelial cells, and endocapillary inflammatory cells ( A and B) Vessels with reactive endothelial cells, mural cryoglobulin deposits extravasated red cells (arrowhead), and karyorrhectic debris are present (C). IgM immunofluorescence revealed granular staining of capillary loops and positive pseudothrombi. An electron micrograph shows a subendothelial deposit with a tubular substructure.

Multiple mononeuropathy or Asymetric polyneuropathy sensory (burning sensation, paresthesia ) ataxia) or motor and sensory Skin manifestations++++ Neuropathic pains

CRYOGLOBULINEMIA Peripheral Neuropathy

CRYOGLOBULINEMIA Peripheral Neuropathy

diagnostic

•Clinical manifestations •Electrophysiological evaluation: axonal pattern

•Biological findings

•Nerve biopsy

Cryoglobulinemic vasculitis

2 to 6%: gastrointestinal tract with intestinal ischemia

5%: pulmonary manifestations with intra alveolar haemorrhage

CRYOGLOBULINEMIA : RARE MANIFESTATIONS

Biology

• Monoclonal IgM • Complement activation (Type II> Type I ) • Rheumatoid factor activity (Type II) • Thermal amplitude is more important than cryocrit • Cryoglobulin can raise serum viscosity • Cryocrit measures the amount of cryoglobulin • HCV infection must be researched in Type II

At > 37°C : from the patient to the laboratory Then to be studied at 4°C

Cryo +

CRYOGLOBULIN DETECTION AND CHARACTERISATION

Cryoglobulin and viscosity

Temperature dependance of relative serum viscosity from a patient with WM and cryoglobuliemia

Cryo with large amount (1-30g/l)

EP/IF: monoclonal IgM

Rheumatoid factor negative

Complement activation: not constant

Type I

cryoglobulinemia Capillary obstruction with precipitation

of the cryoprotein

Type II

cryoglobulinemia Systemic vasculitis by deposition of immune complexes on the wall of small vessels with activation of

complement cascade

EP/IF: monoclonal IgM often complexed with Fc of polyclonal IgG

with rheumatoid factor activity and complement activation

Cryo  with  small  amount      ≤  1  g/l

(CH50, C4 C3 ± )

Type I cryoglobulinemia skin thrombi without vasculitis

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Schnitzler syndrome

Efficacy  of    “IL-1 receptor

antagonist” (Anakinra (Kineret*)

100 mg/day SC)

Simon et al, Allergy. 2013;68:562-8

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Systemic deposition of monoclonal IgM The monoclonal protein can deposit in several tissues, including:

• Skin (macroglobulinemia cutis, skin papules, and nodules),

• Intestine (diarrhea, malabsorption, and gastrointestinal bleeding)

• Kidney (proteinuria)

Cutaneous macroglobulinosis ( IgM storage papules - macroglobulinosis cutis) Deposition of eosinophilic, immunoglobulin-derived material in the dermis.

Shiny, skin-colored papules on the extensor forearm.

Asymptomatic erythematous papules and plaques on the arm

Camp et al, J Cutan Pathol 2012: 39: 962–970

Cutaneous macroglobulinosis ( IgM storage papules and macroglobulinosis cutis)

Occlusion of vessels by a pink homogenous precipitate composed of IgM paraprotein (hematoxylin/eosin stain)

The material is PAS-positive and is also deposited in the extravascular space

The material is intensely IgM positive by immunohistochemistry

Renal lesions include: • Intracapillary monoclonal deposits

disease with granular, electron-dense IgM thrombi occluding capillary lumens;

• Atypical membranoproliferative GN;

• LC amyloidosis ± deposits;

• Acute tubular necrosis;

• CD20 lymphomatous infiltration

Audard et al, Clin J Am Soc Nephrol 2008;3:1339–1349

Renal lesions associated with IgM

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Neuropathy and monoclonal IgM: 2 types: demyelinating or axonal

• 20 to 40% of patients with Waldenström’s macroglobulinemia

(Nobile et Orazio et al 1987, 1994, Levine et Pestronk 2006)

• 5% of IGM « MGUS » AntiMAG demyelinating neuropathy : 25 to 60% of

the patients (Baldini et al 1994, Nobile et Orazio et al 1987)

Axonal neuropathy (30% )

Peripheral Neuropathy (PN) and IgM

Anti-MAG neuropathy:

Most frequent

Sensory neuropathy with ataxia with segmental demyelinisation

Anti MAG neuropathy: easy diagnosis

Electrophysiological pattern: Demyelinating neuropathy

Paresthesia Hypoesthesia Symetric Distal lower limbs weakness > proximal lower limbs weakness

Pain lower limbs burning sensation

Ataxia

Motor deficit Painful distal sensorimotor neuropathy Shaking Upper limbs disease

Anti MAG ++

MAG antibody staining

The antibody recognizes a nerve sugar on MAG called HNK-1

IgM anti-ganglioside Motor neuropathy with muscle atrophy  “Amyotrophic  Lateral  

Sclerosis-like”  (efficacy  of  Ig  IV  #  90%)

“CANOMAD”  syndrome   C hronic A taxic N europathy O phtalmoplegia M Protein A gglutination D isialosyl gangliosides antibodies ( GD1b,  G  D1a,  GT1b  etc…)  (present  on the red blood cell glycophorin

Peripheral Neuropathy (PN) and IgM

Negative Anti MAG neuropathy: difficult diagnosis Chronic inflammatory demyeliniting polyneuropathy (CIDP) like neuropathy

Amyloïd neuropathy

cryoglobulinemic neuropathy

Motor neuropathy anti GM1/GM2 ab

tumoral nerve infiltration

Undetermined neuropathy

EMG: electrophysiological results

AXONAL DEMYELINATING

Perivascular lymphocytic infiltrate

Symptoms and signs of neuropathy and IGM

Usual biological evaluation Search for anti-MAG and

antiganglioside Ab + EMG Demyelinating

CIDP Anti-MAG neuropathy

*Red flag symptoms

Axonal

Anti GM1/GM2/GD1b

axonal neuropathy

Search for amyloid deposit

in tissues

Search for active cryoglobulinemia

Nerve biopsy

Amyloid neuropathy

Tumoral infiltration

Vasculitic neuropathy

Cryoglobulinemic neuropathy

Clinical motor Involvement++ + Anti-GM1/GM2/ GD1b Ab+

Anti-MAG

Ab- Anti-MAG Ab+

+ - +

-

Yes

No

Consider coincidental neuropathy Follow-up

*Red flag features are: pain, multifocal topography, rapidly evolving course, cranial nerve involvement, dysautonomia, weight loss, cutaneous signs, heart/kidney/lung involvement, abnormal serum free light chain concentration and ratio. ( Viala K, J Peripher Nerv Syst. 2012)

Systemic effects of monoclonal IgM

Cryoglobulinemia Schnitzler syndrome Systemic deposition of monoclonal IgM Peripheral neuropathies Treatment options

Plasmapheresis • Plasmapheresis is a safe and well-tolerated procedure.

• Indication in complication mediated by the physicochemical properties of IgM (hyperviscosity, interaction protein-protein, type I cryoglobulinemia, IgM deposit)

However, plasmapheresis should be considered as interim therapy

Stone & Bogen, Blood 2012;119:2205-2208

Pre

-Phe

resi

s P

ost-P

here

sis

Type I Cryoglobulinemia in a patient with WM

Treon S. 2013

Treatment targeting B-cell clone

• Must be used in IgM-related diseases

• Immunotherapy alone (anti CD20)

• Chemo immunotherapy according to WM treatment algorithm

Asymptomatic WM Symptomatic WM*

Hyperviscosity

Plasmapheresis

Yes No

mild Rituximab/ chemotherapy e.g. (DRC)

Rituximab/chemotherapye.g. :Dexamethasone + rituximab+ cyclophosphamide (DRC)

Rituximab/Bendamustine

Fludarabine/Rituximab (FR)

Rituximab/ proteasomeinhibitor

Bortomib/rituximab/ dexametahasone

Observation

Medically Fit

Consider clinical trial

Symptomatic WM*

Medically Non-Fit

Consider clinical trial

Single agent therapye.g. RituximabChlorambucilFludarabine

Bortezomib combinatione.g. Bortezomib/Rituximab

TREATMENT ALGORITHM: WM in first line ( How to manage WM, Buske C, Leblond V. Leukemia

2013)

According to the complication

• In Cryoglobulinemia : cold avoidance (  Côte  d’Azur..),  warmed-up blood transfusion  …

• In chronic inflammatory demyeliniting polyneuropathy (CIDP) like neuropathy and anti ganglioside neuropathy interest of Immunoglobulin infusion

• In  Anti  MAG  neuropathy…

Primary outcome: Protocol Definition

• The main analysis used the delta change in INCAT (inflammatory neuropathy

cause and treatment) sensory sumscore (ISS) (RANGE: 0 (normal sensation) to 20 (more severe sensory deficit)

• ISS measured at baseline will be

compared to ISS at month 12

Secondary end points Change in : • Disability – INCAT score (10 points) • Disability – NDS (sensory sum scale) • Ataxia score (0 = normal to 3 = severe ataxia) • EVA score (Visual analog pain scale 0-10) • Time for the 10 m walk • MRC score in 3 distal muscles in lower and

upper limbs (bilaterally) • Self-evaluation scale Serious adverse events

Immunotherapy-based regimen in anti-MAG

neuropathy: results in 45 patients

Hospital MA, Viala K, Dragomir S, Levy V, Cohen-Aubart F, Neil J, Musset L, Choquet S, leger JM, Leblond V

Haematologica 2013 Dec;98(12):e155-7

Characteristic Rituximab combination Rituximab alone

No. of patients, N 19 26

Median age, y (range) 68 (42-85) 67 (47-86)

Sex: male/female 12/7 14/12

Lymphoplasmacytic cell bone marrow

infiltration, N (%)

8 (42%) 10 (38%)

Spike IgM level, g/L (range) 3.8 (0-18) 3.5 (0-15.2)

Anti-MAG titer, BTU (range) 60000 (1000->70000) 61000 (5800->70000)

Modified Rankin Score 2: 0 patients

3: 7 patients (37%)

4: 12 patients (63%)

2: 8 patients (30%)

3: 13 (50%)

4: 5 (20%)

Pain 14 (73%) 22 (84%)

Ataxia 18 (95%) 17 (65%)

Motor deficit 11 (58%) 14 (54%)

Sensory deficit 19 (100%) 25 (96%)

Previous treatment 7 (36%) 20 (77%)

Rituximab 2 (10%) 0

Chlorambucil 4 (21%) 20 (77%)

IgIV 1 (5%) 0

Patients characteristics: 45 patients

Treatment response

Immunochemotherapy • Sixteen patients (84%)

improved, • 2 patients (10%)

stabilized (one after RDC treatment and one after RF treatment) and

• 1 patient (5%) deteriorated (after RFC treatment).

Immunotherapy • Twenty-one patients

(80%) improved,

• 4 (15%) stabilized and

• 1 (4%) deteriorated.

Faster response with chemoimmunotherapy

Chemo immunotherapy Response median time : 5 months

Immunotherapy Response median time : 9.5 months

P=0.03

Rankin score: degree of disabilty and dependance in daily activities

Changes in IgM and anti-MAG antibody levels after treatment

P< 0.03 P=0.65 IgM Anti MAG

Anti MAG neuropathies

• Treatment is warranted in case of severe desability and/or significant progression of the symptoms

• The choice depends on the rapidity of progression

• If slow: Rituximab alone • If relapse after Rituximab or rapid

progression; chemo + Rituximab • Purine analogs, bendamustine: rapid

response

IgM-related disorders contribute significantly to morbidity in patients with a IgM lympho-plasmacellular clone A multidisciplinary approach involving subspecialists (Neurologists, nephrologists, dermatologists) is necessary for best management Treatment should be graduated according to the severity of the clinical manifestation In some conditions (anti-MAG neuropathy) symptomatic care may be sufficient In life-threatening conditions (progressive neuropathies, crypglobulimia) rapidly acting regimens should be promptly instituted

CONCLUSIONS