Amyloidosis

N Meuleman
May 2017
Rare group of disease < extracellular deposition of amyloid
• fribrillar material <various precursor proteins assembled in
abnormal B-sheet conformation

30 proteins

• Aging process- Intrinsic propensity to assume a

pathologic conformation
• WT transtherythin (prealbumin) transthyretin
• senile systemic amyloidosis
• Prolonged excess abundance of normal protein
• AA (amyloid protein A) : inflammatory reaction
• B2 microglobulin < dialysis
• Abnormal proteins:
• Hereditary Amyloidosis: mutated Transthyretin (130
mutations )
• Immunoglobulin light chain AL
• proteolytic remodeling of the protein precursor
• β-amyloid precursor protein (APP) /Alzheimer's
disease

Merlini G, Bellotti V. N Engl J Med 2003;349:583-596. AD Wechalekar; Lancet 2016

Epidemiology
• 8-12/1.000.000 3-5 AL/ 1.000.000

Evolution
• AL
• AA ↓ 32 % → 7 % on 20 years
(improvement of inflammatory
arthropathies treatments )
• WT ATTR ↑ 0.2 → 6.4 %
(cardiac MRI)

A D Wechalekar, Lancet 2016

Pinney JH,. Br J Haematol 2013
When to suspect amyloidosis?
• Nephrotic syndrome + heart failure
• Simultaneous peripheral and autonomic neuropathy in
nondiabetic patients
• “left ventricular hypertrophy” on echocardiography
without ECG or low limb lead voltages, restrictive CM
with disproportionate signs of right ventricular failure
• Involvement of soft tissues: AL: enlargement of
salivary glands, macroglossia, shoulder pad syndrome
• Isolated periorbital purpura
• Right ventricular dysfunction ( oedema, HMG, HPJ…)
• MGUS+ albuminuria, nephrotic syndrome
• Hepatomegaly with normal imaging (SMG)
• GI tract: diarrhea, constipation, hemorrhage, malabsorption, dyspepsia
• carpal tunnel syndrome
• Nail dystrophy Familial history: cardiac, renal failure, neuropathy
• Factor X deficiency G Merlini et al; Blood 2013
• Pulmonary, articular
E. Kastritis, BJH 2016
Clinical presentation at diagnosis in AL
amyloidosis

Giampaolo Merlini Blood Nov 2012

Amyloidosis : time is life
• The most important diagnostic step to early and correct diagnosis is
the suspicion of amyloidosis

• « Early diagnosis of AL is crucial to avoid end-organ damage. In that regard,

patients with MGUS and an abnormal sFLC ratio should undergo yearly
measurement of proteinuria (alb>0;5gr /day) and NT-proBNP levels (> 332 ng/l)
“. G. Merlini
From suspicion to diagnosis

• Tissue biopsy
• Investigation for paraproteinaemia
• Assessment for systemic disease/organ involvement
• Exclude symptomatic MM or IgM hemopathy
 Tissue biopsy

• Abdomen fat (sensibility 70-80%)+ BM biopsy

: 90 %+
• Labial salivary gland biopsy is positive in >50%
of patients with negative fat biopsy
• Rectal biopsy
• If needed, target organs can be biopsied after
careful assessment of hemostasis

Foli A, Palladini G; Amyoid 2011

G Merlini; Blood 2013
Amyloid deposition
• Congo red staining :
• The β-pleated sheet configuration is responsible of the characteristic green
birefringence after staining with Congo red
• This staining is required for the diagnosis of AL amyloidosis
Typing the amyloidosis

• Immunohistochemistry:
• AA and ATTR
• Difficult in many patients with AL amyloidosis
• immuno–electron microscopy:
• + labelled anti-fibril protein Ab
• Sensitive, limited availability
• Mass spectrometry= new gold standard
• capture of congo red-stained from fixed tissue with laser microdissection
• Tryptic digestion + tandem mass spectrometry
• Computer algorithms, match the peptides to protein reference data base
• Gene sequencing (TTR) is needed when familial amyloidosis is possible
• MGUS is common in individuals over 65 years, and
wild type ATTR amyloidosis of the heart is also
increasingly recognized in older adults.
• In Blacks, both MGUS and the
amyloidogenic TTR V122I mutation are more common
Tc-99m Scintigraphy in amyloidosis
 Evaluation at the diagnosis of AL amyloidosis
• Plasma cell clone: • As clinically indicated:
• Serum + urine electrophoresis and IE
• sFLC dosage • Holter
• BM evaluation: FC and cytogentic • Cardiac MRI
• Assessment of symptomatic MM or • NCS+EMG
IgM hemopathy
• Assessment of organ involvement • Endoscopy +biopsy
• Heart: NT-proBNP, tropo, ECG, echography • Respiratory function test
• Kidney : creatinine + 24h protein
• CT Chest
• Liver: liver function tests
• Coagulation tests: APTT-PT-INR, level of • Scintigraphy (SAP, bone)
factor X
• Neuropathy: clinical assessment
Definition of organ involvement

Gertz and al 2010

 Prognosis of the disease
• Cardiac involvement: • Other
• Mayo Staging System (NT-proBNP/ • Number of organ involved
Tropo)
• NYHA class • Systolic BP <100/mmhg
• Several echographic involvment: • PS
reduced EF, wall thickness > 15 mm
• NT-proBNP response • Automatic neuropathy
• Other biologic markers:
• Cytogenetic:
• t(11-14), gain 1q21 (worse)
• BM plasma cells > 10%
• DFLC > 180mg/dl
 stages I to III

• cTnT<0.035
g/mL
• NT-ProBNP
<332ng/ml

Kumar S et al Mayo Clin Proc, 2011

Revised Prognostic Staging System for AL Amyloidosis
Incorporating Cardiac Biomarkers and Serum Free Light
Chain Measurements

25/27/25/23%
stages I to IV
scores of 0 to 3 points
• FLC-diff 18 mg/dL
• cTnT0.025 ng/mL
• NT-ProBNP 1,800 pg/m

Kumar S et al, JCO 03/2012

Treatment: according to the risk and the age

• The aim of the treatment is to obtain a rapid and profound

decrease of light chain level:
• hematologic CR or VGPR, indispensable for organ responses

• Adapt the treatment to the patient: their age,

comorbidities, extent of organ involvement

• Supportive care
Risk-adapted treatment strategy for patients with AL amyloidosis.

E Kastritis , A.
Dimopoulos
BJH ; 2016
Recommandation of SFH

Importance of early evaluation

and adaptation of treatment

• Stage high risk / stage II-III (cardiac

involvment SFH) evaluation after 1
cycle (or 6 weeks)
• If <50 % reduction of dFLC add
BZM
• At 3 months : need ≥ reduction
dFLC 90%

• Low risk (stage I): evaluation for a

modification of treatment at 3 (≥ 50
% reduction dFLC) and 6 months
(90% reduction)
A Jaccart
 Figure 1

• Use boretzomib with caution in pts with

• without severe heart failure (NT-proBNP >8500ng/l)
• Monitoring
Mayo Clinic Proceedings 2015 90, 1054-1081DOI: (10.1016/j.mayocp.2015.06.009)
Copyright © 2015 Mayo Foundation for Medical Education and Research Terms and Conditions
 Ten‐year survival after autologous stem cell transplantation for immunoglobulin light chain amyloidosis

Eligibility criteria for ASCT:

1) age ≤ 70 years;
2) PS of ≤ 2
3) Creat cl of ≥ 30 mL/minute
(unless patient was
undergoing chronic dialysis)
4) NY HA classes I or II

long-term survivor > 10 years 43% (n= 32 patients/74)

Cancer
Volume 118, Issue 24, pages 6105-6109, 15 JUN 2012 DOI: 10.1002/cncr.27660
http://onlinelibrary.wiley.com/doi/10.1002/cncr.27660/full#fig1
ASCT in fit patient (15-25%)

• Eligibility criterias
• Age: <65 yo (or fit < 70 yo)
• NT-proBNP < 5000 ng
• Troponin-T < 0·06 ng/ml
• PS:0-2
• HDM-ASCT can be considered without prior induction chemotherapy in patients with
low level bone marrow plasma cell infiltration.
• estimated glomerular filtration rate (eGFR) >50 ml/min
• NYHA < III, EF > 45%
• MEL 200mg/m2
• CyBorD induction if BMPC > 10%
• BD consolidation if < CR (evaluation at the day 100)
Merlini G; IMW New Delhi 2017
Response and progression criteria

Gertz et al, 2005; Palladini et al, 2012a, 2014°; BJH 2016

Survival according to hematological
response

Giovanni Palladini et al; J Clin Oncol. 20122

 Survival
according to
cradiac
response
(NT-proBNP
reduction)

Giovanni Palladini et al; J Clin Oncol. 20122

A. Dispenzieri et al. / Blood Reviews 26 (2012) 137–154
IgM-related amyloidosis

• Usually treated with lymphoma regimens

• dexamethasone, rituximab and cyclophosphamide
• Rituximab-COP
• R-bendamustine.
Relapse/ refractory AL
• Re-challenge with a regimen associated with a durable response
• No Bortezomid refractory
• Cybordex or VD
• SC and weekly vel (neuropathy)
• Adapt dose of Dexamethasone
• No alkylor refractory: Mel-dex (as induction)
• Melphalan 10mg/m po D1-4 Dexamethasone 40mg po D1-4 /Cycles 28 days-
2

up to 18 cycles in responders (discontinued after 12 cycles in complete

responders and sooner if serious toxicity).
• Bortezomid refractory
• Len-dex or Pom dex
Jaccard ; 2007
Mayo Clinic Proceedings 2015 90, 1054-1081DOI: (10.1016/j.mayocp.2015.06.009)
Supportive care ASCT
• Cardiac involvement
• Arrhythmia prophylaxis? (amiodarone 200MG)
• High risk of life threatening arrhythmia during stem cell collection+ reinfusion
and aplasia
• Cardiac monitoring: SC collection, infusion • Avoid G-CSF if cardiac
involvement or nephrotic syndrome (fluid retention)
• ! Fluid administration
• Increased risk of GI bleeding
• Transfusions > 20.000 (50.000°
• Daily blood test in stool (evaluation pre-transplant)
Cardiac supportive care
• Supportive care in cardiac amyloid is the management of fluid
overload using loop diuretics and/or spironolactone
• Avoid ACE inhibitors, Beta-blockers and calcium-channel blockers :
• Hypotension, syncope
• Digoxine is CI in atrial fibrillation use amiodarone
• High risk holter: consider prophylactic amiodarone 200mg/day
• Pacemakers /defibrillators to discuss for in selected patients:
recurrent cardiogenic syncope, orcomplex ventricular arrhythmias
• Cardiac transplantation may be considered for young highly selected
patients :
• Severe cardiac involvement
• No other organ involvement
• Followed by chemotherapy
Supportive care
• Nephrotic syndrome:
• Diuretic- Salt and fluid restriction
• Increased risk of VTE-Caution with prophylactic anticoagulation: dosage of FX
level
• ACE inhibitors if no cardiac and autonomic involvment
• Orthostatic hypotension:
• Support stockings
• Low doses of fludrocortisone in selected cases
• Midodrine is the most effective drug for orthostatic hypotension in patients
with amyloidosis (30mg), but can cause supine hypertension
Localised amyloidosis
• Different entity
• Amyloid deposits only at the site of light chain production
• Rare progression to systemic disease (local recurrences)
• Location:
• tracheobronchial tree , gastrointestinal tract, skin, brain, bladder or as solitary
pulmonary nodules
• Treatment:
• Resection or with laser therapy
• severe presentations may justify local radiotherapy.
How to improve?
Doxycycline in AL Amyloidosis
• Doxycycline interferes with amyloid fibril formation in a mouse
model of AL amyloidosis* and abrogates light chain toxicity in vitro.**

• *Diomede L; Blood 2014

• **Ward JA ; blood 2011
Amyloidose AL
• Better diagnostic,
treatment, supportive
care
• Better pronostic..except
stage III
...early diagnostic!