FISH as for myeloma – t(11;14) in 50%
Systemic AL Amyloidosis
Protein folding disorder
Extracellular accumulation of B-pleated fibrillar deposits of monocloncal immunoglobulin light chain fragments.
Progressive accumulation leads to organ failure – kidneys, heart, liver, periph nerves.
Natural history – 80% mortality at 2 years.
Current prognosis – OS Approx 5 years with therapy and supportive care
AL amyloid fibrils are derived from N-terminal region of monoclonal light chains – either the whole region or the Variable (V1) domain.
3:1 Lambda to Kappa associated with AL Amyloidosis
Associated with plasma cell dyscrasia, MGUS in most cases but may be myeloma or WM.
AL Amyloidosis now a myeloma-defining condition
Rare for AL amyloidosis to progress to overt myeloma (due to short life expectancy)
Genetic abnormalities on FISH in 80% of patients, better prognosis than if normal FISH
600 new cases per year in UK. M:F ratio equal. Majority aged 50-70 at diagnosis
Most commonly: Nephrotic syn, Congest. Cardiomyop, Periph neuropathy, Hepatomegaly
Fatigue and weight loss usually present
Multi-organ disease but one organ dysfunction usually dominates
50% of patients present as dominant renal amyloid
Glomerular lesion with nephrotic syndrome
Proteinuria (normal albumin, not bence jones)
25% of patients present as dominant cardiac amyloid. Poor prognosis
ECG shows low voltage QRS
Restrictive cardiomyopathy, thick walls but normal cardiac silhouette on XR
—> Right sided heart failure
Peripheral & Autonomic Neuropathy
15% of patients present with axonal length-dependent peripheral neuropathy
Carpal tunnel syn also common, may precede other signs
Autonomic: Orthostatic hypotension, impotence, GI dysmotility, anhidrosis
GI & hepatic
Macrogloassia in 10% of patients, virtually pathognomonic
GI – early satiety, diarrhoea, nausea, malabsorption, perforation, rectal bleeding
Hepatomegaly – 25% of patients. Either hepatic amyloid or 2o to heart failure
Peri-orbital purpura “raccoon eyes”
50% of patients have abnormal clotting screen
Vascular fragility from endothelial amyloid deposits
Loss of vitamin-K dependent factors through binding to amyloid deposits.
Skin, seronegative arthopathy, bone involvement, vocal cord infiltration, adrenal and thyroid infiltration (hypo-isms), any other organ except the brain.
Note on Localised AL Amyloid
Upper respiratory, urogenital and GI tracts, skin and the orbit
Amyloid produced by infiltration of clonal lymphoplasmacytoid cells at the site of disease
Monoclonal Ig not detectable in serum or urine
Usually benign course, surgical intervention sometimes beneficial.
Principles of Diagnosis
Suspect AL amyloidosis in any patient with nephrotic syn, hepatomegaly, non-dilated cardiomyopathy or peripheral/autonomic neuropathy, regardless of whether paraprotein is detectable in serum or urine.
Multiple organ biopsies not required. Confirmation of amyloid in one organ and a careful search for dysfunction of other organs is sufficient.
Senile Systemic Amyloidosis (aka wild-type ATTR)
AA amyloidosis (there is not always an overt inflammatory disorder)
Localised AL amyloidosis
Note: Any of the above may also co-exist with an MGUS.
Step 1. Evaluate the Amyloid type
Immunohistochemical staining only 60% sensitivity
AL type often diagnosed after exclusion of AA and transthyretin (ATTR) types by immunohistochemistry and hereditary types by genetic sequencing.
SAP Scan - Scintigraphy with radio-labeled serum amyloid P
Demonstrating bone marrow involvement is diagnostic of AL
Congo red stain – amyloid produces green birefringence in cross-polarised light
SC fat aspiration or rectal biopsy – 50-80% sensitivity
Definite results in <60% of patients with AL amyloid
In contrast, it can reliably exclude AA and ATTR
Autosomal dominant hereditary systemic amyloidosis
TTR, FGA, LYZ, APOA1, APOA2, GSN, CST3, B2M gene mutations
Family history may be absent as shows incomplete penetrance
Transythretin (TTR) gene often polyneuropathy or cardiomyopathy
Fibrinogen A a-chain (FGA) gene often exclusively renal
Amyloid fibril protein sequencing and mass spectrometry
Definitive method for determining amyloid fibril type
Uses formalin-fixed tissue biopsy samples
Step 2. Evaluate the plasma cell dyscrasia
SFLC (note normal range increases with renal failure)
If used as a disease marker there should be a >50mg/l difference in the involved and uninvolved light chains at diagnosis
Serum and urine protein electrophoresis
Bone marrow biopsy
Step 3. Evaluate organ involvement (Diagnostic criteria in italics)
Echo – mean left ventricle wall thickness >12mm
BNP - >39 pmol/l in absence of renal failure or AF
ECG – low voltage QRS, MI type changes
Proteinuria >0.5g/24 hours (Non-Bence Jones)
Hepatomegaly >15cm in absence of heart failure
LFT – Alkp >1.5x ULN
Symmetrical lower extremity sensorimotor axonal peripheral neuropathy
Gastric emptying disorder, pseudo-obstruction, postural hypotension, erectile dysfunction, voiding dysfunction
Nerve conduction studies
Direct biopsy + symptoms
Direct biopsy + symptoms, or radiographic interstitial infiltrate
CXR – reticulonodular shadowing
Pulmonary function tests – impaired CO diffusion
Macroglossia, arthropathy, skin changes, myopathy, pseudohypertrophy of muscle, lymphadenopathy, carpal tunnel syndrome
Bone – SAP Scan. Amyloid fibrils associate with normal plasma protein SAP. Using this fact, radio-labeled SAP can be injected and then whole body scintigraphy used to detect areas of deposition.
Stage 1: Both BNP and Troponin normal. Median survival 26 months
Stage 2: Either BNP or Tropnin abnormal. Median survival 10 months
Stage 3: Both BNP and troponin abnormal. Median survival 3 months
Patients should be enrolled in trials where possible
Should be treated at tertiary centres
Based on anti-myeloma therapy but no one standard therapy, tailor to patient
Treatment-related toxicity is higher in Amyloid than myeloma
Supportive care to manage the amyloid-related complications
Who to treat?
Symptomatic systemic amyloidosis with visceral organ involvement, significant soft tissue involvement, coagulopathy or neuropathic involvement should be considered for Rx.
?Isolated carpel tunnel – not clear
Localised amyloidosis should be treated with surgery / radiotherapy
Those with very high risk disease may be better served by early palliation.
First Line Therapy
Only phase 2 trial data to guide decisions
Aim to achieve an adequate haematological response as rapidly as possible, because:
Clinical benefit lags behind haematological response by many months, and so those with a slow response may not live long enough to feel the benefit.
Proteosome inhib-Alkylator-Steroid (e.g. VCD) combination preferred for a rapid response
Treatment at Relapse/Refractory
No randomized trial data
If good response, re-treat with same
If poor response, new regimen, palliation or clinical trial of new agents
Consider lenalidomide and pomalidomide
Melphalan Autograft if <65-70 y.o.
High Dose Melphalan Transplant
1st line, consider if:
Low level bone marrow plasma cell infiltration
Age <65-70, GFR >50ml/min, low cardiac biomarkers
Otherwise fit (e.g. no severe neuropathy / GI / resp / renal involevement)
If VGPR or CR not achieved then continue chemo post transplant
Monitor clonal response after each cycle of chemotherapy
dFLC if difference >50mg/l at diagnosis (approx. 85% of patients)
Paraprotein if >5g/l at diagnosis and can’t use dFLC
Follow-up bone marrows often unhelpful
Monitor organ function every 3-6 months
ECG / Echo / BNP / Trop-T / Cardiac MRI
U&E, Creatinine clearance, 24-hour urine protein
Other organs as indicated
Monitor Amyloid deposits every 6-12 months
Assessment of organ size by imaging
PR: 50% reduction in dFLC
VGPR: dFLC reduced to <40mg/l
CR: normal FLC levels with normal K:L ratio and normal electrophoresis
Heart: BNP decrease or NYHA class improves
Kidney: Decrease in 24 hour urine protein
Liver: Decrease in AlkP and decrease in liver size
Periph Nerve: Improved nerve conduction study
AL Amyloid patients very brittle
Dehydration, overload and infection can precipitate renal and cardiac failure even in patients with apparently normal organ function
Should be treated in tertiary hospitals with access to specialty advice
Nephrotic Syndrome and Renal Impairment
Loop diuretics usually required in high doses
Salt and fluid restriction
ESRF should be treated with dialysis if indicated – survival is worse than age-matched diabetic ESRF on dialysis.
Selected patients have undergone renal transplant
Congestive Cardiac Failure
Very poor prognosis
LV or RV impairment on Echo + a poor Performance Status at diagnosis indicates patients unlikely to survive long enough to benefit from chemotherapy.
Loop diuretics + spironolactone
Cardiac arrhythmias are common
ACEI, B-blockers and digoxin all poorly tolerated
?ICD therapy – appropriate shocks are delivered, but unsuccessfully. More data needed.
Heart transplant immediately followed by Melphalan Autograft and chemo has been used in some very young patients.
Bleeding / Thrombosis
Bleeding managed in conventional way (FX def well recognized but uncommon)
Aspirin + LMWH during treatment if high thrombotic risk
Severe GI involvement may require PN whilst awaiting disease response to treatment
Breaking bad news methods, Patient info leaflet, Specialist nurse contact