AL Amyloidosis: Diagnosis (2014)

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

 

Pathophysiology

-       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

 

Epidemiology

-       600 new cases per year in UK. M:F ratio equal. Majority aged 50-70 at diagnosis

 

Clinical Features

-       Most commonly: Nephrotic syn, Congest. Cardiomyop, Periph neuropathy, hepatomegaly

-       Fatigue and weight loss usually present

-       Multi-organ disease but one organ dysfunction usually dominates

-       Renal

o   50% of patients present as dominant renal amyloid

o   Glomerular lesion with nephrotic syndrome

o   Proteinuria (normal albumin, not bence jones)

-       Cardiac

o   25% of patients present as dominant cardiac amyloid. Poor prognosis

o   ECG shows low voltage QRS

o   Restrictive cardiomyopathy, thick walls but normal cardiac silhouette on XR

o   à Right sided heart failure

-       Peripheral & Autonomic Neuropathy

o   15% of patients present with axonal length-dependent peripheral neuropathy

o   Carpal tunnel syn also common, may precede other signs

o   Autonomic: Orthostatic hypotension, impotence, GI dysmotility, anhidrosis

-       GI & hepatic

o   Macrogloassia in 10% of patients, virtually pathognomonic

o   GI – early satiety, diarrhoea, nausea, malabsorption, perforation, rectal bleeding

o   Hepatomegaly – 25% of patients. Either hepatic amyloid or 2o to heart failure

-       Coagulopathy

o   Peri-orbital purpura “raccoon eyes”

o   50% of patients have abnormal clotting screen

o   Vascular fragility from endothelial amyloid deposits

o   Loss of vitamin-K dependent factors through binding to amyloid deposits.

-       Other systems

o   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.

 

Diagnosis

 

Clinically variable

 

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.

 

Differential Diagnosis

-       Senile Systemic Amyloidosis (aka wild-type ATTR)

-       Hereditary Amyloidosis

-       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.

 

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

o   Demonstrate bone marrow involvement and is diagnostic of AL

-       Histology

o   Congo red stain – amyloid produces green birefringence in cross-polarised light

o   SC fat aspiration or rectal biopsy – 50-80% sensitivity

-       Immunohistochemistry

o   Not standardized

o   Definite results in <60% of patients with AL amyloid

o   In contrast, it can reliably exclude AA and ATTR

-       DNA Analysis

o   Autosomal dominant hereditary systemic amyloidosis

o   TTR, FGA, LYZ, APOA1, APOA2, GSN, CST3, B2M gene mutations

o   Family history may be absent as shows incomplete penetrance

o   Transythretin (TTR) gene often polyneuropathy or cardiomyopathy

o   Fibrinogen A a-chain (FGA) gene often exclusively renal

-       Amyloid fibril protein sequencing and mass spectrometry

o   Definitive method for determining amyloid fibril type

o   Uses formalin-fixed tissue biopsy samples

 

2. Evaluate the plasma cell dyscrasia

-       SFLC (note normal range increases with renal failure)

o   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

3. Evaluate organ involvement (Diagnostic criteria in red italics)

-       Heart

o   Echo – mean left ventricle wall thickness >12mm

o   BNP - >39 pmol/l in absence of renal failure or AF

o   Troponin

o   ECG – low voltage QRS, MI type changes

o   Cardiac MRI

-       Kidney

o   Proteinuria >0.5g/24 hours (Non-Bence Jones)

o   U&E

-       Liver

o   Hepatomegaly >15cm in absence of heart failure

o   LFT – Alkp >1.5x ULN

-       Nerve

o   Symmetrical lower extremity sensorimotor axonal peripheral neuropathy

o   Gastric emptying disorder, pseudo-obstruction, postural hypotension, erectile dysfunction, voiding dysfunction

o   Nerve conduction studies

-       GI tract

o   Direct biopsy + symptoms

-       Lung

o   Direct biopsy + symptoms, or radiographic interstitial infiltrate

o   CXR – reticulonodular shadowing

o   Pulmonary function tests – impaired CO diffusion

-       Soft tissue

o   Macroglossia, arthropathy, skin changes, myopathy, pseudohypertrophy of muscle, lymphadenopathy, carpal tunnel syndrome

-       Other

o   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.

 

 

 

 

Prognostic Staging

 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

AL Amyloidosis: Management (2014)

 

Principles

-       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.

 

Treatment

 

First Line Therapy

-       There is only phase 2 trial data to guide decisions

-       Aims 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:

o   Low level bone marrow plasma cell infiltration

o   Age <65-70, GFR >50ml/min, low cardiac biomarkers

o   Otherwise fit (e.g. no severe neuropathy / GI / resp / renal involevement)

-       If VGPR or CR not achieved then continue chemo post transplant

 

Monitoring Treatment

-       Monitor clonal response after each cycle of chemotherapy

o   Can use:

§  dFLC if difference >50mg/l at diagnosis (approx. 85% of patients)

§  Paraprotein if >5g/l at diagnosis and can’t use dFLC

o   Follow-up bone marrows often unhelpful

-       Monitor organ function every 3-6 months

o   ECG / Echo / BNP / Trop-T / Cardiac MRI

o   U&E, Creatinine clearance, 24-hour urine protein

o   LFTs

o   Other organs as indicated

-       Monitor Amyloid deposits every 6-12 months

o   SAP Scintigraphy

o   Assessment of organ size by imaging

 

 

Response

 

Haematological Response

-       PR: 50% reduction in dFLC

-       VGPR: dFLC reduced to <40mg/l

-       CR: normal FLC levels with normal K:L ratio and normal electrophoresis

 

Organ response

-       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

 

Supportive Care

 

Principles

-       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.

 

Orthostatic hypotension

-       Support stockings

-       Midodrine

 

Bleeding / Thrombosis

-       Bleeding managed in conventional way (FX def well recognized but uncommon)

-       Aspirin + LMWH during treatment if high thrombotic risk

 

Nutrition

-       Severe GI involvement may require PN whilst awaiting disease response to treatment

 

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