AL Amyloidosis: Diagnosis (2014 & 2014(2))

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

    • 50% of patients present as dominant renal amyloid

    • Glomerular lesion with nephrotic syndrome

    • Proteinuria (normal albumin, not bence jones)

  • Cardiac

    • 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

  • Coagulopathy

    • 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.

  • Other systems

    • 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

Principles of 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.

 

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

  • Histology

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

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

  • Immunohistochemistry

    • Not standardized

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

    • In contrast, it can reliably exclude AA and ATTR

  • DNA Analysis

    • 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)

  • Heart

    • Echo – mean left ventricle wall thickness >12mm

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

    • Troponin

    • ECG – low voltage QRS, MI type changes

    • Cardiac MRI

  • Kidney

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

    • U&E

  • Liver

    • Hepatomegaly >15cm in absence of heart failure

    • LFT – Alkp >1.5x ULN

  • Nerve

    • Symmetrical lower extremity sensorimotor axonal peripheral neuropathy

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

    • Nerve conduction studies

  • GI tract

    • Direct biopsy + symptoms

  • Lung

    • Direct biopsy + symptoms, or radiographic interstitial infiltrate

    • CXR – reticulonodular shadowing

    • Pulmonary function tests – impaired CO diffusion

  • Soft tissue

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

  • Other

    • 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

 

Management

 

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.

 

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

 

Monitoring Treatment

  • Monitor clonal response after each cycle of chemotherapy

  • Can use:

    • 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

    • LFTs

    • Other organs as indicated

    • Monitor Amyloid deposits every 6-12 months

    • SAP Scintigraphy

    • 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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