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
- 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
o 50% of patients present as dominant renal amyloid
o Glomerular lesion with nephrotic syndrome
o Proteinuria (normal albumin, not bence jones)
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
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.
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)
- 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
o Congo red stain – amyloid produces green birefringence in cross-polarised light
o SC fat aspiration or rectal biopsy – 50-80% sensitivity
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)
o Echo – mean left ventricle wall thickness >12mm
o BNP - >39 pmol/l in absence of renal failure or AF
o ECG – low voltage QRS, MI type changes
o Cardiac MRI
o Proteinuria >0.5g/24 hours (Non-Bence Jones)
o Hepatomegaly >15cm in absence of heart failure
o LFT – Alkp >1.5x ULN
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
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
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.
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)
- 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
- 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
- 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 Other organs as indicated
- Monitor Amyloid deposits every 6-12 months
o SAP Scintigraphy
o 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.
- Support stockings
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