AL amyloidosis (ORPHA:85443)
A clonal B-cell disorder characterized by the aggregation and deposition of insoluble amyloid fibrils derived from misfolding of monoclonal immunoglobulin light chains. It usually presents as systemic AL amyloidosis with involvement of one or more parenchymal organ(s) and, less frequently, as localized amyloidosis with usually nodular deposits restricted to a single organ and/or system.
Epidemiology
It represents the most common type of systemic amyloidosis in western countries; in Europe and the USA the incidence ranges from 1/80,000-330,000 and prevalence between 1/17,000-50,000. AL amyloidosis affects men slightly more often than women.
Clinical description
The average age of diagnosed patients is 63 years. The clinical manifestations depend on organ involvement and general symptoms, such as fatigue and weight loss, can also occur. The heart (approximately 80%) and the kidneys (65%) are the most commonly involved organs, followed by soft tissues, liver, peripheral and autonomic nervous system, and gastrointestinal tract. This can result in fluid retention, dyspnea, arrhythmias, liver enlargement, macroglossia, swelling if the submandibular glands, carpal tunnel syndrome, peripheral neuropathy, hypotension, diarrhea or constipation. Localized AL amyloidosis can affect the skin, the respiratory, gastrointestinal and urinary tract, and the eye.
Etiology
AL amyloidosis results from conformational changes of monoclonal immunoglobulin light chains produced by a usually small B-cell (most commonly plasma cell) clone. These light chains misfold, aggregate, and deposit in tissue in the form of fibrils. Organ dysfunction and damage is dependent on a direct toxic effect of monoclonal light chains, particularly in the heart, and on the mechanical effect of deposits.
Diagnostic methods
Diagnosis of systemic AL amyloidosis is established by demonstrating amyloid deposits (red-green birefringence with Congo red staining under cross-polarized light) in the affected organ by biopsy or other less invasive alternatives (e.g. subcutaneous fat aspirate) and by demonstrating that amyloid fibrils are formed by immunoglobulin light chains (amyloid typing). Amyloid typing can be achieved by immunohistochemical staining, immunofluorescence on renal biopsies in patients with kidney involvement, and mass spectrometry. A B-cell clone producing a light chain of the same isotype as that documented in the deposits should be searched for and demonstrated. The presence and severity of organ involvement should be assessed (by echocardiography, cardiac magnetic resonance imaging, measurement of proteinuria and renal and liver function parameters) and graded. Cardiac and renal staging systems based on natriuretic peptide type-B or its N-terminal pro-hormone, troponin, free light chain proteinuria, and glomerular filtration rate accurately predict the risk of death and progression to dialysis. Localized AL amyloidosis is diagnosed by biopsy of the deposits.
Differential diagnosis
Systemic AL amyloidosis should be distinguished from other forms of systemic amyloidosis and from non-amyloid light chain deposition disease.
Management and treatment
Treatment of systemic AL amyloidosis is based on therapies targeting the underlying plasma clone aiming at reducing the supply of the amyloid-forming light chain. Successful treatment can improve organ involvement and extend survival. The only licensed therapy is the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD). Other effective regimens are bortezomib, melphalan, dexamethasone (BMDex) and CyBorD. Autologous stem cell transplant is effective and induces long term survival in responders, but only a minority of patients (approximately 20%) are fit enough to safely undergo this procedure. Relapsed and refractory patients are usually rescued with immunomodulatory drugs, such as lenalidomide and pomalidomide. Patients in whom the disease is not caused by a plasma cell clone are treated with regimens used in the corresponding B cell malignancy. Localized AL amyloidosis is treated by surgical removal of the amyloid deposits when this is necessary and possible.
Prognosis
The prognosis of systemic AL amyloidosis depends on the presence and severity of heart involvement and on response to therapy. Patients who are diagnosed when advanced heart involvement is already established are at high risk of early death (within a few months), whereas patients who attain rapid and deep response to therapy can enjoy a prolonged survival. Localized AL amyloidosis has a largely better outcome and only exceptionally is it life threatening.

                            Last update: 
                            September 2021


                            - Expert reviewer(s): 
                            Pr Giovanni PALLADINI | EuroBloodNet*


                                * European Reference Network