Amyloidosis: pathogenesis and new therapeutic options

Abstract

The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. The most common type, immunoglobulin light chain amyloidosis (AL), is caused by clonal plasma cells that produce misfolded light chains. The purpose of this review is to provide up-to-date information on diagnosis and treatment options for AL amyloidosis. Early, accurate diagnosis is the key to effective therapy, and unequivocal identification of the amyloidogenic protein may require advanced technologies and expertise. Prognosis is dominated by the extent of cardiac involvement, and cardiac staging directs the choice of therapy. Treatment for AL amyloidosis is highly individualized, determined on the basis of age, organ dysfunction, and regimen toxicities, and should be guided by biomarkers of hematologic and cardiac response. Alkylator-based chemotherapy is effective in almost two thirds of patients. Novel agents are also active, and trials are ongoing to establish their optimal use. Treatment algorithms will continue to be refined through controlled trials. Advances in basic research have led to the identification of new drug targets and therapeutic approaches, which will be integrated with chemotherapy in the future.

Fig 1.

The cascade of molecular events leading to amyloidosis. The amyloidogenic precursor may trigger amyloid formation when its concentration increases in serum or because a mutation favors misfolding. Some normal proteins with an intrinsic amyloidogenic predisposition can, at a low rate, form amyloid deposits that become symptomatic in the elderly (eg, wild-type transthyretin causing senile systemic amyloidosis). Interaction with the extracellular environment may result in proteolytic cleavage and binding to matrix components such as glycosaminoglycans (GAGs) and collagen that facilitate aggregation. Several lines of evidence support a role for extracellular chaperones in the in vivo clearance of aggregation-prone extracellular proteins. In some types of systemic amyloidosis, such as immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR), oligomers may be the major cytotoxic species. Serum amyloid P (SAP) binds to amyloid fibrils and protects them from reabsorption. The amyloid deposits exhibit a characteristic affinity for Congo red staining with brilliant green birefringence under polarized light and are formed by 10- to 12-nm–wide nonbranching fibrils, as observed by electron microscopy. (A) The synthesis of the amyloidogenic precursor may be eliminated by using chemotherapy in AL amyloidosis or liver transplantation in ATTR amyloidosis; silencing by using RNA interference is being tested in animal models. (B) Inhibitors of proteases (secretase) and metal protein–attenuating compounds are being evaluated in trials. (C) Compounds interfering with the binding of GAGs to the amyloid proteins (eprodisate) have been successful in secondary amyloidosis. (D) Small molecules capable of stabilizing the amyloid precursor and preventing its misfolding and aggregation (diflunisal, tafamidis) are being tested in ATTR amyloidosis. (E) SAP can be cleared from amyloid deposits by using small palindromic drugs. (F) The clearance of amyloid deposits can be promoted and accelerated by specific antibodies through passive and active immunotherapy, or by combining small palindromic drugs with anti-SAP antibodies.

Fig 2.

Diagnostic algorithm for systemic amyloidosis. Patients are generally referred to an oncologist or hematologist because they have a clinical syndrome consistent with immunoglobulin light chain amyloidosis (AL), or a monoclonal gammopathy with associated organ dysfunction. If clinical suggestion of amyloidosis is high and the fat aspirate is negative, a biopsy of the labial salivary gland may detect amyloid deposits in 50% of patients; if this is also negative, then an involved organ (kidney, endomyocardium, GI tract) should be biopsied. Demonstration of amyloid fibrils in the absence of a clonal light chain should precipitate a genetic and immunohistochemical or biochemical work-up for hereditary or other types of amyloidosis. XRT, radiation therapy.

Fig 3.

Treatment algorithm for immunoglobin light chain amyloidosis. Patients who present with advanced cardiac disease may not tolerate high-dose corticosteroids or multidrug regimens. If they have isolated cardiac disease, orthotopic heart transplantation (OHT) should be considered, followed by high-dose intravenous melphalan supported with stem-cell transplantation (HDM/SCT) to prevent amyloid deposition in the transplanted heart. If the patient is not a transplant candidate, a low-dose regimen (low-dose melphalan plus dexamethasone plus low-dose bortezomib, or melphalan-prednisone plus low-dose thalidomide), should be considered. Patients younger than 65 years with adequate organ function may be considered for HDM/SCT at 200 mg/m². Melphalan-dexamethasone (MDex) or thalidomide-cyclophosphamide-dexamethasone (CTD) are reasonable alternatives, particularly for patients at higher risk of toxicity with HDM/SCT. Patients achieving complete response (CR) or partial response (PR) associated with stabilization or reduction of cardiac biomarkers (heart response [HR]) may stop treatment and start close follow-up. Patients who obtain partial response without HR and those with no response (NR) should be treated with novel agents, alone or in combination. Because data from clinical trials are maturing, the combination of novel agents with alkylators may move to the forefront.