The Challenge of Systemic Immunoglobulin Light-Chain Amyloidosis (AL)
The cardiac involvement and associated mortality that occur in systemic AL amyloidosis remain among the most challenging aspects of the systemic amyloid-related diseases. Monoclonal immunoglobulin light chains produced by a clone of plasma cells are usual
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The Challenge of Systemic Immunoglobulin Light-Chain Amyloidosis (AL) Giovanni Palladini and Raymond L. Comenzo
Abstract The cardiac involvement and associated mortality that occur in systemic AL amyloidosis remain among the most challenging aspects of the systemic amyloidrelated diseases. Monoclonal immunoglobulin light chains produced by a clone of plasma cells are usually the cause of symptoms and organ dysfunction via both poorly understood toxic effects of misfolded species and accumulation of interstitial amyloid fibrils in key viscera. Treatment is aimed at eliminating the clonal cells in order to eliminate toxic light chain production. Recent advances in therapy have helped many patients with AL achieve complete hematologic responses and significant reversal of organ damage but these benefits do not extend to that 10–15 % who present with advanced cardiac involvement. Even with cardiac transplant followed by effective therapy such as stem cell transplant, outcomes for these patients remain promising at best. Keywords Free light chains · AL amyloidosis · Immunoglobulin germline genes · Cardiac amyloid · Stem cell transplant · Melphalan · Thalidomide · Lenalidomide · Bortezomib Abbreviations AL AL amyloidosis ARTC Pavia Amyloidosis Research and Treatment Center FLC Free light chains SCT Stem cell transplant
G. Palladini () Amyloidosis Research and Treatment Center, Foundation “IRCCS Policlinico San Matteo”, and Department of Molecular Medicine, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy e-mail: [email protected] R. L. Comenzo Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA e-mail: [email protected]
J. R. Harris (ed.), Protein Aggregation and Fibrillogenesis in Cerebral 609 and Systemic Amyloid Disease, Subcellular Biochemistry 65, DOI 10.1007/978-94-007-5416-4_22, © Springer Science+Business Media Dordrecht 2012
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G. Palladini and R. L. Comenzo
Introduction
Among the systemic amyloidoses theAL type is in many ways the most challenging to explain to patients affected by it and to their families, and the most difficult for which to develop experimental models for scientific study (Merlini and Bellotti 2003). At the same time, because it involves the heart, AL is the most deadly variant and can cause rapid deterioration resulting in death within several months of diagnosis, a happenstance minimally altered by the advances of stem cell transplantation and novel chemotherapeutic agents (Lebovic et al. 2008b; Dietrich et al. 2010b). In this chapter we provide an overview of our current knowledge of the pathophysiology of AL, our current approach to the diagnosis and treatment of patients, and our assessment of the key questions for clinical research in this formidable disease.
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Mechanisms of Disease
In AL amyloidosis the phenomena of disease are caused by the monoclonal immunoglobulin light chains produced by clonal plasma cells or malignant B cells. These circulating free light chains (FLC) are toxic in poorly understood ways and also
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