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Light Chain Amyloidosis in the Era of Novel Agents

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Light Chain Amyloidosis in the Era of Novel Agents Review Hematology 4 Light chain amyloidosis in the era of novel agents K. Beel, MD, PhD1 The development of new immunomodulatory therapies and their implementation in the treatment of mul- tiple myeloma in the past years, offer new perspectives for the treatment of other plasma cell dyscrasias. Light chain amyloidosis is historically associated with a very poor prognosis, despite the small size of the monoclonal plasma cell population, due to progressive amyloid deposition in vital organs. Hence, advances in treatment are eagerly awaited. Luckily, myeloma patients are paving the way for light chain amyloidosis treatment, clearly demonstrating that immunomodulatory drugs and proteasome inhibitors are capable of controlling plasma cell proliferation. Two recently published trials have shown a remarkable survival benefit with CyBorD, a bortezomib containing regimen in light chain amyloidosis, possibly setting a new standard for the treatment of this disease. In this article, we review current insights in the pathogenesis, diagnostic challenges, prognostic markers and available treatments for light chain amyloidosis. (Belg J Hematol 2013;4(4):120-126) Introduction Systemic light chain amyloidosis (AL) is caused by a malities occur both in MM and in AL. The translocation small clone of plasma cells, synthesising immunoglob- t(11;14) is more frequent in AL (40-50%), but in contrast ulin light chain polypeptides, which are prone to mis- to MM, it is associated with a worse prognosis, as is folding and interstitial deposition as insoluble β-sheet the presence of cyclin D1 overexpression. Of interest, fibrils. Without treatment, the associated proteotoxicity marrow plasma cells of amyloidosis patients exert an inevitably leads to progressive organ failure and death. intermediate gene expression profile between a normal AL occurs in approximately one case per 100 000 per- and a myeloma signature.4 sons in western countries, similar to chronic myeloid leukaemia, with a mean age of 63 years at diagnosis. Pathogenesis Historically, AL had a very poor prognosis, with a me- The process of amyloid formation is not completely dian survival of thirteen months.1 Although AL is the understood. Like Parkinson’s disease and Alzheimer’s, most common type of systemic amyloidosis; hereditary, AL is a proteopathy, meaning that changes in protein senile and secondary forms exist and should not be conformation induce toxicity through highly ordered confused with AL because of the different therapies amyloid β-sheet depositions. AL amyloidosis is inher- indicated. An overlap with multiple myeloma (MM) ently linked to the adoptive immune response in jawed exists, as 20% of AL patients meet the criteria for vertebrates. Immunoglobulin formation in the plasma myeloma and up to 30% of myeloma patients have cell relies on recombination and somatic gene mutations. minor amyloid deposition.2 As opposed to other plasma However, genetic plasticity has its downside and amy- cell disorders, a 1:3 κ:λ ratio is found in AL, which loid formation could be considered the price for the supports the concept that λ light chains are intrinsically acquisition of a sophisticated adoptive immune system. more amyloi-dogenic than κ.3 Some cytogenetic abnor- It is assumed that the amyloid deposition process was 1Department of Haematology, Ziekenhuisnetwerk Antwerpen (ZNA), Antwerp, Belgium. Please send all correspondence to: K. Beel, MD, PhD, Ziekenhuisnetwerk Antwerpen (ZNA), Department of Haematology, Middelheim, Lindendreef 1, 2020 Antwerp, Belgium, tel: +32 3 230 34 95, email: [email protected]. Conflict of interest: The author has nothing to disclose and indicates no potential conflict of interest. Key words: diagnosis and treatment of AL amyloidosis, novel agents in AL amyloidosis, systemic immunoglobulin light chain amyloidosis. Belgian Journal of Hematology Volume 4, Issue 4, December 2013 120 Review Hematology clinical: high index of suspicion nephrotic range proteinuria, non-ischemic cardiomyopathy, peripheral neuropathy, autonomic neuropathy with weight loss, unexplained hepatomegaly histological: obtain biopsy fine needle aspiration of abdominal fat: noninvasive, fast, cheap (sensitivity 88%, specificity 97%)9 or minor labial salivary gland (sensitivity 50%), or bone marrow biopsy (sensitivity 60%,)7,8 or rectum, liver or renal biopsy Congo red staining and red-green birefringence under polarized light microscopy or 10 nm fibrils on electron microscopy possible future gold standard with amyloid typing capacity: laser dissection with mass spectrometry9 laboratory: demonstrate monoclonal gammopathy serum electrophoresis + serum immunophenotyping + serum FLC + urine EP/IFE = 98% sensitivity bone marrow biopsy with plasma cell count (median plasma cell precentage is 7%) + - organ distribution: determine extent of disease (no uniform scoring criteria) molecular: typing of non AL amyloidosis -screen the heart with biomarkers troponin T and NT-proBNP <-> low sensitivity for EKG hereditary mutations in amyloid proteins (TTR) (voltage loss), echocardio (atrial septum thickening), or cardiac MRI or direct amyloid fibril sequencing ($) -screen the kidneys with serum creatinine and 24h urine collection -screen other organs guided by signs & symptoms: EMG, pulmonary function, liver biopsy full body scan: SAP scintigraphy (only abroad, does not detect cardiac involvement)11 Figure 1. Diagnostic algorithm for light chain amyloidosis. selected during evolution, as a last resort to prevent Diagnosis misfolded peptides from interaction with physiological The diagnosis of AL can be challenging and a high processes, by concentrating them in certain tissues.5 index of suspicion is required by all physicians, since Some mutations in the genes, encoding the variable AL is a systemic disease with a variable phenotype. domain of the light chains, can cause thermodynamic, A diagnostic delay results in more organ impairment, hydrophobic or electrostatic instability, giving rise to which jeopardises treatment tolerability, which in turn an amyloidogenic light chain. Up to 28 different amy- has a negative impact on prognosis. A diagnostic algo- loidogenic proteins have been recognised in humans, rithm is presented in Figure 1. but only a few are common.6 Once the secondary structure of an α-helix-rich peptide, typical of most The four most frequent presentations of AL are nephrotic proteins, refolds and forms more β-sheet structures, syndrome with preserved glomerular filtration rate, non- peptides start to associate in an antiparallel way, allow- ischemic cardiomyopathy, autonomic (orthostatism) or ing continued amyloid polymerisation. Besides immu- peripheral neuropathy (carpal tunnel) and hepatomegaly noglobulin light chains, many stabilising proteins are with cholestasis.8 Kidney involvement is most frequent, present in amyloid fibrils, such as the serum amyloid but cardiac involvement is most dangerous. Fatigue (in protein (SAP) and apolipoproteins. Specific tissue char- 68%), peripheral oedema (in 62%) and weight loss (in acteristics (‘tropism’), e.g. matrix components glycos- 43%) are the most common systemic symptoms. Diar- aminoglycans and proteoglycans in the target organ, rhoea, due to gastro-intestinal amyloid deposition, occurs play a role in the amyloid deposition. As an example, the in 9%. Macroglossia (in 14%) or periorbital ecchymosis 6a λ light chain is classically mentioned as preferentially (raccoon eye) (in 11%) are rare, but pathognomonic for associated with kidney involvement. However, later AL, as is the shoulder-pad-sign (in 15%), caused by studies have shown that some cases involve the heart.7 periarticular amyloid infiltration. Factor X absorption Belgian Journal of Hematology Volume 4, Issue 4, December 2013 121 4 of amyloid deposits and capillary fragility increase the for monitoring response in the vast majority of patients risk of bleeding.3 A biopsy needs to be obtained to con- and normalisation of the serum FLC ratio is a strong firm a clinical suspicion of amyloidosis. Fine needle predictor of survival. Classically, the more organs invol- aspiration of abdominal fat is the preferred diagnostic ved the worse the prognosis, but cardiac involvement test, as it is non-invasive, fast and cheap with a high has the greatest impact on survival with >70% of AL sensitivity (88%) and specificity (97%).3 Confirmation patients dying of amyloid cardiomyopathy. Dispenzieri of AL by the demonstration of a monoclonal gammopa- et al. developed the Mayo cardiac staging system, based thy and/or exclusion of other types of amyloidosis is on Troponin T and NT-pro-BNP levels, both sensitive important, to spare patients unnecessary chemotherapy. and reliable markers of cardiac function. Troponin T Common types of amyloidosis besides AL are senile, correlates with cardiac damage and NT-pro-BNP with hereditary transthyretin (ATTR) and serum amyloid A wall strain.8 Prognosis and survival differ significantly (AA) secondary to chronic inflammation. Senile amyloi- between patients with 0 (stage I), 1 (stage II) or 2 (stage dosis classically occurs in old men with isolated cardiac III) elevated markers.11 A reduction of 30% of NT-pro- involvement and the treatment is merely supportive. BNP with treatment qualifies as response and normal- Hereditary ATTR amyloidosis, particularly common in isation of NT-pro-BNP correlates with improved survival. African-Americans (3%), is a contra-indication for che- These biomarkers are less reliable for cardiac monitoring motherapy and requires liver
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