Advances in diagnostics and therapy of systemic amyloidoses

For decades therapeutical options to alter the clinical course of systemic amyloidoses have been very limited. However, recent progress in understanding the pathogenesis of these rare disorders have led to the development of novel diagnostic tools and targeted therapies. Here, we briefly review the most important advances in this challenging and interdisciplinary field. Amyloidoses constitute a heterogeneous group of rare diseases characterized by local or systemic extracellular formation of insoluble amyloid deposits in tissues leading to organ dysfunctions [1]. Tissue deposits are formed by stable and non-branching amyloid fibers resulting from misfolding of different precursor proteins characterized by a beta-sheet structure. The above features of amyloid are common to all amyloidoses regardless of etiology [1]. The type of the precursor protein is the base for nomenclature of amyloidoses developed by the International Society of Amyloidosis (ISA) [1]. Until now 36 amyloidogenic proteins associated with human diseases have been identified including 17 proteins known to cause systemic amyloidoses [2]. The most common types are immunoglobulin light chain amyloidosis (AL amyloidosis), transthyretin amyloidoses (ATTR amyloidosis) comprising wild-type (wtATTR) and hereditary or mutated type (hATTR), and reactive amyloidosis (AA amyloidosis) [1]. The diagnosis of amyloidosis relies on positive staining of tissue deposits with Congo Red that results in characteristic green, yellow or orange tint under polarized light [1]. This test does not distinguish between different types of the disease, thus additional typing is necessary in majority of cases. Unfortunately, access to the gold standard method of amyloid typing using mass spectrometry is very limited, while immunohistochemistry when used by an experienced pathologist may diagnose only up to 70% of patients [1]. Interestingly, it was found that bone radiotracers, such as 99mTc-DPD or Tc-99m-PYP, bind heart amyloid in ATTR amyloidosis, but not in AL amyloidosis [3]. This observation led to development of non-invasive scintigraphy/SPECT-based typing algorithms, particularly useful to distinguish between isolated cardiac AL amyloidosis and ATTR in the context of monoclonal gammopathy [3]. Furthermore, rapid progress of genetic testing, incorporating next-generation sequencing (NGS) methods, has facilitated screening for hATTR and other extremely rare inherited types of amyloidosis. From academic perspective treatment of amyloidosis could be divided into two types of strategies: therapies preventing amyloid formation and directed against stable amyloid deposits. Significant progress has been recently achieved concerning the first type of strategies in two most common systemic amyloidoses: AL and ATTR. Amyloid precursors in AL amyloidosis are monoclonal immunoglobulin light chains produced by clonal plasma cells [4]. Unlike multiple myeloma (MM), the end-organ symptoms in AL amyloidosis are the consequence of the capacity of these light chains to form amyloid deposits, most typically in the heart and kidney [4]. Treatment of AL amyloidosis is based on MM-type chemotherapy; however, regimen type and intensity need to be individually adjusted due to significantly higher risk of toxicity [4]. An important step forward has been a recent introduction of anti-CD38 monoclonal antibody daratumumab to the treatment armamentarium against AL amyloidosis following its promising outcomes in MM [4]. The phase 3 ANDROMEDA study has evaluated daratumumab-CyBorD (cyclophosphamide, bortezomib, dexamethasone) combination in newly diagnosed AL amyloidosis [5]. Early results of the trial demonstrated robust hematologic and organ responses without important safety concerns, making it very likely that daratumumab will soon become the first drug approved for AL amyloidosis [5].