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AL amyloidosis treatment

Arnaud Jaccard, Frank Bridoux
AL amyloidosis is caused by the conversion of monoclonal immunoglobulin light chains into amyloid fibrillar aggregates that deposit in tissue and lead to organ dysfunction. Diagnosis is histological and relies primarily on non-invasive biopsies, showing Congo red-positive amorphous deposits containing immunoglobulin light chains, most commonly of lambda isotype. The clinical presentation is extremely polymorphous, due to the large number of organs that can be affected by the disease. The kidneys and the heart are most frequently involved organs, in about two thirds of patients each, responsible for nephrotic syndrome and restrictive cardiomyopathy...
April 2019: Néphrologie & Thérapeutique
Gareth J Morgan, Nicholas L Yan, David E Mortenson, Enrico Rennella, Joshua M Blundon, Ryan M Gwin, Chung-Yon Lin, Robyn L Stanfield, Steven J Brown, Hugh Rosen, Timothy P Spicer, Virneliz Fernandez-Vega, Giampaolo Merlini, Lewis E Kay, Ian A Wilson, Jeffery W Kelly
In Ig light-chain (LC) amyloidosis (AL), the unique antibody LC protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. As a step toward developing treatments for AL patients with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, we introduce small-molecule kinetic stabilizers of the native dimeric structure of full-length LCs, which can slow or stop the amyloidogenicity cascade at its origin...
April 10, 2019: Proceedings of the National Academy of Sciences of the United States of America
Eric Christopher Ehman, Mohamed Samir El-Sady, Marie Foley Kijewski, Yiu Ming Khor, Sophia Jacob, Frederick L Ruberg, Vaishali Sanchorawala, Heather Landau, Andrew Jenho Yee, Giada Bianchi, Marcelo F Di Carli, Rodney H Falk, Hyewon Hyun, Sharmila Dorbala
Immunoglobulin light chain amyloidosis (AL) affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with 18 F-florbetapir PET/CT offers the potential to detect AL amyloid deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL amyloid deposits in the various organs of subjects with systemic AL amyloidosis using 18 F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy proven AL amyloidosis including active AL amyloidosis ( n = 30) or AL amyloidosis in hematological remission for >1 year ( n = 10)...
April 6, 2019: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Thomas Anthony Rowland, Julian Gillmore, Sunil Bhandari
BACKGROUND: AL amyloidosis is a disease that causes significant end-organ damage via deposition of insoluble amyloid fibrils, which cause disruption of normal tissue architecture and function. The mainstay of current treatment employs various chemotherapy regimens, all of which aim to suppress the underlying plasma cell dyscrasia and reduce the production of amyloidogenic precursor proteins. Renal disease is found in between 50 and 80% of sufferers and is often both progressive and irreversible, ultimately leading to end-stage renal failure and death...
April 2, 2019: Clinical Nephrology
Monique C Minnema, Kazem Nasserinejad, Bouke Hazenberg, Ute Hegenbart, Philip Vlummens, Paula F Ypma, Nicolaus Kröger, Ka Lung Wu, Marie Jose Kersten, M Ron Schaafsma, Sandra Croockewit, Esther de Waal, Sonja Zweegman, Lidwien Tick, Annemiek Broijl, Harry Koene, Gerard Bos, Pieter Sonneveld, Stefan Schönland
This prospective, multicenter, phase II study investigated the use of 4 cycles of bortezomib-dexamethasone induction treatment, followed by high dose melphalan and autologous stem cell transplantation (SCT) in patients with newly diagnosed light chain (AL) amyloidosis. The aim of the study was to improve the hematologic CR rate 6 months after SCT from 30% to 50%. Fifty patients were enrolled and 72% had 2 or more organs involved. The overall hematologic response rate after induction treatment was 80% including 20% CR and 38% VGPR...
March 28, 2019: Haematologica
Piotr Smolewski, Dominika Rydygier
Ixazomib is a new, orally-administered, reversible proteasome inhibitor which is under investigation for the treatment of refractory/relapsed multiple myeloma (MM), systemic light chain amyloidosis (AL) and Waldenström macroglobulinemia WM). Areas covered: This article covers the mechanism of action, pharmacology and clinical trial results of ixazomib while under investigation for the treatment of various lymphoproliferative disorders. We examine the findings from several phase 3 clinical trials (i) the pivotal TOURMALINE-MM1 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone (ii) the TOURMALINE-MM3 study investigating ixazomib versus placebo as a maintenance therapy in newly-diagnosed MM following induction therapy and autologous stem cell transplantation,(iii) the TOURMALINE-MM2 study investigating ixazomib versus placebo in combination with lenalidomide and dexamethasone in patients with newly-diagnosed MM, and (iv) TOURMALINE-AL1 investigating ixazomib plus dexamethasone in patients with relapsed/refractory AL amyloidosis...
March 25, 2019: Expert Opinion on Investigational Drugs
Po-Jen Hsiao, Ya-Chieh Chang, Yuan-Heng Tsao, Kun-Lin Wu, Yung-Hsi Kao, Jenq-Shyong Chan, Chih-Hung Wang, Yen-Yue Lin, Chih-Pin Chuu, Yaoh-Shiang Lin
BACKGROUND: Amyloidosis is a rare and variable disease, characterized by extracellular deposits of amyloid protein in different tissues and organs. Patients may present with a range of symptoms, depending on the extent of involvement. Rapid, accurate diagnosis is still challenging in clinical practice. CASE REPORT: A 72-y-old woman presented with a 1-y history of droopy upper left eyelid, resulting in decreased visual acuity, and progressive tongue swelling, resulting in dysarthria, dysphagia, and sleep apnea...
March 21, 2019: Clinica Chimica Acta; International Journal of Clinical Chemistry
Shikha Mishra, Shaurya Joshi, Jennifer E Ward, Eva P Buys, Deepak Mishra, Deepa Mishra, Isabel Morgado, Sudeshna Fisch, Francesca Lavatelli, Giampaolo Merlini, Sharmila Dorbala, Calum A MacRae, Ronglih Liao
Cardiac dysfunction is the most frequent cause of morbidity and mortality in immunoglobulin light chain (AL) amyloidosis. Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a AL patient-derived lambda light chain (LC) is conditionally expressed in the liver under the control of UAS-Gal4 enhancer system...
March 15, 2019: American Journal of Physiology. Heart and Circulatory Physiology
Lidong He, Lissa C Anderson, David R Barnidge, David L Murray, Surendra Dasari, Angela Dispenzieri, Christopher L Hendrickson, Alan G Marshall
The current five-year survival rate for systemic AL amyloidosis or multiple myeloma is ∼51%, indicating the urgent need for better diagnosis methods and treatment plans. Here, we describe highly specific and sensitive top-down and middle-down MS/MS methods owning the advantages of fast sample preparation, ultrahigh mass accuracy, and extensive residue cleavages with 21 telsa FT-ICR MS/MS. Unlike genomic testing, which requires bone marrow aspiration and may fail to identify all monoclonal immunoglobulins produced by the body, the present method requires only a blood draw...
February 25, 2019: Analytical Chemistry
Malte Kircher, Sandra Ihne, Joachim Brumberg, Caroline Morbach, Stefan Knop, K Martin Kortüm, Stefan Störk, Andreas K Buck, Theresa Reiter, Wolfgang R Bauer, Constantin Lapa
PURPOSE: Cardiac amyloidosis (CA) is a rare cause of heart failure with frequently delayed diagnosis, because specific early signs or symptoms are missing. Recently, direct amyloid imaging using positron emission tomography/computed tomography (PET/CT) has emerged. The aim of this study was to examine the performance of 18 F-florbetaben-PET/CT in detection of CA, and compare it to echocardiography (echo), cardiac MRI (CMR) and scintigraphy. Additionally, the use of 18 F-florbetaben-PET/CT for quantification of amyloid burden and monitoring of treatment response was assessed...
February 23, 2019: European Journal of Nuclear Medicine and Molecular Imaging
Kristen L McCausland, Avery A Rizio, Michelle K White, Martha S Bayliss, Tiffany P Quock
INTRODUCTION: Light-chain (AL) amyloidosis is a rare, progressive, and typically fatal disease. Health-related quality of life (HRQoL) has been shown to be a significant prognostic factor associated with clinical outcomes such as survival and response to treatment. A better understanding of how patterns of HRQoL may be prospectively associated with costly healthcare resource utilization, such as emergency department (ED) visits and inpatient hospitalizations, is warranted. METHODS: A secondary data analysis of a non-interventional, longitudinal online study of patients with AL amyloidosis (n = 224) was conducted...
February 22, 2019: PharmacoEconomics Open
Angelos G Rigopoulos, Muhammad Ali, Elena Abate, Abdel-Rahman Torky, Marios Matiakis, Mammad Mammadov, Hannes Melnyk, Alexander Vogt, Renato de Vecchis, Boris Bigalke, Walter Wohlgemuth, Sophie Mavrogeni, Michel Noutsias
Amyloidosis is caused by extracellular deposition of insoluble abnormal fibrils constituted by misfolded proteins, which can modify tissue anatomy and hinder the function of multiple organs including the heart. Amyloidosis that can affect the heart includes mostly systemic amyloidosis (amyloid light chain, AL) and transthyretin amyloidosis (ATTR). The latter can be acquired in elderly patients (ATTRwt), or be inherited in younger individuals (ATTRm). The diagnosis is demanding given the high phenotypic heterogeneity of the disease...
February 21, 2019: Heart Failure Reviews
Jun Feng, Congli Zhang, Kaini Shen, Jian Sun, Quan Fang, Lu Zhang, Xinxin Cao, Daobin Zhou, Jian Li, Zhuang Tian
BACKGROUND: Cardiac involvement occurs in more than half of the patients with light-chain amyloidosis (AL), but the characteristics, treatment and prognosis of cardiac AL (CAL) are not fully described. Methods and Results: A total of 227 patients with CAL diagnosis between January 2009 and March 2017 at Peking Union Medical College Hospital were included. Patients with Mayo stages I, II and III AL accounted for 0.9%, 49.8% and 49.3%, respectively. Autologous stem cell transplantation, bortezomib combinations, non-bortezomib regimens and palliative treatment were given as first line therapy in 3...
February 16, 2019: Circulation Journal: Official Journal of the Japanese Circulation Society
Antonella Tufano, Domenico Rendina, Paolo Conca, Beniamino Matani, Giovanni Di Minno
No abstract text is available yet for this article.
February 15, 2019: Internal and Emergency Medicine
Yi L Hwa, Morie A Gertz, Shaji K Kumar, Martha Q Lacy, Francis K Buadi, David Dingli, Prashant Kapoor, Steve R Zeldenrust, Nelson Leung, Susanne R Hayman, Wilson I Gonsalves, Taxiarchis V Kourelis, Rahma Warsame, Ronald S Go, Eli Muchtar, Miriam A Hobbs, Amie L Fonder, Stephen Russell, Robert A Kyle, S Vincent Rajkumar, Angela Dispenzieri
It is well known that staging of patients with AL amyloidosis at diagnosis predicts for survival, but there is a paucity of literature delineating the prognostic value of these systems at relapse. We evaluated the prognostic value of AL staging among 413 patients initiated with second-line therapy between 2000 and 2015. Both the Revised Mayo 2012 and the European revision of Mayo 2004 staging systems were used. The median time from initial treatment to second-line therapy was 11.7 months. The first-line therapy was autologous stem cell transplant (ASCT) in 179 (43%) patients and non-ASCT therapies in 234 patients...
February 8, 2019: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Baojian Liu, Yan Wang, Ming Bai, Di Wang, Jin Zhao, Ming Zhang, Shiren Sun
PURPOSE: At present, a diverse array of treatment regimens are available for systemic amyloid light-chain (AL) amyloidosis. Both cyclophosphamide + thalidomide + dexamethasone (CTD) and melphalan + dexamethasone (MD) regimens have been recommended as first-line therapies, but no detailed comparative studies of the two have been performed. This study is the first to compare the efficacy and tolerability of the CTD and MD regimens in the treatment of AL amyloidosis. METHODS: We retrospectively reviewed data from consecutive patients with AL amyloidosis who were treated with MD or CTD as the initial regimen between June 2012 and January 2018...
February 1, 2019: Clinical Therapeutics
Kevin Domingues, Mariana Saraiva, Liliana Marta, Isabel Monteiro, Margarida Leal
Cardiac amyloidosis is an infiltrative cardiomyopathy, resulting from amyloid deposition within the myocardium. In primary systemic (AL-type) amyloidosis, the amyloid protein is composed of light chains resulting from plasma-cell dyscrasia, and cardiac involvement occurs in up to 50% of the patients We present a case of a 43-year-old man, with complaints of periodical swollen tongue and xerostomia, bleeding gums and haematuria for two months. His blood results showed normocytic anaemia, thrombocytopenia and a high spontaneous INR, therefore he was referred to the Internal Medicine clinic...
September 2018: Revista da Associação Médica Brasileira
Vaishali Sanchorawala
No abstract text is available yet for this article.
January 22, 2019: Blood Advances
Giovanni Palladini, Giampaolo Merlini
No abstract text is available yet for this article.
January 22, 2019: Blood Advances
Gonzalo Gutiérrez-García, María Teresa Cibeira, Montserrat Rovira, Carlos Fernández de Larrea, Natalia Tovar, Luis Gerardo Rodríguez-Lobato, Laura Rosiñol, Pedro Marín, Julio Solano-Vega, María Suárez-Lledó, Alex Bataller, María Teresa Solano, Noemí de Llobet, Ariadna Domenech, Nuria Borràs, Miquel Lozano, Joan Cid, Carmen Martínez, Álvaro Urbano-Ispizua, Jordi Esteve, Enric Carreras, Francesc Fernández-Avilés, Joan Bladé
Autologous stem cell transplant (ASCT) has demonstrated to be an effective treatment for patients with light-chain (AL) amyloidosis. However, a high transplant-related mortality (TRM) rate was reported in previous series of patients and questioned the role of transplant in this disease. Recently, experienced groups have shown a significant TRM decrease that has been attributed to an accurate selection of patients. Moreover, application of several supportive measures has decreased toxicity over amyloid-involved organs...
January 21, 2019: Bone Marrow Transplantation
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