|
1
|
Edwards CV, Ferri GM, Villegas-Galaviz J, Ghosh S, Singh Bawa P, Wang F, Klimtchuk E, Ajayi TB, Morgan GJ, Prokaeva T, Staron A, Ruberg FL, Sanchorawala V, Giadone RM, Murphy GJ. Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition. Amyloid 2025; 32:179-192. [PMID: 40134188 DOI: 10.1080/13506129.2025.2478397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/27/2025]
Abstract
BACKGROUND Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity remain unclear. METHODS We identified gene expression changes correlating with human cardiac cell exposure to cardiomyopathy-associated AL LCs. We then confirmed these findings in a clinical dataset focusing on clinical parameters associated with pathways dysregulated at the gene expression level. RESULTS Upon exposure to cardiomyopathy-associated AL LCs, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesise that there could be clinically detectable changes in global longitudinal strain (GLS) on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal interventricular septum diameter (IVSd) but abnormal cardiac biomarkers, suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. CONCLUSION Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.
Collapse
Affiliation(s)
- Camille V Edwards
- Section of Hematology and Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Grace M Ferri
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Josue Villegas-Galaviz
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Sabrina Ghosh
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Pushpinder Singh Bawa
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Feiya Wang
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Elena Klimtchuk
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Tinuola B Ajayi
- Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Gareth J Morgan
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Tatiana Prokaeva
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Andrew Staron
- Section of Hematology and Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Frederick L Ruberg
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
- Section of Cardiovascular Medicine, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - Vaishali Sanchorawala
- Section of Hematology and Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
- Amyloidosis Center, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA
| | - Richard M Giadone
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| | - George J Murphy
- Section of Hematology and Oncology, Department of Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
- Center for Regenerative Medicine, Boston University Chobanian & Avedisian School of Medicine and Boston Medical Center, Boston, Massachusetts, USA
| |
Collapse
|
|
2
|
Martinez-Rivas G, Ayala MV, Bender S, Codo GR, Swiderska WK, Lampis A, Pedroza L, Merdanovic M, Sicard P, Pinault E, Richard L, Lavatelli F, Giorgetti S, Canetti D, Rinsant A, Kaaki S, Ory C, Oblet C, Pollet J, Naser E, Carpinteiro A, Roussel M, Javaugue V, Jaccard A, Bonaud A, Delpy L, Ehrmann M, Bridoux F, Sirac C. A mouse model of cardiac immunoglobulin light chain amyloidosis reveals insights into tissue accumulation and toxicity of amyloid fibrils. Nat Commun 2025; 16:2992. [PMID: 40148271 PMCID: PMC11950232 DOI: 10.1038/s41467-025-58307-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis but there is no reliable in vivo model for better understanding this disease. Here, we develop a transgenic mouse model producing a human AL LC. We show that the soluble full length LC is not toxic but a single injection of pre-formed amyloid fibrils or an unstable fragment of the LC leads to systemic amyloid deposits associated with early cardiac dysfunction. AL fibrils in mice are highly similar to that of human, arguing for a conserved mechanism of amyloid fibrils formation. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC is likely to initiate the formation of amyloid fibrils in vivo, which in turn leads to cardiac dysfunction. This is a valuable model for research on AL amyloidosis and preclinical evaluation of new therapies.
Collapse
Affiliation(s)
- Gemma Martinez-Rivas
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Maria Victoria Ayala
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Sebastien Bender
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Gilles Roussine Codo
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Weronika Karolina Swiderska
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Alessio Lampis
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Laura Pedroza
- University Duisburg-Essen, Centre for Medical Biotechnology, Essen, Germany
| | - Melisa Merdanovic
- University Duisburg-Essen, Centre for Medical Biotechnology, Essen, Germany
| | - Pierre Sicard
- PhyMedExp, IPAM/Biocampus (IBiSa/France Life Imaging), UMR INSERM 1046-CNRS 9214, universityof Montpellier, Montpellier, France
| | - Emilie Pinault
- BISCEm (Biologie Intégrative Santé Chimie Environnement) Platform, US 42 INSERM/UAR 2015 CNRS, University of Limoges, Limoges, France
| | | | - Francesca Lavatelli
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy
- Research Area, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Sofia Giorgetti
- Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy
- Research Area, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Diana Canetti
- Centre for Amyloidosis, Division of Medicine, University College London, London, UK
| | - Alexa Rinsant
- Department of Pathology, University Hospital, Poitiers, France
| | - Sihem Kaaki
- Department of Pathology, University Hospital, Poitiers, France
| | - Cécile Ory
- Department of Pathology, University Hospital, Poitiers, France
| | - Christelle Oblet
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
| | - Justine Pollet
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
| | - Eyad Naser
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Alexander Carpinteiro
- Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Muriel Roussel
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Vincent Javaugue
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
- Department of Nephrology, University Hospital, Poitiers, France
| | - Arnaud Jaccard
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Amélie Bonaud
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Laurent Delpy
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
| | - Michael Ehrmann
- University Duisburg-Essen, Centre for Medical Biotechnology, Essen, Germany
| | - Frank Bridoux
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France
- Department of Nephrology, University Hospital, Poitiers, France
| | - Christophe Sirac
- CNRS UMR7276/INSERM U1262, University of Limoges, CRIBL lab, team 3 BioPIC, Limoges, France.
- French National Reference Centre for AL Amyloidosis and Other Monoclonal IG Deposition Diseases, University Hospital, Limoges, France.
| |
Collapse
|
|
3
|
Atanasova M. Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part A: Endogenous Compounds and Repurposed Drugs. Pharmaceuticals (Basel) 2025; 18:306. [PMID: 40143085 PMCID: PMC11944459 DOI: 10.3390/ph18030306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 02/19/2025] [Accepted: 02/21/2025] [Indexed: 03/28/2025] Open
Abstract
The amyloid hypothesis is the predominant model of Alzheimer's disease (AD) pathogenesis, suggesting that amyloid beta (Aβ) peptide is the primary driver of neurotoxicity and a cascade of pathological events in the central nervous system. Aβ aggregation into oligomers and deposits triggers various processes, such as vascular damage, inflammation-induced astrocyte and microglia activation, disrupted neuronal ionic homeostasis, oxidative stress, abnormal kinase and phosphatase activity, tau phosphorylation, neurofibrillary tangle formation, cognitive dysfunction, synaptic loss, cell death, and, ultimately, dementia. Molecular dynamics (MD) is a powerful structure-based drug design (SBDD) approach that aids in understanding the properties, functions, and mechanisms of action or inhibition of biomolecules. As the only method capable of simulating atomic-level internal motions, MD provides unique insights that cannot be obtained through other techniques. Integrating experimental data with MD simulations allows for a more comprehensive understanding of biological processes and molecular interactions. This review summarizes and evaluates MD studies from the past decade on small molecules, including endogenous compounds and repurposed drugs, that inhibit amyloid beta. Furthermore, it outlines key considerations for future MD simulations of amyloid inhibitors, offering a potential framework for studies aimed at elucidating the mechanisms of amyloid beta inhibition by small molecules.
Collapse
|
|
4
|
Sheehan K, Jeon H, Corr SC, Hayes JM, Mok KH. Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease. Protein J 2025; 44:1-20. [PMID: 39527351 DOI: 10.1007/s10930-024-10237-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2024] [Indexed: 11/16/2024]
Abstract
Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings.
Collapse
Affiliation(s)
- Kate Sheehan
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - Hyesoo Jeon
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- Lonza Biologics Tuas Pte. Ltd., 35 Tuas South Ave 6, Singapore, 637377, Republic of Singapore
| | - Sinéad C Corr
- School of Genetics & Microbiology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
- School of Microbiology and APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - Jerrard M Hayes
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland
| | - K H Mok
- Trinity Biomedical Sciences Institute (TBSI), School of Biochemistry & Immunology, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
- Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.
| |
Collapse
|
|
5
|
Lewis E, Fine N, McCulloch S, Tay J, Duggan P, Neri P, Bahlis N, Jimenez-Zepeda VH. Doxycycline Plus Bortezomib-Containing Regimens for the Treatment of Light-Chain Amyloidosis in the Frontline Setting: Experience from the Amyloidosis Program of Calgary. Curr Oncol 2024; 31:5608-5616. [PMID: 39330043 PMCID: PMC11431705 DOI: 10.3390/curroncol31090415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/14/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
Background: Pre-clinical and retrospective data suggest that doxycycline added to treatment regimens has benefit in AL amyloidosis. However, a recent multicenter, open-label, randomized controlled trial in AL amyloidosis patients treated with CyBorD did not demonstrate a progression-free survival (PFS) or cardiac PFS benefit with added doxycycline. Objective: The main objective of this study was to explore the role of doxycycline combined with bortezomib-containing regimens (BCRs) for newly diagnosed AL amyloidosis patients with cardiac involvement and to compare them with a cohort of concurrent patients treated with BCR only. Material and Methods: AL amyloidosis patients, newly diagnosed between January 2012 and March 2022, who were treated with BCR at the Amyloidosis Program of Calgary (APC) were evaluated. Results: Sixty-four concurrent patients were identified. Thirty-nine patients received doxycycline in addition to BCR (BCR-D) for a median of 8 months. The overall response rate was similar among the groups. No significant differences in VGPR/CR, dFLC at 1 month, time to first response, time to best response, or organ responses were noted between the BCR alone and BCR-D groups. Summary and Conclusions: Our retrospective study demonstrated that doxycycline combined with BCR failed to prolong OS, PFS, or cardiac responses compared with BCR alone in patients with cardiac AL amyloidosis.
Collapse
Affiliation(s)
- Ellen Lewis
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
| | - Nowell Fine
- Department of Cardiac Sciences, University of Calgary, Calgary, AB T2N 4N2, Canada;
| | - Sylvia McCulloch
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
| | - Jason Tay
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
- Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N2, Canada
| | - Peter Duggan
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
- Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N2, Canada
| | - Paola Neri
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
- Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N2, Canada
| | - Nizar Bahlis
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
- Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N2, Canada
| | - Victor H. Jimenez-Zepeda
- Tom Baker Cancer Centre, 1331 29th St., NW, Calgary, AB T2N 4N2, Canada; (E.L.); (S.M.); (J.T.); (P.D.); (P.N.); (N.B.)
- Arnie Charbonneau Cancer Research Institute, Calgary, AB T2N 4N2, Canada
| |
Collapse
|
|
6
|
Wang XF, Li T, Yang M, Huang Y. Periorbital purpura can be the only initial symptom of primary light chain amyloidosis: A case report. World J Clin Cases 2024; 12:5946-5951. [PMID: 39286381 PMCID: PMC11287502 DOI: 10.12998/wjcc.v12.i26.5946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 06/20/2024] [Accepted: 06/27/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND Primary light chain amyloidosis is a rare and complex disease with complex clinical features and is highly susceptible to misdiagnosis and underdiagnosis in the early stages. CASE SUMMARY We report a case of a 47-year-old female patient whose only initial symptom was periorbital purpura, which was not taken seriously enough. As the disease progressed, pleural effusion gradually appeared, and after systematic diagnosis and treatment, she was diagnosed with "primary light chain amyloidosis". She achieved rapid hematological remission after treatment with a daratumumab + bortezomib + cyclophosphamide + dexamethasone regimen. CONCLUSION Periorbital purpura can be the only initial symptom of primary light chain amyloidosis; we should pay attention to the cases where the initial clinical symptoms are only periorbital purpura.
Collapse
Affiliation(s)
- Xiu-Feng Wang
- Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, Henan Province, China
| | - Ting Li
- Department of Blood Purification, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, Henan Province, China
| | - Man Yang
- Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, Henan Province, China
| | - Yan Huang
- Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453100, Henan Province, China
| |
Collapse
|
|
7
|
Wang J, Li J, Zhong L. Current status and prospect of anti-amyloid fibril therapy in AL amyloidosis. Blood Rev 2024; 66:101207. [PMID: 38692939 DOI: 10.1016/j.blre.2024.101207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 04/11/2024] [Accepted: 04/14/2024] [Indexed: 05/03/2024]
Abstract
Amyloid light-chain (AL) amyloidosis is a rare hematological disease that produces abnormal monoclonal immunoglobulin light chains to form amyloid fibrils that are deposited in tissues, resulting in organ damage and dysfunction. Advanced AL amyloidosis has a very poor prognosis with a high risk of early mortality. The combination of anti-plasma cell therapy and amyloid fibrils clearance is the optimal treatment strategy, which takes into account both symptoms and root causes. However, research on anti-amyloid fibrils lags far behind research on anti-plasma cells, and there is currently no approved treatment that could clear amyloid fibrils. Nevertheless, anti-amyloid fibril therapies are being actively investigated recently and have shown potential in clinical trials. In this review, we aim to outline the preclinical work and clinical efficacy of fibril-directed therapies for AL amyloidosis.
Collapse
Affiliation(s)
- Jinghua Wang
- Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jian Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Liye Zhong
- Department of Hematology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
| |
Collapse
|
|
8
|
Muthu SA, Qureshi A, Sharma R, Bisaria I, Parvez S, Grover S, Ahmad B. Redesigning the kinetics of lysozyme amyloid aggregation by cephalosporin molecules. J Biomol Struct Dyn 2024:1-16. [PMID: 38682862 DOI: 10.1080/07391102.2024.2335304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Accepted: 03/20/2024] [Indexed: 05/01/2024]
Abstract
In lysozyme amyloidosis, fibrillar aggregates of lysozyme are associated with severe renal, hepatic, and gastrointestinal manifestations, with no definite therapy. Current drugs are now being tested in amyloidosis clinical trials as aggregation inhibitors to mitigate disease progression. The tetracycline group among antimicrobials in use is in phase II of clinical trials, whereas some macrolides and cephalosporins have shown neuroprotection. In the present study, two cephalosporins, ceftazidime (CZD) and cefotaxime (CXM), and a glycopeptide, vancomycin (VNC), are evaluated for inhibition of amyloid aggregation of hen egg white lysozyme (HEWL) under two conditions (i) 4 M guanidine hydrochloride (GuHCl) at pH 6.5 and 37° C, (ii) At pH 1.5 and 65 °C. Fluorescence quench titration and molecular docking methods report that CZD, CXM, and VNC interact more strongly with the partially folded intermediates (PFI) in comparison to the protein's natural state (N). However, only CZD and CXM proficiently inhibit the aggregation. Transmission electron microscopy, tinctorial assessments, and aggregation kinetics all support oligomer-level inhibition. Transition structures in CZD-HEWL and CXM-HEWL aggregation are shown by circular dichroism (CD). On the other hand, kinetic variables and soluble fraction assays point to a localized association of monomers. Intrinsic fluorescence (IF),1-Anilino 8-naphthalene sulphonic acid, and CD demonstrate structural and conformational modifications redesigning the PFI. GuHCl-induced unfolding and differential scanning fluorimetry suggested that the PFI monomers bound to CZD and CXM exhibited partial stability. Our results present two mechanisms that function in both solution conditions, creating a novel avenue for the screening of putative inhibitors for drug repurposing. We extend our proposed mechanisms in the designing of physical inhibitors of amyloid aggregation considering shorter time frames and foolproof methods.
Collapse
Affiliation(s)
- Shivani A Muthu
- Protein Assembly Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
- Department of Molecular Medicine, School of Interdisciplinary Studies, Jamia Hamdard, New Delhi, India
| | - Afnaan Qureshi
- Protein Assembly Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Rahul Sharma
- Department of Molecular Medicine, School of Interdisciplinary Studies, Jamia Hamdard, New Delhi, India
| | - Ishita Bisaria
- Protein Assembly Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Suhel Parvez
- Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Sonam Grover
- Department of Molecular Medicine, School of Interdisciplinary Studies, Jamia Hamdard, New Delhi, India
| | - Basir Ahmad
- Protein Assembly Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| |
Collapse
|
|
9
|
Edwards CV, Ferri GM, Villegas-Galaviz J, Ghosh S, Bawa PS, Wang F, Klimtchuk E, Ajayi TB, Morgan GJ, Prokaeva T, Staron A, Ruberg FL, Sanchorawala V, Giadone RM, Murphy GJ. Abnormal global longitudinal strain and reduced serum inflammatory markers in cardiac AL amyloidosis patients without significant amyloid fibril deposition. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.14.584987. [PMID: 38558967 PMCID: PMC10980073 DOI: 10.1101/2024.03.14.584987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Background Cardiac dysfunction in AL amyloidosis is thought to be partly related to the direct impact of AL LCs on cardiomyocyte function, with the degree of dysfunction at diagnosis as a major determinant of clinical outcomes. Nonetheless, mechanisms underlying LC-induced myocardial toxicity are not well understood. Methods We identified gene expression changes correlating with human cardiac cells exposed to a cardiomyopathy-associated κAL LC. We then sought to confirm these findings in a clinical dataset by focusing on clinical parameters associated with the pathways dysregulated at the gene expression level. Results Upon exposure to a cardiomyopathy-associated κAL LC, cardiac cells exhibited gene expression changes related to myocardial contractile function and inflammation, leading us to hypothesize that there could be clinically detectable changes in GLS on echocardiogram and serum inflammatory markers in patients. Thus, we identified 29 patients with normal IVSd but abnormal cardiac biomarkers suggestive of LC-induced cardiac dysfunction. These patients display early cardiac biomarker staging, abnormal GLS, and significantly reduced serum inflammatory markers compared to patients with clinically evident amyloid fibril deposition. Conclusion Collectively, our findings highlight early molecular and functional signatures of cardiac AL amyloidosis, with potential impact for developing improved patient biomarkers and novel therapeutics.
Collapse
|
|
10
|
Metcalf BD, Huang J, Kanaan HD, Abukhaled J, Li W, Samarapungavan D, Zarouk S, Zhang PL. The Role of Bone Marrow Biopsy Evaluation in the Workup for Monoclonal Gammopathy of Renal Significance: A Diagnosis of Exclusion. Arch Pathol Lab Med 2024; 148:e57-e62. [PMID: 37787408 DOI: 10.5858/arpa.2022-0342-oa] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2023] [Indexed: 10/04/2023]
Abstract
CONTEXT.— Monoclonal gammopathy of renal significance (MGRS) is a relatively new concept for patients with renal monoclonal protein deposition (RMPD) (except monoclonal cast nephropathy) and has been used as a reason for nephrologists to obtain a bone marrow biopsy (BMB). It takes a team of pathologists and clinicians to determine when RMPD at our institution can be defined as MGRS. OBJECTIVE.— To identify the proportion of various subtypes of tentative MGRS diagnosed by renal biopsy that can be confirmed as final MGRS after BMB. DESIGN.— One hundred thirty kidney biopsies with variants of RMPD were identified during the past 10 years. Biopsy cases with known myeloma, B-cell lymphoma, or monoclonal cast nephropathy were separated as a heavy-burden group. The remaining biopsies with RMPD were considered tentative MGRS. Their BMB and clinical indices were further analyzed to determine the final percentage of MGRS diagnoses. RESULTS.— Among the 130 renal paraprotein deposition cases, 44 (33.8%) were categorized as the heavy-burden group. In the remaining 86 cases, 33 (38.4%) with subsequent identification of myeloma (>10% of monoclonal plasma cells) or lymphoma in BMB were further considered as heavy-burden cases. Eighteen cases (18 of 86; 20.9%) did not receive follow-up BMB; thus, no further analysis was performed. BMBs diagnosed as either nonmalignant (no plasma cells; 8 of 86 cases; 9.3%) or premalignant (<10% plasma cells; 27 of 86 cases; 31.4%) were confirmed to be final MGRS (35 of 86; 40.7%). CONCLUSIONS.— The data indicate that BMB is an important element in the confirmation of MGRS.
Collapse
Affiliation(s)
- Brandon D Metcalf
- From the Department of Pathology (Metcalf, Huang, Kanaan, Li, Zhang)
| | - James Huang
- From the Department of Pathology (Metcalf, Huang, Kanaan, Li, Zhang)
| | - Hassan D Kanaan
- From the Department of Pathology (Metcalf, Huang, Kanaan, Li, Zhang)
| | | | - Wei Li
- From the Department of Pathology (Metcalf, Huang, Kanaan, Li, Zhang)
| | | | - Sami Zarouk
- the Division of Nephrology (Abukhaled, Zarouk)
| | - Ping L Zhang
- From the Department of Pathology (Metcalf, Huang, Kanaan, Li, Zhang)
| |
Collapse
|
|
11
|
Mendelson L, Prokaeva T, Lau KHV, Sanchorawala V, McCausland K, Spencer B, Dasari S, McPhail ED, Kaku MC. Hereditary gelsolin amyloidosis: a rare cause of cranial, peripheral and autonomic neuropathies linked to D187N and Y447H substitutions. Amyloid 2023; 30:357-363. [PMID: 37140928 DOI: 10.1080/13506129.2023.2204999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 04/11/2023] [Indexed: 05/05/2023]
Abstract
INTRODUCTION Hereditary gelsolin (AGel) amyloidosis is a systemic disease that is characterised by neurologic, ophthalmologic, dermatologic, and other organ involvements. We describe the clinical features with a focus on neurological manifestations in a cohort of patients with AGel amyloidosis referred to the Amyloidosis Centre in the United States. METHODS Fifteen patients with AGel amyloidosis were included in the study between 2005 and 2022 with the permission of the Institutional Review Board. Data were collected from the prospectively maintained clinical database, electronic medical records and telephone interviews. RESULTS Neurologic manifestations were featured in 15 patients: cranial neuropathy in 93%, peripheral and autonomic neuropathy in 57% and bilateral carpal tunnel syndrome in 73% of cases. A novel p.Y474H gelsolin variant featured a unique clinical phenotype that differed from the one associated with the most common variant of AGel amyloidosis. DISCUSSION We report high rates of cranial and peripheral neuropathy, carpal tunnel syndrome and autonomic dysfunction in patients with systemic AGel amyloidosis. The awareness of these features will enable earlier diagnosis and timely screening for end-organ dysfunction. The characterisation of pathophysiology will assist the development of therapeutic options in AGel amyloidosis.
Collapse
Affiliation(s)
- Lisa Mendelson
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
- Section of Hematology and Oncology, Department of Medicine, Boston Medical Center, Boston, MA, USA
| | - Tatiana Prokaeva
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
- Department of Pathology and Laboratory Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA
| | - K H Vincent Lau
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
- Neurology Department, Boston Medical Center, Boston, MA, USA
| | - Vaishali Sanchorawala
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
- Section of Hematology and Oncology, Department of Medicine, Boston Medical Center, Boston, MA, USA
| | | | - Brian Spencer
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Ellen D McPhail
- Department of Laboratory of Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Michelle C Kaku
- Amyloidosis Center, Boston University School of Medicine, Boston, MA, USA
- Neurology Department, Boston Medical Center, Boston, MA, USA
| |
Collapse
|
|
12
|
Campbell CM, Baiyee CAMT, Almaani S, Bumma N, Sharma N, LoRusso S, Redder E, Bittengle J, Pfund K, Friemer M, Tong M, Kahwash R, Efebera Y, Parikh S, Vallakati A. Targeted Therapeutics for Transthyretin Amyloid Cardiomyopathy. Am J Ther 2023; 30:e447-e453. [PMID: 37713689 DOI: 10.1097/mjt.0000000000001296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate. AREAS OF UNCERTAINTY To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data. DATA SOURCES A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal." THERAPEUTIC ADVANCES We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72). CONCLUSION Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.
Collapse
Affiliation(s)
- Courtney M Campbell
- Division of Cardiovascular Medicine, the Ohio State University Wexner Medical Center, Columbus, OH
| | | | - Salem Almaani
- Division of Nephrology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Naresh Bumma
- Division of Oncology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Nidhi Sharma
- Division of Oncology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Samantha LoRusso
- Division of Neurology, the Ohio State University Wexner Medical Center, Columbus, OH; and
| | - Elyse Redder
- Department of Oncology Rehabilitation, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Jordan Bittengle
- Division of Oncology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Katherine Pfund
- Division of Oncology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Miriam Friemer
- Division of Neurology, the Ohio State University Wexner Medical Center, Columbus, OH; and
| | - Matthew Tong
- Division of Cardiovascular Medicine, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Rami Kahwash
- Division of Cardiovascular Medicine, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Yvonne Efebera
- Division of Oncology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Samir Parikh
- Division of Nephrology, the Ohio State University Wexner Medical Center, Columbus, OH
| | - Ajay Vallakati
- Division of Cardiovascular Medicine, the Ohio State University Wexner Medical Center, Columbus, OH
| |
Collapse
|
|
13
|
Abdallah N, Dispenzieri A, Muchtar E, Buadi FK, Kapoor P, Lacy MQ, Hwa YL, Fonder A, Hobbs MA, Hayman SR, Leung N, Dingli D, Go RS, Lin Y, Gonsalves WI, Binder M, Kourelis T, Warsame R, Kyle RA, Rajkumar SV, Gertz MA, Kumar SK. The impact of Post-Transplant doxycycline in AL amyloidosis - updated results after Long-Term follow up. Amyloid 2023; 30:261-267. [PMID: 36533960 DOI: 10.1080/13506129.2022.2155809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/14/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION The current treatment paradigm of AL amyloidosis lacks effective fibril-directed therapies. Doxycycline has been shown to have anti-fibril properties in preclinical models. In 2012, we reported that posttransplant prophylaxis with doxycycline was associated with improved survival compared to penicillin in patients with haematologic response. We provide here updated results after long-term follow up. METHODS We included 553 patients who underwent transplant between July 24th, 1996, and June 24th, 2014. Doxycycline 100 mg daily was used for prophylaxis in patients with penicillin allergy; since 2013, doxycycline was used as the standard for prophylaxis. Prophylaxis was typically continued for a year after transplant. RESULTS The median follow-up from transplant was 12.7 years. Doxycycline was used for prophylaxis in 33% of patients; the rest received penicillin. The median time to next treatment was 6.0 (95%CI; 4.4-8.8) years and 6.0 (95%CI; 4.9-7.1) years in the doxycycline and penicillin groups, respectively (p = .89). The median overall survival was 12.0 (95%CI: 11.0-19.6) years and 11.0 (95%CI: 9.6-12.7) years in the 2 groups, respectively (p = .17). There was a minimal trend towards improved survival with doxycycline among patients with ≥ very good partial response and among patients with organ response that was not statistically significant. CONCLUSION After long-term follow-up, there is no clear evidence to support benefit of doxycycline in the post-transplant setting.
Collapse
Affiliation(s)
| | | | - Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Martha Q Lacy
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Yi L Hwa
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Amie Fonder
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | | | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
- Division of Nephrology, Mayo Clinic, Rochester, MN, USA
| | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | - Moritz Binder
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | - Rahma Warsame
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Robert A Kyle
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | | | - Morie A Gertz
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| | - Shaji K Kumar
- Division of Hematology, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
14
|
Zhang W, Ding J, Wang W, Wang D, Pan Y, Xu D. Status and Future Directions of Therapeutics and Prognosis of Cardiac Amyloidosis. Ther Clin Risk Manag 2023; 19:581-597. [PMID: 37457506 PMCID: PMC10348342 DOI: 10.2147/tcrm.s414821] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Accumulation of aberrant proteins in the heart causes cardiac amyloidosis, an uncommon and complicated illness. It can be classified into two main types: light chain (AL) and transthyretin (ATTR). The diagnosis of cardiac amyloidosis is challenging due to its non-specific clinical presentation and lack of definitive diagnostic tests. Diagnostic accuracy has increased with the advent of modern imaging methods, including cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Depending on the severity of cardiac amyloidosis, a number of treatments may be attempted and specified according to the subtype of amyloidosis and the presence of complications. However, there are still significant challenges in treating this condition due to its complexity and lack of effective treatments. The prognosis for patients with cardiac amyloidosis is poor. Despite recent advances in diagnosis and treatment, there is still a need for more effective treatments to improve outcomes for patients with this condition. Therefore, we aim to review the current and future therapeutics reported in the literature and among ongoing clinical trials recruiting patients with CA.
Collapse
Affiliation(s)
- Wenbing Zhang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| | - Jian Ding
- Department of Electrodiagnosis, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| | - Wenhai Wang
- Department of Cardiology, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| | - Duo Wang
- Department of Geriatrics, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| | - Yinping Pan
- Department of Pediatrics, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| | - Dexin Xu
- Department of Orthopedics, Jilin Province FAW General Hospital, Changchun, 130000, People’s Republic of China
| |
Collapse
|
|
15
|
Absmeier RM, Rottenaicher GJ, Svilenov HL, Kazman P, Buchner J. Antibodies gone bad - the molecular mechanism of light chain amyloidosis. FEBS J 2023; 290:1398-1419. [PMID: 35122394 DOI: 10.1111/febs.16390] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/19/2022] [Accepted: 02/03/2022] [Indexed: 12/19/2022]
Abstract
Light chain amyloidosis (AL) is a systemic disease in which abnormally proliferating plasma cells secrete large amounts of mutated antibody light chains (LCs) that eventually form fibrils. The fibrils are deposited in various organs, most often in the heart and kidney, and impair their function. The prognosis for patients diagnosed with AL is generally poor. The disease is set apart from other amyloidoses by the huge number of patient-specific mutations in the disease-causing and fibril-forming protein. The molecular mechanisms that drive the aggregation of mutated LCs into fibrils have been enigmatic, which hindered the development of efficient diagnostics and therapies. In this review, we summarize our current knowledge on AL amyloidosis and discuss open issues.
Collapse
Affiliation(s)
- Ramona M Absmeier
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Georg J Rottenaicher
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Hristo L Svilenov
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Pamina Kazman
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| | - Johannes Buchner
- Center for Functional Protein Assemblies and Department of Chemistry, Technische Universität München, Garching, Germany
| |
Collapse
|
|
16
|
Dima D, Mazzoni S, Anwer F, Khouri J, Samaras C, Valent J, Williams L. Diagnostic and Treatment Strategies for AL Amyloidosis in an Era of Therapeutic Innovation. JCO Oncol Pract 2023; 19:265-275. [PMID: 36854070 DOI: 10.1200/op.22.00396] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2023] Open
Abstract
Despite significant progress and improving outcomes in the management of plasma cell disorders, AL amyloidosis remains diagnostically and therapeutically challenging for clinicians across practice settings. There is, however, a reason for optimism with the advent of new combination therapy approaches and novel targets offering the promise of improvement in end organ function, survival, and quality of life. This review offers a clinically applicable overview of an approach to diagnosis, risk stratification, and clinical management of AL amyloidosis in an era of rapid therapeutic innovation.
Collapse
Affiliation(s)
- Danai Dima
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Sandra Mazzoni
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Faiz Anwer
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Jack Khouri
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | | | - Jason Valent
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| | - Louis Williams
- Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
| |
Collapse
|
|
17
|
Almeida ZL, Brito RMM. Amyloid Disassembly: What Can We Learn from Chaperones? Biomedicines 2022; 10:3276. [PMID: 36552032 PMCID: PMC9776232 DOI: 10.3390/biomedicines10123276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/14/2022] [Accepted: 09/26/2022] [Indexed: 12/23/2022] Open
Abstract
Protein aggregation and subsequent accumulation of insoluble amyloid fibrils with cross-β structure is an intrinsic characteristic of amyloid diseases, i.e., amyloidoses. Amyloid formation involves a series of on-pathway and off-pathway protein aggregation events, leading to mature insoluble fibrils that eventually accumulate in multiple tissues. In this cascade of events, soluble oligomeric species are formed, which are among the most cytotoxic molecular entities along the amyloid cascade. The direct or indirect action of these amyloid soluble oligomers and amyloid protofibrils and fibrils in several tissues and organs lead to cell death in some cases and organ disfunction in general. There are dozens of different proteins and peptides causing multiple amyloid pathologies, chief among them Alzheimer's, Parkinson's, Huntington's, and several other neurodegenerative diseases. Amyloid fibril disassembly is among the disease-modifying therapeutic strategies being pursued to overcome amyloid pathologies. The clearance of preformed amyloids and consequently the arresting of the progression of organ deterioration may increase patient survival and quality of life. In this review, we compiled from the literature many examples of chemical and biochemical agents able to disaggregate preformed amyloids, which have been classified as molecular chaperones, chemical chaperones, and pharmacological chaperones. We focused on their mode of action, chemical structure, interactions with the fibrillar structures, morphology and toxicity of the disaggregation products, and the potential use of disaggregation agents as a treatment option in amyloidosis.
Collapse
Affiliation(s)
| | - Rui M. M. Brito
- Chemistry Department and Coimbra Chemistry Centre—Institute of Molecular Sciences (CQC-IMS), University of Coimbra, 3004-535 Coimbra, Portugal
| |
Collapse
|
|
18
|
Martinez-Rivas G, Bender S, Sirac C. Understanding AL amyloidosis with a little help from in vivo models. Front Immunol 2022; 13:1008449. [PMID: 36458006 PMCID: PMC9707859 DOI: 10.3389/fimmu.2022.1008449] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 10/27/2022] [Indexed: 08/01/2023] Open
Abstract
Monoclonal immunoglobulin (Ig) light chain amyloidosis (AL) is a rare but severe disease that may occur when a B or plasma cell clone secretes an excess of free Ig light chains (LCs). Some of these LCs tend to aggregate into organized fibrils with a β-sheet structure, the so-called amyloid fibrils, and deposit into the extracellular compartment of organs, such as the heart or kidneys, causing their dysfunction. Recent findings have confirmed that the core of the amyloid fibrils is constituted by the variable (V) domain of the LCs, but the mechanisms underlying the unfolding and aggregation of this fragment and its deposition are still unclear. Moreover, in addition to the mechanical constraints exerted by the massive accumulation of amyloid fibrils in organs, the direct toxicity of these variable domain LCs, full-length light chains, or primary amyloid precursors (oligomers) seems to play a role in the pathogenesis of the disease. Many in vitro studies have focused on these topics, but the variability of this disease, in which each LC presents unique properties, and the extent and complexity of affected organs make its study in vivo very difficult. Accordingly, several groups have focused on the development of animal models for years, with some encouraging but mostly disappointing results. In this review, we discuss the experimental models that have been used to better understand the unknowns of this pathology with an emphasis on in vivo approaches. We also focus on why reliable AL amyloidosis animal models remain so difficult to obtain and what this tells us about the pathophysiology of the disease.
Collapse
|
|
19
|
Wang Y, Wang X, Yu J, Wu S, Xu Z, Sun W. Idiopathic membranous nephropathy with renal amyloidosis: A case report. Front Med (Lausanne) 2022; 9:986065. [PMID: 36388894 PMCID: PMC9659563 DOI: 10.3389/fmed.2022.986065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 10/12/2022] [Indexed: 11/22/2022] Open
Abstract
Background Immunoglobulin light chain amyloidosis is a clonal, non-proliferative plasma cell disorder, in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Membranous nephropathy (MN) is a group of diseases characterized by deposition of immune complexes under the epithelial cells of glomerular basement and diffuse thickening of the basement membrane. Most patients with idiopathic MN (IMN) have been exposed to phospholipase A2 receptor (PLA2R) antigen, and anti-PLA2R antibodies that attack podocytes can be detected in their blood. IMN combined with amyloidosis nephropathy without secondary factors is rare. The present study describes a patient with IMN combined with immunoglobulin light chain amyloidosis nephropathy. Case report A 39-year-old man was admitted to our hospital because of weight loss and edema. His clinical manifestation was nephrotic syndrome. Renal pathology revealed MN. A positive Congo red staining and the pathognomonic apple-green birefringence under cross-polarized light were considered to be associated with amyloid nephropathy. Immunofluorescence showed that λ light chain was positive. Heavy chain deposition disease and amyloid-associated protein amyloidosis were excluded by immunofluorescence and immunohistochemistry, respectively. Subsequent examinations showed that his serum was negative for antibodies against the PLA2R, but PLA2R was present in renal tissue. The final diagnosis was IMN with light chain amyloid nephropathy. Conclusion Renal amyloidosis accompanied by IMN is uncommon. Attention should be paid to the subtype of the disease and the exclusion of secondary factors. Perfect clinical and pathological examination are helpful for the classification and staging of the disease. Congo red staining, light microscopy, immunofluorescence, immunohistochemistry, electron microscopic examination, pathological tissue staining for PLA2R antigen and testing for anti-PLA2R antibody in serum are helpful.
Collapse
Affiliation(s)
- Yue Wang
- Department of Nephrology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Xueyao Wang
- Department of Nephrology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Jinyu Yu
- Second Department of Urology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Shan Wu
- Department of Nephrology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Zhonggao Xu
- Department of Nephrology, The First Affiliated Hospital of Jilin University, Changchun, China
| | - Weixia Sun
- Department of Nephrology, The First Affiliated Hospital of Jilin University, Changchun, China
- *Correspondence: Weixia Sun,
| |
Collapse
|
|
20
|
Natale C, Barzago MM, Colnaghi L, De Luigi A, Orsini F, Fioriti L, Diomede L. A Combined Cell-Worm Approach to Search for Compounds Counteracting the Toxicity of Tau Oligomers In Vivo. Int J Mol Sci 2022; 23:11277. [PMID: 36232578 PMCID: PMC9569484 DOI: 10.3390/ijms231911277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo, we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days significantly reduced the worm's locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as a prototype drug. Doxy affected tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and the C. elegans-based approach as a platform for pharmacological screening.
Collapse
Affiliation(s)
- Carmina Natale
- Department of Molecular Biochemistry and Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Maria Monica Barzago
- Department of Molecular Biochemistry and Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Luca Colnaghi
- Department of Molecular Biochemistry and Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Ada De Luigi
- Department of Molecular Biochemistry and Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Franca Orsini
- Dulbecco Telethon Institute and Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Luana Fioriti
- Dulbecco Telethon Institute and Department of Neuroscience, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| | - Luisa Diomede
- Department of Molecular Biochemistry and Pharmacology, Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milan, Italy
| |
Collapse
|
|
21
|
Adrogue HE. Amyloidosis of the Heart and Kidney. Methodist Debakey Cardiovasc J 2022; 18:27-33. [PMID: 36132587 PMCID: PMC9461691 DOI: 10.14797/mdcvj.1150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
Amyloidosis encompasses a collection of disorders of pathological protein folding. The extracellular location where these "amyloid fibril" proteins are deposited determines the clinical presentation of the disease. The abnormal architecture of these fibrils makes them insoluble and not easily removed, leading to disruption of normal tissue structure and interference with normal physiology. Amyloidosis of the heart and kidney can be inherited, secondary to unrelated diseases, or due to a plasma cell disorder. This review will focus on immunoglobulin light chain amyloidosis, which is life-threatening and must be diagnosed as early as possible by employing precise and accurate typing to ensure timely and frequently curative therapy.
Collapse
Affiliation(s)
- Horacio E. Adrogue
- Division of Nephrology, Transplantation, and Hypertension, Department of Medicine, Houston Methodist Hospital, Houston, Texas, US
- Texas A&M Medical School, Houston, Texas, US
| |
Collapse
|
|
22
|
Derman B, Castillo JJ, Sarosiek S, Beksac M. When a Monoclonal Gammopathy Is Not Multiple Myeloma. Am Soc Clin Oncol Educ Book 2022; 42:1-10. [PMID: 35394823 DOI: 10.1200/edbk_349643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Our knowledge of monoclonal gammopathies is continuously evolving. Once accepted as a possible precursor condition to multiple myeloma, monoclonal gammopathies as an entity are now associated with many renal, neurologic, and dermatologic disorders of clinical significance. This change has created a challenge for patients and clinicians, as a monoclonal gammopathy may be a harbinger not of multiple myeloma but of other lymphoproliferative disorders such as light-chain amyloidosis and Waldenström macroglobulinemia. Early recognition of monoclonal gammopathies along with a careful workup are essential in determining the next steps in the care of a given patient. Recognition has become all the more important as we understand how to triage the 4% to 9% of patients with monoclonal gammopathies depending on age, with the goal of limiting overdiagnosis and misdiagnosis. In this review, we focus on treatment strategies for patients with monoclonal gammopathies that are not multiple myeloma, including smoldering multiple myeloma, light-chain amyloidosis, and Waldenström macroglobulinemia.
Collapse
Affiliation(s)
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Shayna Sarosiek
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - Meral Beksac
- Department of Hematology, Cebeci Hospital, Ankara University Dikimevi, Ankara, Turkey
| |
Collapse
|
|
23
|
Rodriguez M, Lenihan D, Merlini G. Future Developments in Light Chain Amyloidosis Management. Am J Med 2022; 135 Suppl 1:S53-S57. [PMID: 35081388 DOI: 10.1016/j.amjmed.2022.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 01/14/2022] [Indexed: 11/01/2022]
Abstract
Light chain (AL) amyloidosis is challenging to diagnose, and it should be considered a cardiac emergency. There have been a great deal of advances in the treatment of AL amyloidosis from initial descriptions of melphalan therapy until the recent approval of the first AL amyloidosis specific drug (daratumumab). Comprehension of the pathophysiology and biology of AL amyloidosis is crucial to understanding the major therapeutic targets in which light chain stability remains as a major key target of therapy. Organ dysfunction is a result not only from disruption of organ architecture but also direct cellular toxicity. Novel antiplasma cell agents for AL like isatuximab (anti CD-38 monoclonal antibody), belantamab (anti-BCMA monoclonal antibody), and elotuzumab (anti-SLAMF7 monoclonal antibody) are currently under investigation. Both diagnostic and therapeutic advances make the future of AL management bright while acknowledging the complexity of this patient population and focusing on a multidisciplinary approach.
Collapse
Affiliation(s)
- Mario Rodriguez
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Mo.
| | - Daniel Lenihan
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Mo
| | - Giampaolo Merlini
- Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| |
Collapse
|
|
24
|
Stern LK, Patel J. Cardiac Amyloidosis Treatment. Methodist Debakey Cardiovasc J 2022; 18:59-72. [PMID: 35414852 PMCID: PMC8932359 DOI: 10.14797/mdcvj.1050] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 12/07/2021] [Indexed: 01/17/2023] Open
Abstract
Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA). The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene (TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.
Collapse
Affiliation(s)
- Lily K. Stern
- Smidt Heart Institute, Cedars-Sinai, Los Angeles, California, US
| | - Jignesh Patel
- Smidt Heart Institute, Cedars-Sinai, Los Angeles, California, US
| |
Collapse
|
|
25
|
Markulin I, Matasin M, Turk VE, Salković-Petrisic M. Challenges of repurposing tetracyclines for the treatment of Alzheimer's and Parkinson's disease. J Neural Transm (Vienna) 2022; 129:773-804. [PMID: 34982206 DOI: 10.1007/s00702-021-02457-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/20/2021] [Indexed: 12/13/2022]
Abstract
The novel antibiotic-exploiting strategy in the treatment of Alzheimer's (AD) and Parkinson's (PD) disease has emerged as a potential breakthrough in the field. The research in animal AD/PD models provided evidence on the antiamyloidogenic, anti-inflammatory, antioxidant and antiapoptotic activity of tetracyclines, associated with cognitive improvement. The neuroprotective effects of minocycline and doxycycline in animals initiated investigation of their clinical efficacy in AD and PD patients which led to inconclusive results and additionally to insufficient safety data on a long-standing doxycycline and minocycline therapy in these patient populations. The safety issues should be considered in two levels; in AD/PD patients (particularly antibiotic-induced alteration of gut microbiota and its consequences), and as a world-wide threat of development of bacterial resistance to these antibiotics posed by a fact that AD and PD are widespread incurable diseases which require daily administered long-lasting antibiotic therapy. Recently proposed subantimicrobial doxycycline doses should be thoroughly explored for their effectiveness and long-term safety especially in AD/PD populations. Keeping in mind the antibacterial activity-related far-reaching undesirable effects both for the patients and globally, further work on repurposing these drugs for a long-standing therapy of AD/PD should consider the chemically modified tetracycline compounds tailored to lack antimicrobial but retain (or introduce) other activities effective against the AD/PD pathology. This strategy might reduce the risk of long-term therapy-related adverse effects (particularly gut-related ones) and development of bacterial resistance toward the tetracycline antibiotic agents but the therapeutic potential and desirable safety profile of such compounds in AD/PD patients need to be confirmed.
Collapse
Affiliation(s)
- Iva Markulin
- Community Health Centre Zagreb-Centre, Zagreb, Croatia
| | | | - Viktorija Erdeljic Turk
- Division of Clinical Pharmacology, Department of Medicine, University Hospital Centre Zagreb, Zagreb, Croatia
| | - Melita Salković-Petrisic
- Department of Pharmacology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Salata 11, 10 000, Zagreb, Croatia.
| |
Collapse
|
|
26
|
Affiliation(s)
- Justin L Grodin
- Divisions of Cardiology (J.L.G.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| | - Larry D Anderson
- Hematology and Oncology (L.D.A., A.K.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| | - Ankit Kansagra
- Hematology and Oncology (L.D.A., A.K.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
| |
Collapse
|
|
27
|
Molecular Mechanisms of Cardiac Amyloidosis. Int J Mol Sci 2021; 23:ijms23010025. [PMID: 35008444 PMCID: PMC8744761 DOI: 10.3390/ijms23010025] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 12/18/2021] [Accepted: 12/18/2021] [Indexed: 12/22/2022] Open
Abstract
Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis.
Collapse
|
|
28
|
Bianchi G, Zhang Y, Comenzo RL. AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies: JACC: CardioOncology State-of-the-Art Review. JACC: CARDIOONCOLOGY 2021; 3:467-487. [PMID: 34729520 PMCID: PMC8543128 DOI: 10.1016/j.jaccao.2021.09.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/10/2021] [Accepted: 09/12/2021] [Indexed: 12/19/2022]
Abstract
Immunoglobulin light chain (AL) amyloidosis is an incurable plasma cell disorder characterized by deposition of fibrils of misfolded immunoglobulin free light chains (FLC) in target organs, leading to failure. Cardiac involvement is common in AL amyloidosis and represents the single most adverse prognostic feature. A high index of clinical suspicion with rapid tissue diagnosis and commencement of combinatorial, highly effective cytoreductive therapy is crucial to arrest the process of amyloid deposition and preserve organ function. The clinical use of molecularly targeted drugs, such as proteasome inhibitors and immunomodulatory agents, monoclonal antibodies such as daratumumab, and risk-adjusted autologous stem cell transplant in eligible patients, has radically changed the natural history of AL amyloidosis. Here, we review the state-of-the-art treatment landscape in AL amyloidosis with an eye toward future therapeutic venues to impact the outcome of this devastating illness.
Collapse
Affiliation(s)
- Giada Bianchi
- Amyloidosis Program, Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yifei Zhang
- John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Division of Hematology-Oncology, Division of Cardiovascular Diseases, Boston, Massachusetts, USA
| | - Raymond L Comenzo
- John C Davis Myeloma and Amyloid Program, Tufts Medical Center, Division of Hematology-Oncology, Division of Cardiovascular Diseases, Boston, Massachusetts, USA
| |
Collapse
|
|
29
|
Abstract
Paraproteinemia is associated with different peripheral neuropathies. The major causes of neuropathy correlated with paraproteinemia are the deposition of immunoglobulin in the myelin, represented by anti-myelin-associated glycoprotein (MAG) neuropathy; deposition of immunoglobulin or its fragment in the interstitium, represented by immunoglobulin light chain amyloidosis (AL amyloidosis); and paraneoplastic mechanisms that cannot be solely attributed to the deposition of immunoglobulin or its fragment, represented by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS) syndrome. Patients with anti-MAG neuropathy and POEMS syndrome present with slowing of nerve conduction parameters. This characteristic fulfills the electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) defined by the European Academy of Neurology and Peripheral Nerve Society (EAN/PNS). Although direct damage caused by the deposition of amyloid can induce axonal damage in AL amyloidosis, some patients with this condition have features fulfilling the EAN/PNS electrodiagnostic criteria for CIDP. Conventional immunotherapies for CIDP, such as steroids, intravenous immunoglobulin, and plasma exchange, offer no or only minimal-to-modest benefit. Although rituximab can reduce the level of circulating autoantibodies, it may only be effective in some patients with anti-MAG neuropathy. Drugs including melphalan, thalidomide, lenalidomide, and bortezomib for POEMS syndrome and those including melphalan, thalidomide, lenalidomide, pomalidomide, bortezomib, ixazomib, and daratumumab for AL amyloidosis are considered. Since there will be more therapeutic options in the future, thereby enabling appropriate treatments for individual neuropathies, there is an increasing need for early diagnosis.
Collapse
Affiliation(s)
- Haruki Koike
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
| | - Masahisa Katsuno
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| |
Collapse
|
|
30
|
The discovery and development of transthyretin amyloidogenesis inhibitors: what are the lessons? Future Med Chem 2021; 13:2083-2105. [PMID: 34633220 DOI: 10.4155/fmc-2021-0248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Transthyretin (TTR) is associated with several human amyloid diseases. Various kinetic stabilizers have been developed to inhibit the dissociation of TTR tetramer and the formation of amyloid fibrils. Most of them are bisaryl derivatives, natural flavonoids, crown ethers and carborans. In this review article, we focus on TTR tetramer stabilizers, genetic therapeutic approaches and fibril remodelers. The binding modes of typical bisaryl derivatives, natural flavonoids, crown ethers and carborans are discussed. Based on knowledge of the binding of thyroxine to TTR tetramer, many stabilizers have been screened to dock into the thyroxine binding sites, leading to TTR tetramer stabilization. Particularly, those stabilizers with unique binding profiles have shown great potential in developing the therapeutic management of TTR amyloidogenesis.
Collapse
|
|
31
|
Morgan GJ, Buxbaum JN, Kelly JW. Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis. HEMATO 2021; 2:645-659. [PMID: 35757512 PMCID: PMC9218996 DOI: 10.3390/hemato2040042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the natively folded state of full-length light chains could act as pharmacological kinetic stabilizers, protecting light chains against unfolding, proteolysis and aggregation. Although the sequence of the pathological light chain is unique to each patient, fortunately light chains have highly conserved residues that form binding sites for small molecule kinetic stabilizers. We envision that such stabilizers could complement existing and emerging therapies to benefit light chain amyloidosis patients.
Collapse
Affiliation(s)
- Gareth J. Morgan
- Section of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
- The Amyloidosis Center, Boston University School of Medicine, Boston, MA 02118, USA
- Correspondence:
| | - Joel N. Buxbaum
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Jeffery W. Kelly
- Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
- The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
| |
Collapse
|
|
32
|
Abstract
The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a pre-symptomatic stage checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.
Collapse
|
|
33
|
Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation 2021; 145:8-17. [PMID: 34503349 DOI: 10.1161/circulationaha.121.055953] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background: Doxycycline was demonstrated in a retrospective study to be associated with greater survival in patients with light chain (AL) amyloidosis. Therefore, we prospectively compared the efficacy of bortezomib-cyclophosphamide-dexamethasone (CyBorD) and CyBorD combined with doxycycline for cardiac AL amyloidosis. Methods: This was a multicenter, open-label randomized controlled trial. Patients with Mayo 2004 stage II-III AL amyloidosis were included. Patients were randomized to doxycycline 100 mg twice daily along with 9 cycles of CyBorD (doxycycline group) or to 9 cycles of CyBorD alone (control group). The primary outcome was 2-year progression-free survival (PFS). PFS was defined as the time from randomization to death, hematologic progression or organ progression (heart, kidney or liver). Hematologic progression was defined based on substantial increase in free light chain. Increase in either N-terminal pro B-type natriuretic peptide or cardiac troponin was the main criterion for defining cardiac progression. Cardiac PFS, defined as the time from randomization to cardiac progression or death, was compared between groups in an exploratory analysis. The corresponding treatment hazard ratio was estimated using a Cox regression model. Results: 140 patients underwent randomization, with 70 in each group. The median age was 61 (range, 33-78) years with a male: female ratio of 1.75:1. Stage II disease was present in 34 (48.6%) and 33 (47.1%) patients in the doxycycline and control groups, respectively. After a median follow-up duration of 24.4 months, 32/70 (45.7%) of patients in the doxycycline group and 30/70 (42.9%) of patients in the control group experienced progression. PFS was not significantly different between groups (hazard ratio 0.97, 95% CI, 0.59-1.60, p=0.91). Cardiac progression occurred in 29/70 (41.4%) of patients in the doxycycline group and 26/70 (37.1%) of patients in the control group. The death rates for both groups by the end of follow-up was the same, 25/70 (35.7%). There were no significant differences observed for either cardiac PFS (hazard ratio 0.91, 95% CI, 0.54-1.55, p=0.74) or overall survival (hazard ratio 1.04, 95% CI, 0.60-1.81, p=0.89). Conclusions: Our trial demonstrated that doxycycline combined with CyBorD failed to prolong PFS or cardiac PFS compared with CyBorD alone in cardiac AL amyloidosis. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03401372.
Collapse
Affiliation(s)
- Kai-Ni Shen
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Wei-Jun Fu
- Department of Hematology, Changzheng Hospital, The Second Military Medical University, Shanghai, People's Republic of China
| | - Yu Wu
- Department of Hematology and Hematology Research Laboratory, West China Hospital, Sichuan University, Sichuan, People's Republic of China
| | - Yu-Jun Dong
- Department of Hematology, Peking University First Hospital, Beijing, People's Republic of China
| | - Zhong-Xia Huang
- Multiple Myeloma Medical Center of Beijing, Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yong-Qiang Wei
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Chun-Rui Li
- Department of Hematology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Chun-Yan Sun
- Institute of Hematology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Ye Chen
- Department of Hematology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Hui-Lei Miao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Yue-Lun Zhang
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Xin-Xin Cao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Dao-Bin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Jian Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| |
Collapse
|
|
34
|
Elsayed M, Usher S, Habib MH, Ahmed N, Ali J, Begemann M, Shabbir SA, Shune L, Al-Hilli J, Cossor F, Sperry BW, Raza S. Current Updates on the Management of AL Amyloidosis. J Hematol 2021; 10:147-161. [PMID: 34527111 PMCID: PMC8425803 DOI: 10.14740/jh866] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022] Open
Abstract
Systemic immunoglobulin light chain (AL) amyloidosis is a rare but fatal disease. It results from clonal proliferation of plasma cells with excessive production of insoluble misfolded proteins that aggregate in the extracellular matrix, causing damage to the normal architecture and function of various organs. For decades, treatment for AL amyloidosis was based mainly on therapeutic agents previously studied for its more common counterpart, multiple myeloma. As the prevalence and incidence of AL amyloidosis have increased, ongoing research has been conducted with treatments typically used in myeloma with varying success. In this review, we focus on current treatment strategies and updates to clinical guidelines and therapeutics for AL amyloidosis.
Collapse
Affiliation(s)
- Marwa Elsayed
- St Luke’s Hospital of Kansas City, University of Missouri Kansas City, Wornall Rd, Kansas City, MO 64111, USA
| | - Sara Usher
- St Luke’s Cancer Institute, University of Missouri Kansas City, 4321 Washington St, Ste 4000, Kansas City, MO 64111, USA
| | - Muhammad Hamza Habib
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA
| | - Nausheen Ahmed
- University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Jawad Ali
- West Midland Deanery, 213 Hagley Road, Birmingham, B16 9RG, UK
| | - Madeline Begemann
- St Luke’s Cancer Institute, University of Missouri Kansas City, 4321 Washington St, Ste 4000, Kansas City, MO 64111, USA
| | | | - Leila Shune
- University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
| | - Jaffar Al-Hilli
- University of Missouri Columbia, 1 Hospital Dr, Columbia, MO 65212, USA
| | - Furha Cossor
- St Luke’s Cancer Institute, University of Missouri Kansas City, 4321 Washington St, Ste 4000, Kansas City, MO 64111, USA
| | - Brett W. Sperry
- Mid America Heart Institute, St Luke’s Hospital of Kansas City, Wornall Rd, Kansas City, MO 64111, USA
| | - Shahzad Raza
- St Luke’s Cancer Institute, University of Missouri Kansas City, 4321 Washington St, Ste 4000, Kansas City, MO 64111, USA
| |
Collapse
|
|
35
|
Morgan GJ. Barriers to Small Molecule Drug Discovery for Systemic Amyloidosis. Molecules 2021; 26:3571. [PMID: 34208058 PMCID: PMC8230685 DOI: 10.3390/molecules26123571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 11/16/2022] Open
Abstract
Inhibition of amyloid fibril formation could benefit patients with systemic amyloidosis. In this group of diseases, deposition of amyloid fibrils derived from normally soluble proteins leads to progressive tissue damage and organ failure. Amyloid formation is a complex process, where several individual steps could be targeted. Several small molecules have been proposed as inhibitors of amyloid formation. However, the exact mechanism of action for a molecule is often not known, which impedes medicinal chemistry efforts to develop more potent molecules. Furthermore, commonly used assays are prone to artifacts that must be controlled for. Here, potential mechanisms by which small molecules could inhibit aggregation of immunoglobulin light-chain dimers, the precursor proteins for amyloid light-chain (AL) amyloidosis, are studied in assays that recapitulate different aspects of amyloidogenesis in vitro. One molecule reduced unfolding-coupled proteolysis of light chains, but no molecules inhibited aggregation of light chains or disrupted pre-formed amyloid fibrils. This work demonstrates the challenges associated with drug development for amyloidosis, but also highlights the potential to combine therapies that target different aspects of amyloidosis.
Collapse
Affiliation(s)
- Gareth J Morgan
- Section of Hematology and Medical Oncology, Amyloidosis Center, Department of Medicine, School of Medicine, Boston University, Boston, MA 02118, USA
| |
Collapse
|
|
36
|
Abstract
Opportunities and challenges in the field of systemic amyloidosis can be grouped into 4 categories. First, a deeper understanding of the pathogenesis of the disease is required. Second, a greater awareness of the disease, which will lead to an earlier diagnosis, is imperative. Third, end points for interventional trials are required to convey us to our fourth aspirations, which are novel therapies for patients with light chain amyloidosis.
Collapse
Affiliation(s)
- Angela Dispenzieri
- Division of Hematology, Mayo Clinic, 200 First Street SW Rochester, MN 55905, USA.
| | - Giampaolo Merlini
- Amyloidosis Center, Foundation IRCCS Policlinico San Matteo, University of Pavia, Viale Golgi 19, Pavia 27100, Italy
| |
Collapse
|
|
37
|
Obici L, Adams D. Acquired and inherited amyloidosis: Knowledge driving patients' care. J Peripher Nerv Syst 2021; 25:85-101. [PMID: 32378274 DOI: 10.1111/jns.12381] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 04/30/2020] [Accepted: 05/01/2020] [Indexed: 12/19/2022]
Abstract
Until recently, systemic amyloidoses were regarded as ineluctably disabling and life-threatening diseases. However, this field has witnessed major advances in the last decade, with significant improvements in therapeutic options and in the availability of accurate and non-invasive diagnostic tools. Outstanding progress includes unprecedented hematological response rates provided by risk-adapted regimens in light chain (AL) amyloidosis and the approval of innovative pharmacological agents for both hereditary and wild-type transthyretin amyloidosis (ATTR). Moreover, the incidence of secondary (AA) amyloidosis has continuously reduced, reflecting advances in therapeutics and overall management of several chronic inflammatory diseases. The identification and validation of novel therapeutic targets has grounded on a better knowledge of key molecular events underlying protein misfolding and aggregation and on the increasing availability of diagnostic, prognostic and predictive markers of organ damage and response to treatment. In this review, we focus on these recent advancements and discuss how they are translating into improved outcomes. Neurological involvement dominates the clinical picture in transthyretin and gelsolin inherited amyloidosis and has a significant impact on disease course and management in all patients. Neurologists, therefore, play a major role in improving patients' journey to diagnosis and in providing early access to treatment in order to prevent significant disability and extend survival.
Collapse
Affiliation(s)
- Laura Obici
- Amyloidosis Research and Treatment Centre, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - David Adams
- National Reference Center for Familial Amyloid Polyneuropathy and Other Rare Neuropathies, APHP, Université Paris Saclay, INSERM U1195, Le Kremlin Bicêtre, France
| |
Collapse
|
|
38
|
Muchtar E, Dispenzieri A, Gertz MA, Kumar SK, Buadi FK, Leung N, Lacy MQ, Dingli D, Ailawadhi S, Bergsagel PL, Fonseca R, Hayman SR, Kapoor P, Grogan M, Abou Ezzeddine OF, Rosenthal JL, Mauermann M, Siddiqui M, Gonsalves WI, Kourelis TV, Larsen JT, Reeder CB, Warsame R, Go RS, Murray DL, McPhail ED, Dasari S, Jevremovic D, Kyle RA, Lin Y, Lust JA, Russell SJ, Hwa YL, Fonder AL, Hobbs MA, Rajkumar SV, Roy V, Sher T. Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update. Mayo Clin Proc 2021; 96:1546-1577. [PMID: 34088417 DOI: 10.1016/j.mayocp.2021.03.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/31/2021] [Accepted: 03/03/2021] [Indexed: 12/17/2022]
Abstract
Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients' frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti-plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti-plasma cell therapy, and supportive care.
Collapse
Affiliation(s)
- Eli Muchtar
- Division of Hematology, Mayo Clinic, Rochester, MN.
| | | | | | | | | | - Nelson Leung
- Division of Hematology, Mayo Clinic, Rochester, MN; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | - David Dingli
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | - Rafael Fonseca
- Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
| | | | | | - Martha Grogan
- Division of Hematology, Mayo Clinic, Rochester, MN; Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | | | | | | | | | | | | | - Jeremy T Larsen
- Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
| | - Craig B Reeder
- Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
| | | | - Ronald S Go
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - David L Murray
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Ellen D McPhail
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Surendra Dasari
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN
| | - Dragan Jevremovic
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | - Yi Lin
- Division of Hematology, Mayo Clinic, Rochester, MN
| | - John A Lust
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | - Yi Lisa Hwa
- Division of Hematology, Mayo Clinic, Rochester, MN
| | | | | | - S Vincent Rajkumar
- Division of Hematology, Mayo Clinic, Rochester, MN; Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN
| | - Vivek Roy
- Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
| | - Taimur Sher
- Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL
| |
Collapse
|
|
39
|
Hasib Sidiqi M, Gertz MA. Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2021. Blood Cancer J 2021; 11:90. [PMID: 33993188 PMCID: PMC8124067 DOI: 10.1038/s41408-021-00483-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 04/11/2021] [Accepted: 04/28/2021] [Indexed: 12/29/2022] Open
Abstract
Immunoglobulin light chain amyloidosis (AL) commonly presents with nephrotic range proteinuria, heart failure with preserved ejection fraction, nondiabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea, and should be considered in patients presenting with these symptoms. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Herein we provide a review of established and investigational treatments for patients with AL amyloidosis and provide algorithms for workup and management of these patients.
Collapse
Affiliation(s)
- M Hasib Sidiqi
- Haematology Department, Fiona Stanley Hospital, Perth, WA, Australia
| | - Morie A Gertz
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
40
|
Diteepeng T, Del Monte F, Luciani M. The long and winding road to target protein misfolding in cardiovascular diseases. Eur J Clin Invest 2021; 51:e13504. [PMID: 33527342 DOI: 10.1111/eci.13504] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/18/2021] [Accepted: 01/26/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. DESIGN In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. RESULTS In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. CONCLUSIONS At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians.
Collapse
Affiliation(s)
- Thamonwan Diteepeng
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Federica Del Monte
- Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.,Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna Alma Mater, Bologna, Italy
| | - Marco Luciani
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland.,Department of Internal Medicine, Cantonal Hospital of Baden, Baden, Switzerland
| |
Collapse
|
|
41
|
Addison D, Slivnick JA, Campbell CM, Vallakati A, Jneid H, Schelbert E. Recent Advances and Current Dilemmas in the Diagnosis and Management of Transthyretin Cardiac Amyloidosis. J Am Heart Assoc 2021; 10:e019840. [PMID: 33899502 PMCID: PMC8200718 DOI: 10.1161/jaha.120.019840] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure, arrhythmias, and sudden cardiac death. While CA was previously rapidly fatal, recent advances in diagnosis and treatment have significantly improved outcomes. Advances in cardiac imaging and biomarkers have critically improved the accuracy and efficiency with which CA is diagnosed, even allowing for the noninvasive diagnosis of transthyretin CA. Cardiac magnetic resonance imaging, technetium nuclear imaging, echocardiography, and blood-based biomarkers have established important and complementary roles in the management and advancement of care. At the same time, the development of novel targeted amyloid therapies has allowed patients with CA to live longer and potentially achieve better quality of life. Still, despite this significant progress, there remain critical ongoing questions in the field. Accordingly, within this review we will highlight recent advances in cardiac imaging and therapeutics for CA, while focusing on key opportunities for further optimization of care and outcomes among this growing population. Specifically, we will discuss ongoing debates in the diagnosis of CA, including the interpretation of indeterminate cardiac imaging findings, the best technique to screen asymptomatic transthyretin amyloidosis gene mutation carriers for cardiac involvement, and the ideal method for monitoring response to CA treatment. We will additionally focus on recent advances in treatment for transthyretin amyloidosis-CA, including a discussion of available agents as well as highlighting ongoing clinical trials. Together, these data will allow clinicians to emerge with a greater understanding of the present and future of diagnosis, management, and potentially enhanced outcomes in this rapidly advancing field.
Collapse
Affiliation(s)
- Daniel Addison
- Cardio-Oncology Program Division of Cardiology Department of Internal Medicine The Ohio State University Medical Center Columbus OH
| | - Jeremy A Slivnick
- Cardio-Oncology Program Division of Cardiology Department of Internal Medicine The Ohio State University Medical Center Columbus OH
| | - Courtney M Campbell
- Cardio-Oncology Program Division of Cardiology Department of Internal Medicine The Ohio State University Medical Center Columbus OH
| | - Ajay Vallakati
- Cardio-Oncology Program Division of Cardiology Department of Internal Medicine The Ohio State University Medical Center Columbus OH
| | - Hani Jneid
- Division of Cardiology Baylor College of MedicineMichael E. DeBakey VA Medical Center Houston TX
| | - Erik Schelbert
- Division of Cardiology Department of Internal Medicine University of Pittsburgh PA
| |
Collapse
|
|
42
|
Medina L, González-Lizárraga F, Dominguez-Meijide A, Ploper D, Parrales V, Sequeira S, Cima-Omori MS, Zweckstetter M, Del Bel E, Michel PP, Outeiro TF, Raisman-Vozari R, Chehín R, Socias SB. Doxycycline Interferes With Tau Aggregation and Reduces Its Neuronal Toxicity. Front Aging Neurosci 2021; 13:635760. [PMID: 33828477 PMCID: PMC8020845 DOI: 10.3389/fnagi.2021.635760] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/22/2021] [Indexed: 01/15/2023] Open
Abstract
Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.
Collapse
Affiliation(s)
- Luciana Medina
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| | - Florencia González-Lizárraga
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| | - Antonio Dominguez-Meijide
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.,Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, Santiago de Compostela, Spain.,Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
| | - Diego Ploper
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| | - Valeria Parrales
- Sorbonne Université, Paris Brain Institute -ICM, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Paris (APHP), Hôpital de la Pitié Salpêtrière, Paris, France
| | - Sabrina Sequeira
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| | - Maria-Sol Cima-Omori
- German Center for Neurodegenerative Diseases Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
| | - Markus Zweckstetter
- German Center for Neurodegenerative Diseases Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany.,Department for NMR-based Structural Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany
| | - Elaine Del Bel
- Physiology- Dental School of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Patrick P Michel
- Sorbonne Université, Paris Brain Institute -ICM, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Paris (APHP), Hôpital de la Pitié Salpêtrière, Paris, France
| | - Tiago Fleming Outeiro
- Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany.,Max Planck Institute for Experimental Medicine, Goettingen, Germany.,Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Rita Raisman-Vozari
- Sorbonne Université, Paris Brain Institute -ICM, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Paris (APHP), Hôpital de la Pitié Salpêtrière, Paris, France
| | - Rosana Chehín
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| | - Sergio B Socias
- Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina
| |
Collapse
|
|
43
|
Cruz Rodriguez JB, Tallaj JA. Narrative review of pharmacotherapy for transthyretin cardiac amyloid. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:519. [PMID: 33850916 PMCID: PMC8039703 DOI: 10.21037/atm-20-4636] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Treatment of cardiac amyloidosis is determined by the amyloid type and degree of involvement. Two types of amyloid commonly infiltrate the heart: immunoglobulin light-chain amyloid (AL), and transthyretin amyloid (ATTR), that encompasses other two forms, a hereditary form (hATTR), and a sporadic, age-related wild-type (wtATTR). The prevalence is expected to increase with aging population. The natural history of ATTR cardiomyopathy includes progressive heart failure (HF), complicated by arrhythmias and conduction system disease. New therapies options have been approved or are under investigation. We performed a narrative literature review, manually-searched the reference lists of included articles and relevant reviews. Treatment for cardiac ATTR should be directed towards alleviation of HF symptoms and to slow or stop progressive amyloid deposition. Conventional HF medications are poorly tolerated and may not alter the disease progression or symptoms, except perhaps with the administration of diuretics. There are three approaches of therapy for ATTR cardiomyopathy: tetramer stabilizers, inhibition of ATTR protein synthesis and clearance of deposited fibrils. Tafamidis diminishes the progression of cardiomyopathy, functional parameters, improves overall outcome in patients with early disease stages, irrespective of ATTR status and is well tolerated. Diflunisal has shown promising results in early studies, but at the expense of significant side effects. Two new agents, antisense oligonucleotides, patisiran and inotersen are under investigation in cardiac amyloidosis. Patisiran appears to be the most effective treatment for hATTR, although evidence is limited, with a relatively small cardiac subpopulation. Therapies considering clearance of amyloid fibrils from tissue remain experimental. In conclusion, tafamidis is the only approved agent for the treatment of ATTR cardiomyopathy although multiple other agents have shown promising early results and are undergoing clinical trials. Careful consideration of the type of ATTR, comorbidities and disease stage will be key in deciding the optimal therapy for ATTR patients.
Collapse
Affiliation(s)
- Jose B Cruz Rodriguez
- Division of Cardiovascular Diseases, Texas Tech University Health Science Center El Paso, El Paso, TX, USA
| | - Jose A Tallaj
- Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL, USA.,Department of Medicine, Birmingham VA Medical Center, Birmingham, AL, USA
| |
Collapse
|
|
44
|
Abstract
PURPOSE OF REVIEW Light chain (AL) amyloidosis is an insidious progressive disease which results in significant morbidity and inevitable mortality if not diagnosed and treated promptly. This review will highlight recent developments and summarize critical clinical points and updated practice changes for the clinician in 2020. RECENT FINDINGS Comparative analyses of staging systems, updated prognostic tools, and treatment response criteria now allow for improved patient stratification and treatment decisions; the role of minimal residual disease in response assessment is still being assessed. Clinical and genetic predictors for long-term survivors have been highlighted. Standard-of-care front-line bortezomib and the integration of anti-CD38 monoclonal antibodies in the relapsed disease have transformed treatment approach in recent years. Various clinical trials in the pipeline include novel anti-plasma cell therapies and therapies directed against amyloid deposits which promise to further advance the treatment landscape. Diagnosis, response assessment, and treatment paradigms for AL amyloidosis have evolved significantly in the past 15 years, translating into superior outcomes and increased chances of long-term survival for AL amyloidosis.
Collapse
|
|
45
|
Valero-Muñoz M, Wilson RM, Bretón-Romero R, Croteau D, Seldin DC, Sam F. Doxycycline decreases amyloidogenic light chain-induced autophagy in isolated primary cardiac myocytes. Int J Cardiol 2020; 321:133-136. [DOI: 10.1016/j.ijcard.2020.07.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/09/2020] [Accepted: 07/13/2020] [Indexed: 11/16/2022]
|
|
46
|
Chakraborty R, Lentzsch S. Emerging drugs for the treatment of light chain amyloidosis. Expert Opin Emerg Drugs 2020; 25:299-317. [PMID: 32731778 DOI: 10.1080/14728214.2020.1803829] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Systemic AL amyloidosis is a protein-misfolding disorder that is characterized by the deposition of insoluble amyloid fibrils derived from kinetically unstable light chains. Achieving a rapid and deep hematologic response is critical for long-term survival. AREAS COVERED This review covers the existing and emerging treatment options for systemic AL, divided into anti-plasma cell and fibril-directed therapies. The anti-CD38 monoclonal antibody daratumumab has demonstrated an unprecedented hematologic response rate and will become the new standard-of-care in newly diagnosed patients in combination with CyBorD/VCD. Other plasma cell-directed drugs that have prospective data on safety and efficacy in AL include proteasome inhibitors [bortezomib and ixazomib], immunomodulatory drugs [lenalidomide and pomalidomide], and alkylating agents [melphalan and bendamustine]. A major unmet need is the development of fibril-directed therapies with the goal of eliminating amyloid fibrils that are already deposited in vital organs. EXPERT OPINION The treatment of newly diagnosed AL in the future will likely include daratumumab-based therapy in conjunction with fibril-directed therapy. The most promising second line drugs are venetoclax [for t(11;14)] and pomalidomide, with several others in the pipeline, including antibody-drug conjugates. Minimal residual disease will emerge as a new endpoint for drug development and will potentially guide treatment duration.
Collapse
Affiliation(s)
- Rajshekhar Chakraborty
- Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center , New York, USA
| | - Suzanne Lentzsch
- Department of Medicine, Division of Hematology and Oncology, Columbia University Medical Center , New York, USA
| |
Collapse
|
|
47
|
Schönland S, Palladini G. DUAL expectations in light chain amyloidosis. EClinicalMedicine 2020; 24:100461. [PMID: 32695963 PMCID: PMC7364018 DOI: 10.1016/j.eclinm.2020.100461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 06/30/2020] [Indexed: 11/29/2022] Open
Affiliation(s)
- Stefan Schönland
- Medical Department V and Amyloidosis Center, University Hospital Heidelberg, Germany
- Corresponding author.
| | - Giovanni Palladini
- Amyloidosis Research and Treatment Center, Foundation "Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo" and Department of Molecular Medicine, University of Pavia, Pavia, Italy
| |
Collapse
|
|
48
|
Van Doren L, Lentzsch S. Nonchemotherapy Treatment of Immunoglobulin Light Chain Amyloidosis. Acta Haematol 2020; 143:373-380. [PMID: 32526750 DOI: 10.1159/000507724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 04/03/2020] [Indexed: 01/19/2023]
Abstract
Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.
Collapse
|
|
49
|
Brunger AF, Nienhuis HLA, Bijzet J, Roeloffzen WWH, Vellenga E, Hazenberg BPC. A real-life cohort study of immunoglobulin light-chain (AL) amyloidosis patients ineligible for autologous stem cell transplantation due to severe cardiac involvement or advanced disease. Amyloid 2020; 27:119-127. [PMID: 32052655 DOI: 10.1080/13506129.2020.1714581] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Objective: To study the outcome of patients with AL amyloidosis who were ineligible for high dose melphalan (HDM) and autologous stem cell transplantation (ASCT).Methods: A real-life retrospective observational cohort study of Dutch patients with AL amyloidosis ineligible for HDM and ASCT was performed at the University Medical Center Groningen from January 2001 until April 2017. Primary outcome measure was overall survival (OS). Secondary outcome measures were hematological response (HR), organ responses, and treatment toxicity.Results: Eighty-four patients were included. Ineligibility was due to NYHA class III/IV (n = 58), otherwise advanced disease (n = 11), advanced age (n = 14), or treatment refusal (n = 1). Early death (<3 months) rate was high (44%). Median OS improved from 4 months in period 2001-2009 (n = 36) to 8 months in period 2009-2017 (n = 48, p = .02). HR was seen in 29%, and 42% of the patients, respectively. Median OS was 36 months after induction treatment with bortezomib (n = 32) and 18 months with immunomodulatory imide drug (IMID) (n = 16), both higher than median OS (7 months) with other regimens (n = 27). Incidence of toxicity was high (51%).Conclusion: OS improved in this high-risk group over the years, especially after introduction of new treatment modalities. However, early death rate remains high, illustrating the need for more effective treatment.
Collapse
Affiliation(s)
- Anne F Brunger
- Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hans L A Nienhuis
- Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Division of Vascular Medicine, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Johan Bijzet
- Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Wilfried W H Roeloffzen
- Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Division of Hematology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Edo Vellenga
- Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Division of Hematology, Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Bouke P C Hazenberg
- Department of Rheumatology & Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
|
50
|
D'Souza A, Szabo A, Flynn KE, Dhakal B, Chhabra S, Pasquini MC, Weihrauch D, Hari PN. Adjuvant doxycycline to enhance anti-amyloid effects: Results from the dual phase 2 trial. EClinicalMedicine 2020; 23:100361. [PMID: 32529175 PMCID: PMC7280748 DOI: 10.1016/j.eclinm.2020.100361] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Although, doxycycline use is associated with improved outcomes in amyloidosis in retrospective studies, evidence from clinical trials is limited. METHODS This phase 2 trial of doxycycline (clinicaltrials.gov: NCT02207556) in newly diagnosed light chain (AL) amyloidosis enrolled 25 patients with systemic AL amyloidosis on treatment with doxycycline for 1 year along with chemotherapy. Outcomes of interest included mortality, organ response, and hematologic response rates at 1 year. FINDINGS The median age was 62 years, 64% were male, and 68% had the AL lambda subtype. Patients had Mayo 2012 stage 3 in 24% and stage 4 in 28%. Cardiac involvement was present in 60% of patients, renal involvement in 72%, and 60% patients had 3 or more organs involved. Target organ was cardiac in 14(56%), renal in 7(28%), hepatic in 1(4%) and soft tissue in 3(12%). At 1 year, mortality was 20% (95% confidence interval, 8.9-41.6%) and organ response was 36% (18-57%). Hematologic response in 1-year survivors was 100%, including 30% complete and 55% very good partial response. Autologous hematopoietic cell transplant was performed in 60%; among transplanted patients, day-100 transplant-related mortality was 0. Doxycycline use was safe and not attributed to any grade 2 or higher toxicity. INTERPRETATION In addition to a low 1-year mortality, doxycycline use was safe and associated with high transplant utilization rate. We thus contend that doxycycline should be studied in a placebo-controlled study in newly diagnosed AL patients in the first year, particularly among patients with advanced disease and cardiac involvement.
Collapse
Affiliation(s)
- Anita D'Souza
- Division of Hematology/Oncology, Department of Medicine, United States
- Corresponding author.
| | - Aniko Szabo
- Division of Biostatistics, Institute of Health and Safety, United States
| | - Kathryn E. Flynn
- Division of Hematology/Oncology, Department of Medicine, United States
| | - Binod Dhakal
- Division of Hematology/Oncology, Department of Medicine, United States
| | - Saurabh Chhabra
- Division of Hematology/Oncology, Department of Medicine, United States
| | | | - Dorothee Weihrauch
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | | |
Collapse
|