Special Issue "Advances in Amyloidosis: A Theme Issue in Honor of Prof. Dr. Giampaolo Merlini"

A special issue of Hemato (ISSN 2673-6357). This special issue belongs to the section "Plasma Cell Disorders".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editors

Prof. Dr. Giovanni Palladini
E-Mail Website
Guest Editor
Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, Viale Golgi, 19, 27100 Pavia, Italy
Interests: amyloidosis; monoclonal gammopathies of clinical significance; biomarkers
Prof. Dr. Stefan Schönland
E-Mail Website
Guest Editor
Amyloidosis Center and Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
Interests: local and systemic amyloidosis; genetic of plasma cell dyscrasias; monoclonal gammopathies of clinical significance; auto and allo transplantation
Dr. Laurent Garderet
E-Mail Website
Guest Editor
Service d'Hématologie, Hôpital Pitié Salpêtrière, 47‐83 boulevard de l'hôpital, F‐75013 Paris, France
Interests: myeloma; AL amyloidosis; monoclonal gammopathy of clinical significance; POEMS; transplantation
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Special Issue Information

Dear Colleagues,

This Theme Issue aims to honor Prof. Giampaolo Merlini’s outstanding scientific and clinical achievements in the field of systemic amyloidosis. Prof. Merlini was introduced to the concept of “sick molecules and diseases” and to the then neglected and enigmatic condition of amyloidosis by his two mentors, Jan Waldenström and Elliott Osserman at the brink of his career. Since then, he has been devoting his life to elucidating the mechanism of this disease and translating his observations in better care for patients. Patients, in turn, are the constant source of inspiration for his research. Prof. Merlini demonstrated that amyloidogenic light chain exert a direct organ toxicity, discovered the first small molecule, iodo-deoxy-doxorubicin, which could interfere with the amyloidogenic process, set up innovative methods for the diagnosis of amyloidosis, introduced biomarkers in the staging and monitoring of this disease, and contributed to the development of most of the currently available therapeutic regimens. In the last forty years, our understanding of the mechanisms of amyloidosis has advanced greatly, providing novel therapeutic targets and reliable tools for diagnosis. In addition, prognostic stratification and monitoring of the disease became available, and we can now choose between an increasing number of effective therapeutic agents. Thanks to these developments, we are witnessing a constant improvement of the outcome of patients with amyloidosis.
This Special Issue will cover a diverse range of topics, from the classification and differential diagnosis of the various types of amyloidosis to the pathogenesis of clonal and organ disease in light chain amyloidosis. The placing of old and novel therapeutic strategies according to patients’ risk level will be discussed, as well as established and promising tools for disease monitoring.

Prof. Dr. Giovanni Palladini
Prof. Dr. Stefan Schönland
Dr. Laurent Garderet
Guest Editors

Manuscript Submission Information

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Keywords

  • Amyloidosis
  • Biology of amyloid plasma cell clone and light chains
  • Amyloid typing
  • Biomarkers (staging and response assessment)
  • Stem cell transplant in AL amyloidosis
  • Non-transplant chemo-immuno-therapy in AL amyloidosis
  • MRD in AL amyloidosis

Published Papers (3 papers)

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Review

Review
Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis
Hemato 2021, 2(4), 645-659; https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2040042 - 05 Oct 2021
Viewed by 811
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 [...] Read more.
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. Full article
Review
The AL Amyloid Fibril: Looking for a Link between Fibril Formation and Structure
Hemato 2021, 2(3), 505-514; https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2030032 - 06 Aug 2021
Viewed by 372
Abstract
The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, [...] Read more.
The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particularly remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunoglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, I review recent biochemical and biophysical studies that have expanded our knowledge on how versatile the structure of AL fibrils in patients is and highlight their implications for the molecular mechanism of fibril formation in AL amyloidosis. Full article
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Review
Epidemiology of Amyloidosis and Genetic Pathways to Diagnosis and Typing
Hemato 2021, 2(3), 429-440; https://0-doi-org.brum.beds.ac.uk/10.3390/hemato2030027 - 13 Jul 2021
Viewed by 824
Abstract
We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which [...] Read more.
We reviewed our studies on epidemiology and germline genetics of amyloidosis. In epidemiology, we considered both hereditary and non-hereditary amyloidosis. As the source of data, we used the nationwide Swedish hospital discharge register. We estimated the incidence of hereditary ATTR amyloidosis, for which Sweden is a global endemic area, at 2/million. Surprisingly, the disease was also endemic within Sweden; the incidence in the province with the highest incidence was 100 times higher than in the rest of Sweden. Risk of non-Hodgkin lymphoma increased five-fold in the affected individuals. Among non-hereditary amyloidosis, the incidence for AL amyloidosis (abbreviated as AL) was estimated at 3.2/million, with a median survival time of 3 years. Secondary systemic amyloidosis (most likely AA amyloidosis) showed an incidence of 1.15/million for combined sexes. The female rate was two times higher than the male rate, probably relating to the higher female prevalence of rheumatoid arthritis. The median survival time was 4 years. We also identified patients who likely had familial autoinflammatory disease, characterized by early onset and immigrant background from the Eastern Mediterranean area. Young Syrian descendants had the highest incidence rate, which was over 500 times higher than that in individuals with Swedish parents. Germline genetics focused on AL on which we carried out a genome-wide association study (GWAS) in three AL cohorts (N = 1129) from Germany, UK, and Italy. Single nucleotide polymorphisms (SNPs) at 10 loci showed evidence of an association at p < 10−5; some of these were previously documented to influence multiple myeloma (MM) risk, including the SNP at the IRF4 binding site. In AL, SNP rs9344 at the splice site of cyclin D1, influencing translocation (11;14), reached the highest significance, p = 7.80 × 10−11; the SNP was only marginally significant in MM. The locus close to gene SMARCD3, involved in chromatin remodeling, was also significant. These data provide evidence for common genetic susceptibility to AL and MM. We continued by analyzing genetic associations in nine clinical profiles, characterized by organ involvement or Ig profiles. The light chain only (LCO) profile associated with the SNP at the splice site of cyclin D1 with p = 1.99 × 10−12. Even for the other profiles, distinct genetic associations were found. It was concluded that the strong association of rs9344 with LCO and t(11;14) amyloidosis offer attractive mechanistic clues to AL causation. Mendelian randomization analysis identified associations of AL with increased blood monocyte counts and the tumor necrosis factor receptor superfamily member 17 (TNFRSF17 alias BCMA) protein. Two other associations with the TNFRSF members were found. We discuss the corollaries of the findings with the recent success of treating t(11;14) AL with a novel drug venetoclax, and the application of BCMA as the common target of plasma cell immunotherapies. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: The AL amyloid fibril: looking for a link between fibril formation and structure
Authors: Christian Haupt
Affiliation: Institute of Protein Biochemistry, Ulm University, Helmholtzstraße 8/1, 89081, Ulm
Abstract: The formation and deposition of fibrils derived from immunglobulin light chains is a hallmark of systemic AL amyloidosis. A particular remarkable feature of the disease is the diversity and complexity in pathophysiology and clinical manifestations. This is related to the variability of immunglobulins, as virtually every patient has a variety of mutations resulting in their own unique AL protein and thus a unique fibril deposited in the body. Here, we review recent biochemical and biophysical studies that expanded our knowledge in how versatile the structure of AL fibrils is and highlight the mechanistic implications of patient-specific mutations in AL amyloidosis.

Title: The amyloid clone: moving towards targeted therapy?
Authors: Ute Hegenbart
Affiliation: Universität Heidelbergdisabled, Heidelberg, Germany
Abstract: Systemic amyloid light chain (AL) amyloidosis is a very rare disease caused by a clonal B cell disorder. The underlying diseases can be plasma cell disorders (monoclonal gammopathy, smoldering or symptomatic myeloma) or B cell Non-Hodgkin’s lymphoma (e.g. Waldenstrom´s disease or marginal zone lymphoma). It is crucial to diagnose the underlying disease very careful as the treatment of AL amyloidosis is directed to this (often small) B cell clone with specific drugs. The detection of cytogenetic aberrations at diagnosis will play an even more important role in the future.

Title: Future developments in the treatment of AL amyloidosis
Authors: Efstathios Kastritis, Foteini Theodorakakou, Despina Fotiou, Meletios A Dimopoulos
Affiliation: Department of Clinical Therapeutics , National and Kapodistrian University of Athens , Greece
Abstract: The treatment of AL amyloidosis has evolved, and outcomes have improved, but mostly for patients with low or intermediate risk disease; however, recent advances have been limited to improvements in anti-clonal therapies. For patients with high risk disease anti-clonal therapy alone cannot change their poor prognosis and new strategies are needed, that combine different approaches to the disease. Targeted therapies against plasma/B-cell clones that avoid chemotherapy or potentially cardiotoxic drugs may improve depth of hematologic responses and reduce complications. Amyloid fibril targeting may reduce direct toxicity and enhance tissue clearance. Future combinations should be tailored to clone characteristics and specific amyloid properties but early identification of those at high risk will also be integrated in management algorithms.

Title: Differences and similarities in treatment paradigms and goals between AL amyloidosis and multiple myeloma
Authors: Monique Minnema
Affiliation: Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands
Abstract: Although there are basic similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. One similarity is of course the use of the same anti-clonal drugs in both diseases, but the most important mistake a hemato-oncologist can make, is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as applied in myeloma patients. Especially AL amyloidosis patients with >10% bone marrow infiltration of plasmacells are at risk to receive a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for most anti clonal drugs but best apparent in the use of high dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group ≤ 70 years, >80% of patients are fit enough to receive this intensive treatment, this is the case in <20% of AL amyloidosis patients. Another similarity is the alignment in the goal of treatment. Whereas in AL amyloidosis it is already recognized for a long time that the goal should be complete hematological remission, this has become more clear in multiple myeloma in the last years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.

Title: Learning from patients: the interplay between clinical and laboratory research
Authors: Moshe E. Gatt
Affiliation: Faculty of Medicine, Hebrew University of Jerusalem, Israel; The Hematology Department Hadassah Medical Center, Israel
Abstract: Primary systemic light chain amyloidosis (AL) is a rare monoclonal plasma cell (PC) disorder. Much research has been performed to determine the factors that underly amyloidogenicity. However, there is increasing evidence that the primary clone and also patient related factors influences the mechanism and rate of the process. Lessons learnt from patient care definitely imply that this is not solely due to the deposition of material in the tissues that causes organ injury but amyloid light chains precursors are likely to mediate cellular toxicity. Because of disease rarity, combined with the lack of in-vitro tools, and given the fact that multiorgan failure has a wide clinical spectrum causing investigative challenges and treatment limitations due to AL patient frailty, make the disease difficult to diagnose and to further study its origins and treatments. This review will focus on the various aspects of the amyloidogenic plasma cell clone as learnt from the patient care and clinics, and its implications on basic as well as clinical trials amyloidosis research. From etiology understanding to diagnosis and patient, to the future perspectives of individualized patient therapy.

Title: Epidemiology of amyloidosis and pathways to diagnosis and typing
Authors: Kari Hemminki and Asta Försti
Affiliation: German Cancer Research Center
Abstract: We carried out a genome-wide association study in 3 AL amyloidosis cohorts (N=1129) from Germany, UK and Italy, and analyzed genetic associations in 9 clinical profiles, characterized by organ involvement or Ig profiles. In 4 profiles highly significant associations were noted. The odds ratio (OR) for rs9344 in the λ/κ LCO profile was 1.62 (p=1.99x10-12). rs9344 at 11q13.3 maps to a splice site in the cyclin D1 gene. For the IgG profile, rs10507419 at 13q13.2 showed an OR of 1.49, p-value=5.63x10-8. The SNP maps close to the NBEA locus (13q13.3) which is a fragile site causing deletion of the chromosomal end. SNP rs6752376 (2p25.2) in the heart & kidney profile reached an OR of 1.54, p=2.88 x 10-8. In the liver profile rs7820212 (8q11.23) reached an OR of 1.86, p= 1.86 x 10-8; rs7820212 maps close to FAM150A, which is a ligand for receptor tyrosine kinases LTK and ALK. Further work is needed for mechanistic understanding but the strong association of rs9344 with LCO amyloidosis is one attractive clue.

Title: Monitoring patients during and after therapy: response assessment and identification of relapse
Authors: Paolo Milani (1), M. Teresa Cibeira (2)
Affiliation: 1. 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 2. Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, August Pi Sunyer Biomedical Research Institute, Barcelona, Spain
Abstract: Light chain amyloidosis is a complex disease where a small B-cell clone produces a monoclonal immunoglobulin light chain that causes deposits and specific organ dysfunction. The available treatment strategies can target the clone, reducing or even suppressing the production of the amyloidogenic light chain. An international effort allowed the definition of validated hematologic and organ response criteria based on biomarkers. Recently, new methods for the assessment of minimal residual disease were also proposed but need international validation. Lastly, a joint effort is still needed to define specific progression criteria in order to find the right moment for rescue therapy. In our review, we will describe the validated criteria and report the future direction for the definition of progression-criteria in this disease.

Title: Mechanisms of organ damage and novel treatment targets in AL amyloidosis
Authors: Francesca Lavatelli
Affiliation: Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy
Abstract: Deposition of amyloid light chains (LC) in target sites translates into tissue damage and organ dysfunction. Clinical and experimental advances have cast new light on the pathophysiology of damage in AL amyloidosis. The currently accepted view is that, besides the alterations caused by fibrillar deposits in the extracellular space, direct proteotoxicity exerted by prefibrillar LC species is an important pathogenic factor. As our knowledge on the pathological species and altered cellular pathways grows, novel potential therapeutic strategies to prevent or reduce damage can be rationally explored. Complementing chemotherapy with approaches aimed at disrupting the deposited fibrils and stabilizing prefibrillar amyloidogenic LC may allow halting or even reverting damage in target sites. This review will recapitulate the current knowledge and the most recent acquisitions regarding the mechanisms of organ damage in AL amyloidosis, with special emphasis on the heart, and will provide a critical discussion on possible novel treatment targets.

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