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Blood Reviews Mar 2020Amyloidosis is a group of disorders characterized by a misfolded protein that deposits in organs and compromise their function. Clinician should have a high index of... (Review)
Review
Amyloidosis is a group of disorders characterized by a misfolded protein that deposits in organs and compromise their function. Clinician should have a high index of suspicion because in most cases, the clinical picture is non-specific. Typing of amyloid is of utmost importance and should be an integral part of accurately diagnosing a patient. AL amyloidosis is the most common systemic amyloidosis in the western world in which the misfolded proteins are immunoglobulin light chains secreted by clonal plasma cells. New data about prognostication of AL amyloidosis patients are accumulating. The treatment goal is to eradicate the amyloidogenic plasma cell clone, by using high dose melphalan and/or novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies against CD38). Early diagnosis is important for effectively treating the patient as late diagnosis hampers chances for organ recovery. ATTR amyloidosis is less recognized but is increasingly seen due to better recognition and improved diagnostic tools. New data about treatment options (patisiran, inotersen and tafamidis) have recently been published and are discussed.
Topics: Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Plasma Cells; Risk Assessment
PubMed: 31706583
DOI: 10.1016/j.blre.2019.100636 -
Blood Dec 2010Immunoglobulin free light chains (FLCs) are the precursors of amyloid fibrils in primary amyloidosis (AL). We studied the relationship between FLC levels and clinical...
Immunoglobulin free light chains (FLCs) are the precursors of amyloid fibrils in primary amyloidosis (AL). We studied the relationship between FLC levels and clinical features in 730 patients with newly diagnosed AL. The plasma cell clone was λ in 72% patients, and κ in 28% patients. κ-AL had more GI tract and liver involvement, where as renal involvement was more with λ-AL. While the overall survival (OS) was similar for κ and λ-AL, the median OS for those without an identifiable serum heavy chain was significantly shorter (12.6 vs 29.9 months; P = .02). The OS was shorter among those with a higher dFLC (involved FLC-uninvolved FLC; κ > 29.4 mg/dL or λ > 18.2 mg/dL using median for cutoff); 10.9 vs 37.1 months; P < .001. In multivariate analysis, dFLC was independent of other prognostic factors. The type of light chain impacts the spectrum of organ involvement and the FLC burden correlates with survival in AL.
Topics: Adult; Aged; Aged, 80 and over; Amyloidosis; Female; Heart Diseases; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunoglobulin kappa-Chains; Immunoglobulin lambda-Chains; Kidney Diseases; Liver Diseases; Male; Middle Aged; Plasma Cells; Prognosis; Survival Analysis
PubMed: 20798235
DOI: 10.1182/blood-2010-06-290668 -
British Journal of Haematology Sep 2019Published studies on the epidemiology of amyloidosis have relied on death certificate data for case ascertainment. We estimated the incidence and mortality burden of... (Clinical Trial)
Clinical Trial
Published studies on the epidemiology of amyloidosis have relied on death certificate data for case ascertainment. We estimated the incidence and mortality burden of amyloidosis among residents of the Australian state, Queensland, aged ≥20 years for the years 1999-2013 based on case ascertainment from histopathology reports. Information systems for participating laboratories were scrutinised to identify histopathology reports that documented a diagnosis of amyloidosis. Case mortality status was determined via linkage to the National Death Index. A total of 447 cases of amyloidosis were identified, with a median age at diagnosis of 66 years. A plasma cell dyscrasia was identified in 72% of patients who had paraprotein studies performed. The estimated incidence for Queenslanders aged ≥20 years was 12·1 cases per million person years. The median survival was 2·45 years. Age at diagnosis, presence of a paraprotein, earlier year of diagnosis, and inner regional location of residence (compared with residence in a major city) were independently associated with reduced survival. Our data confirms previously reported incidence data for amyloidosis of approximately 10 cases per million patient years and indicates that survival for Queensland patients with amyloidosis is improving, though it remains poor for the elderly and patients with AL amyloidosis.
Topics: Age Factors; Aged; Disease-Free Survival; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Incidence; Male; Middle Aged; Queensland; Retrospective Studies; Survival Rate
PubMed: 31148162
DOI: 10.1111/bjh.16000 -
JACC. Cardiovascular Imaging Jun 2020
Topics: Amyloid Neuropathies, Familial; Cardiac Imaging Techniques; Cardiomyopathies; Humans; Immunoglobulin Light-chain Amyloidosis; Multimodal Imaging; Predictive Value of Tests
PubMed: 32498923
DOI: 10.1016/j.jcmg.2020.05.002 -
Circulation. Heart Failure Jun 2022Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal... (Review)
Review
Immunoglobulin light chain amyloidosis is a rare, multisystemic, phenotypically heterogenous disease affecting cardiovascular, renal, neurological, and gastrointestinal systems to varying degrees. Its underlying cause is a plasma cell dyscrasia characterized by misfolding of monoclonal immunoglobulin light chains which leads to aggregation and deposition of insoluble amyloid fibrils in target organs. Prognosis is primarily dependent on extent of cardiac involvement and depth of hematologic response to treatment. To facilitate development of new therapies, a public-private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify novel/composite end points and analytic strategies to expedite clinical trials for development of new therapies for the primary hematologic disorder and organ system manifestations. Specialized working groups identified organ-specific end points; additional working groups reviewed health-related quality of life measures and statistical approaches to data analysis. Each working group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Agency, and pharmaceutical companies. This review summarizes the proceedings and recommendations of the Cardiac Working Group. Using a modified Delphi method, the group identified, reviewed, and prioritized cardiac end points relevant to immunoglobulin light chain amyloidosis in the context of an antiplasma cell therapy. Prioritized cardiovascular end points included overall survival, hospitalization, N-terminal pro-B-type natriuretic peptide level, 6-minute walk test, Kansas City Cardiac Questionnaire, and cardiac deterioration progression-free survival. These recommended components will be further explored through evaluation of clinical trial datasets and formal guidance from regulatory authorities.
Topics: Amyloidosis; Heart Failure; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Quality of Life; United States
PubMed: 35331001
DOI: 10.1161/CIRCHEARTFAILURE.121.009038 -
Archivos de Cardiologia de Mexico 2023To describe the evolution of serum free light chains (FLC) in the period between orthotopic heart transplantation (OHT) and autologous stem cell transplantation (ASCT),...
OBJECTIVE
To describe the evolution of serum free light chains (FLC) in the period between orthotopic heart transplantation (OHT) and autologous stem cell transplantation (ASCT), the hematological response one year after ASCT and chemotherapy and immunosuppressive treatment in patients with AL amyloidosis.
METHOD
Case series of consecutive patients diagnosed with AL amyloidosis who received OHT followed by ASCT from the Institutional Registry of Amyloidosis of the Italian Hospital of Buenos Aires, between January 2010 and November 2021. FLC values between transplants and at year post ASCT. Quantitative variables were described with their median and interquartile range. Categorical variables as absolute and relative frequencies.
RESULTS
Of 106 patients with AL amyloidosis, 6 had an OHT followed by ASCT. The median age was 55 years. Most were men (n = 5). In the period between transplants, the involved CLL decreased in two patients and remained stable in three. All achieved complete hematologic remission 1 year after ASCT. A single patient presented relapse in the transplanted solid organ. Tacrolimus, mycophenolate mofetil, and corticosteroids were the immunosuppressive regimen used after OHT.
CONCLUSIONS
OHT represents a treatment option in patients with severe heart failure due to amyloidosis, allowing later intensive treatment with induction chemotherapy and ASCT. Although studies are lacking, immunosuppressive therapy after OHT might have some effect on clonal plasma cells.
Topics: Male; Humans; Middle Aged; Female; Immunoglobulin Light-chain Amyloidosis; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Neoplasm Recurrence, Local; Amyloidosis; Retrospective Studies; Treatment Outcome
PubMed: 37972368
DOI: 10.24875/ACM.22000208 -
BMC Ophthalmology Jan 2022Amyloidosis is a rare, progressive and variable group of diseases characterized by extracellular deposits of amyloid protein in different tissues and organs. It is a...
BACKGROUND
Amyloidosis is a rare, progressive and variable group of diseases characterized by extracellular deposits of amyloid protein in different tissues and organs. It is a protein-misfolding disease in which small proteins of about 10 to 15 kDa acquire an alternative and relatively misfolded state at minimum energy and subsequently aggregate into oligomers and polymers. It mimics other eyelid diseases, such as involutional ptosis, eyelid granulomatous or cancerous lesions. Misdiagnosis of eyelid amyloidosis is usual when the lesion grows slowly and insidiously. Definite diagnosis depends on clinical suspicion and tissue-proven biopsy.
CASE PRESENTATION
A 50-year-old female had painless progressive ptosis in both eyes for 6 months. She presented with limited upward gaze due to swelling of the upper eyelids OU. She complained of mild foreign body sensation. Upon examination, we observed an infiltrated irregular yellowish mass on the surface of her upper palpebral conjunctiva in both eyes. The mass was non-movable without tenderness. We performed excisional biopsy for the masses and subsequent histopathology of the biopsy specimens revealed amyloidosis. Systemic workup showed no other lesions. Unfortunately, her ptosis and upward gaze restriction was not improved after the operation. However, the masses did not enlarge in the following 3 months.
CONCLUSIONS
The varied presentations of ocular adnexal and orbital amyloidosis often lead to a significant delay between first symptoms and diagnosis. Immediate confirmatory biopsy and subsequent systemic workup should be performed whenever amyloidosis is highly suspected.
Topics: Amyloidosis; Blepharoptosis; Conjunctival Diseases; Eyelid Diseases; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Middle Aged
PubMed: 35093058
DOI: 10.1186/s12886-022-02267-4 -
Medicine Jan 2020Although pathological confirmation is the gold standard for diagnosis of amyloidosis, there is a need for a relevant imaging modality to identify involved organs and... (Comparative Study)
Comparative Study Observational Study
Although pathological confirmation is the gold standard for diagnosis of amyloidosis, there is a need for a relevant imaging modality to identify involved organs and evaluate disease extent. Thus, we prospectively investigated imaging findings of Tc-DPD scintigraphy in AL and ATTR amyloidosis.A total of 21 subjects with pathologically confirmed AL or ATTR amyloidosis were included. Pretreatment whole body Tc-DPD planar scanning and regional SPECT/CT were performed in all subjects. For allegedly involved organs, Tc-DPD uptake was visually and semi-quantitatively evaluated on a 4-point scale (grade 0: no uptake, 1: uptake less than spine, 2: uptake similar to spine, and 3: uptake greater than spine).There were 29 organs involved in AL and 12 in ATTR. Significant Tc-DPD uptake was found in 24 organs (sensitivity = 82.8%) in AL and 9 organs (sensitivity = 75.0%) in ATTR. Additional SPECT/CT was helpful to ensure abnormal DPD uptake in the involved organs, which was uncertain by attenuation in planar imaging. Degree of Tc-DPD uptake was significantly higher in ATTR compared with AL amyloidosis (P = .017). Diffuse soft tissue uptake with photon defects in the liver area was found only in ATTR amyloidosis.This study showed that Tc-DPD scintigraphy might have capacity to differentiate between AL and ATTR subtypes with good sensitivity in various organs involving primary systemic AL and ATTR amyloidosis. Additional SPECT/CT significantly improved the diagnostic efficacy of Tc-DPD scintigraphy.
Topics: Adult; Aged; Amyloid Neuropathies, Familial; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Organotechnetium Compounds; Radionuclide Imaging; Single Photon Emission Computed Tomography Computed Tomography; Whole Body Imaging
PubMed: 31977903
DOI: 10.1097/MD.0000000000018905 -
Biophysical Chemistry Jan 2022Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such... (Review)
Review
Dynamic and disordered regions in native proteins are often critical for their function, particularly in ligand binding and signaling. In certain proteins, however, such regions can contribute to misfolding and pathologic deposition as amyloid fibrils in vivo. For example, dynamic and disordered regions can promote amyloid formation by destabilizing the native structure, by directly triggering the aggregation, by promoting protein condensation, or by acting as sites of early proteolytic cleavage that favor a release of aggregation-prone fragments or facilitate fibril maturation. At the same time, enhanced dynamics in the native protein state accelerates proteolytic degradation that counteracts amyloid accumulation in vivo. Therefore, the functional need for dynamic protein regions must be balanced against their inherently labile nature. How exactly this balance is achieved and how is it shifted upon amyloidogenic mutations or post-translational modifications? To illustrate possible scenarios, here we review the beneficial and pathologic roles of dynamic and disordered regions in the native states of three families of human plasma proteins that form amyloid precursors in systemic amyloidoses: immunoglobulin light chain, apolipoproteins, and serum amyloid A. Analysis of structure, stability and local dynamics of these diverse proteins and their amyloidogenic variants exemplifies how disordered/dynamic regions can provide a functional advantage as well as an Achilles heel in pathologic amyloid formation.
Topics: Amyloid; Amyloidogenic Proteins; Amyloidosis; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis
PubMed: 34773861
DOI: 10.1016/j.bpc.2021.106699 -
Current Oncology (Toronto, Ont.) Oct 2023While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have...
Anti-B Cell Maturation Antigen Chimeric Antigen Receptor T Cell Therapy for the Treatment of AL Amyloidosis and Concurrent Relapsed/Refractory Multiple Myeloma: Preliminary Efficacy and Safety.
While immunotherapies, such as CAR T therapy and bi-specific antibodies, have revolutionized the treatment of multiple myeloma (MM), patients with AL amyloidosis have been excluded from trials with these agents due to concerns of underlying autonomic, cardiac, and renal dysfunction, leading to potentially fatal toxicities from these therapies. In this communication, we described the outcomes of two patients with AL amyloidosis and concurrent MM with underlying cardiac and/or renal dysfunction who underwent anti-BCMA CAR T cell therapy with ide-cel or cilta-cel, received cytokine release syndrome prophylaxis, and tolerated therapy well with manageable toxicities and achieved a MRD-negative state. We described the preliminary efficacy and safety of CAR T in patients with AL amyloidosis and highlighted the importance of patient selection and medical optimization of cardiac and renal function prior to CAR T.
Topics: Humans; Multiple Myeloma; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Immunoglobulin Light-chain Amyloidosis; B-Cell Maturation Antigen; Cell- and Tissue-Based Therapy; Kidney Diseases
PubMed: 37999117
DOI: 10.3390/curroncol30110697