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Blood Reviews Jul 2017Amyloid light-chain (AL) amyloidosis is a plasma-cell dyscrasia, as well as the most common type of systematic amyloidosis. Pathogenic plasma cells that have distinct... (Review)
Review
Amyloid light-chain (AL) amyloidosis is a plasma-cell dyscrasia, as well as the most common type of systematic amyloidosis. Pathogenic plasma cells that have distinct cytogenetic and molecular properties secrete an excess amount of amyloidogenic light chains. Assisted by post-translational modifications, matrix components, and other environmental factors, these light chains undergo a conformational change that triggers the formation of amyloid fibrils that overrides the extracellular protein quality control system. Moreover, the amyloidogenic light-chain itself is cytotoxic. As a consequence, organ dysfunction is caused by both organ architecture disruption and the direct cytotoxic effect of amyloidogenic light chains. Here, we reviewed the molecular mechanisms underlying this sequence of events that ultimately leads to AL amyloidosis and also discuss current in vitro and in vivo models, as well as relevant novel therapeutic approaches.
Topics: Animals; Cardiomyopathies; Extracellular Matrix; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Kidney; Molecular Chaperones; Plasma Cells; Protein Processing, Post-Translational
PubMed: 28336182
DOI: 10.1016/j.blre.2017.03.002 -
Cardiovascular & Hematological... 2020The estimated prevalence of AL CA in the US is approximately 8-12 cases per million. Almost 30-50% diagnosed cases of AL amyloid in the US have multisystem involvement,... (Review)
Review
The estimated prevalence of AL CA in the US is approximately 8-12 cases per million. Almost 30-50% diagnosed cases of AL amyloid in the US have multisystem involvement, including cardiac involvement. Even with the availability of advanced diagnostic testing and novel therapies, prognosis remains poor. It is overlooked as a cause of heart failure with preserved ejection fraction leading to a delay in diagnosis when management options are limited and associated with poor survival outcomes. Therefore, the education of physicians is needed to ensure that it would be highly considered as a differential diagnosis. The purpose of this manuscript is to review the advances in the diagnosis and management of cardiac amyloidosis with the aim of educating colleagues who provide care in the primary care setting. We have summarized the pathogenesis of amyloidosis, its association with plasma cell dyscrasias, novel diagnostic and surveillance approaches including echocardiography, cardiovascular magnetic resonance imaging, histopathologic techniques, systemic biomarkers, and advanced treatment approaches including supportive symptomatic management and standard of care chemotherapy targeting the amyloid deposits. Given the overall poor prognosis of amyloidosis, we have also discussed the role of palliative and hospice care.
Topics: Animals; Biomarkers; Disease Management; Echocardiography; Heart Diseases; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Myocardium; Paraproteinemias
PubMed: 33256586
DOI: 10.2174/1871529X20666201130110036 -
Hematology. American Society of... Dec 2021Systemic light chain (AL) amyloidosis is a protein misfolding disorder characterized by the deposition of abnormal immunoglobulin light chains in fibrillary aggregates,... (Review)
Review
Systemic light chain (AL) amyloidosis is a protein misfolding disorder characterized by the deposition of abnormal immunoglobulin light chains in fibrillary aggregates, resulting in end-organ damage. Several unique challenges face treating physicians, including delayed diagnosis, advanced vital organ involvement, and morbidity with treatment. Aggressive supportive care and risk-adapted application of plasma cell-directed therapies are the cornerstones of management. The therapeutic revolution in multiple myeloma will likely further expand the arsenal against plasma cells. Careful investigation of these agents will be critical to establish their role in this fragile population. The promise of fibril-directed therapies to restore organ function remains despite early disappointments. In this review, we discuss new therapies to tackle AL amyloidosis using a case-based approach.
Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dexamethasone; Disease Management; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Teniposide
PubMed: 34889374
DOI: 10.1182/hematology.2021000305 -
The American Journal of Medicine Apr 2022Light chain (AL) amyloidosis is a potentially fatal disease of monoclonal plasma cells that leads to accumulation of light chain amyloid fibrils, organ damage, and the...
Light chain (AL) amyloidosis is a potentially fatal disease of monoclonal plasma cells that leads to accumulation of light chain amyloid fibrils, organ damage, and the manifestations of clinical disease. Meanwhile, coronavirus disease 2019 (COVID-19) is a disease caused by infection with the severe acute respiratory syndrome coronavirus 2 virus, with the potential to cause severe systemic illness and death. There is significant overlap in the demographics and comorbidities observed in AL amyloidosis and those associated with highest risk for severe morbidity and mortality due to COVID-19. This overlap creates unique challenges in caring for patients with AL amyloidosis, which are further compounded by the immunosuppressive nature of anti-plasma cell therapies, the need for frequent clinical assessments, and the exclusion of AL amyloidosis patients from initial COVID-19 vaccine trials. Herein, we highlight many of the relevant concerns related to COVID-19 and the treatment of AL amyloidosis, summarize a general approach for AL amyloidosis management amidst the ongoing COVID-19 pandemic, and discuss current guidance about COVID-19 vaccination of patients with AL amyloidosis.
Topics: Amyloidosis; COVID-19; COVID-19 Vaccines; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Pandemics
PubMed: 35081378
DOI: 10.1016/j.amjmed.2022.01.005 -
Arkhiv Patologii 2021The paper describes an autopsy observation of a 71-year-old male with primary generalized AL amyloidosis lasting about 4 months after its manifestation to the onset of...
The paper describes an autopsy observation of a 71-year-old male with primary generalized AL amyloidosis lasting about 4 months after its manifestation to the onset of death from hepatic and renal failure. Total damage to the liver and spleen, as well as amyloid deposits in the kidneys, adrenal glands, and pancreas were noted.
Topics: Aged; Amyloid; Amyloidosis; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Liver; Male
PubMed: 33512125
DOI: 10.17116/patol20218301131 -
American Journal of Hematology Jul 2021
Topics: Aged; Bone Marrow; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Multiple Myeloma; Nail Diseases; Nails
PubMed: 33180338
DOI: 10.1002/ajh.26046 -
Vnitrni Lekarstvi 2021Amyloidosis is a rare disorder caused by amyloid deposits in various organs and tissues resulting in vital organ dysfunction, eventually death. There are two forms of...
Amyloidosis is a rare disorder caused by amyloid deposits in various organs and tissues resulting in vital organ dysfunction, eventually death. There are two forms of amyloidosis - systemic, characterized by multiple organs affected, and localized (focal). Localized forms of amyloidosis usually affect urinary bladder, skin and lungs. Pulmonary amyloidosis may be localized or systemic such as diffuse alveolo-septal pulmonary amyloidosis which usually accompanies systemic AL amyloidosis. Other two forms of pulmonary amyloidosis are tracheobronchial and nodular. All three forms are usually detected by accident when patients undergo chest examination for different reasons as most cases of pulmonary amyloidosis are asymptomatic. The prognosis of localized amyloidosis is good with 5-year overall survival being 90,6 %. In our case report we present three patients diagnosed with localized pulmonary amyloidosis at our center. In all cases the diagnoses were made following the resection of affected lung segments with no further treatment needed.
Topics: Amyloidosis; Humans; Immunoglobulin Light-chain Amyloidosis; Lung Diseases; Prognosis
PubMed: 35459379
DOI: No ID Found -
BMC Surgery Sep 2016Primary amyloidosis of the breast is an unusual benign disease that mostly occurs in postmenopausal elderly women. Amyloidosis is the deposition of amorphous protein... (Review)
Review
BACKGROUND
Primary amyloidosis of the breast is an unusual benign disease that mostly occurs in postmenopausal elderly women. Amyloidosis is the deposition of amorphous protein within tissues. Breast biopsy is necessary to make a definite diagnosis in order to avoid unnecessary surgical methods. Localized primary amyloidosis of the breast has a good prognosis. However, secondary amyloidosis is a systemic disease and has a poor prognosis.
CASE PRESENTATION
We report the case of a 77-year-old female with primary amyloidosis of the breast. She noticed a lump in her left breast. Mammographic and ultrasonographic examinations indicated breast cancer. However, core needle biopsy showed amyloidosis, not cancer of the breast. For further examinations, the patient visited the outpatient clinics of the hematology, dermatology, and gastroenterology departments. She underwent bone marrow aspiration, computed tomography, cardiac ultrasonography, random skin biopsy, gastrofiberscopy, and colonofiberscopy. Plasma cell myeloma and systemic amyloidosis were ruled out, and localized breast amyloidosis was highly suspected. Lumpectomy was performed to make a definite diagnosis, and histological evaluations revealed that this patient had localized amyloidosis of the breast, and the deposited amyloid protein was of the amyloid light chain kappa type.
CONCLUSIONS
Breast biopsy is necessary in order to avoid unnecessary surgical technique. A diagnosis should be achieved only through a histological evaluation. The main treatment of localized primary amyloidosis of the breast is surgical removal.
Topics: Aged; Amyloidosis; Biopsy; Breast; Breast Neoplasms; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Mammography; Mastectomy, Segmental
PubMed: 27624800
DOI: 10.1186/s12893-016-0178-6 -
Advances in Therapy Nov 2023Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded... (Review)
Review
Systemic immunoglobulin light chain (AL) amyloidosis is a heterogeneous rare disease driven by a destructive monoclonal gammopathy and typified by misfolded immunoglobulin light and/or heavy chains which aggregate and deposit in organs as insoluble amyloid fibrils. Disease heterogeneity is driven by the degree of multi-systemic involvement; cardiac, renal, neurological, and gastrointestinal (GI) systems are affected to varying degrees in different patients. While prognosis is primarily driven by hematologic response to treatment and outcomes associated with cardiac events and overall survival, the involvement of the peripheral nervous, hepatic, and GI systems can also have a significant impact on patients. The Amyloidosis Forum ( https://amyloidosisforum.org ) is a public-private partnership between the nonprofit Amyloidosis Research Consortium ( www.arci.org ) and the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research formed to advance drug development for the treatment of systemic amyloid disorders. A series of virtual workshops focused on the development of novel, patient-relevant endpoint components and analytical strategies for clinical trials in AL amyloidosis. This review summarizes the proceedings and recommendations of the Multi-Systemic Working Group which identified, reviewed, and prioritized endpoints relevant to the impacts of AL amyloidosis on the peripheral nervous, hepatic, and GI systems. The Working Group comprised amyloidosis experts, patient representatives, statisticians, and representatives from the FDA, Medicines and Healthcare products Regulatory Agency (MHRA), and pharmaceutical companies. Prioritized neuropathy/autonomic endpoints included a modified form of the Neuropathy Impairment Score (NIS + 7) and the Composite Autonomic Symptom Score (COMPASS-31), respectively. Alkaline phosphatase was identified as the most relevant indicator of liver involvement and disease progression. Following extensive review of potential GI endpoints, the Working Group identified multiple exploratory endpoints. These recommended components will be further explored through evaluation of clinical trial datasets and possible integration into composite endpoint analysis.
Topics: United States; Humans; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Amyloid; Immunoglobulin Light Chains; Liver
PubMed: 37658177
DOI: 10.1007/s12325-023-02637-4 -
Blood Advances Oct 2019Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data...
Bortezomib and dexamethasone with cyclophosphamide (CyBorD) or melphalan (BMDex) are commonly used primary treatments for light-chain (AL) amyloidosis, but limited data exist on bortezomib with immunomodulatory drug combinations. We report our experience with primary therapy with a bortezomib, lenalidomide, and dexamethasone (VRD) "light" regimen in 34 consecutive patients with AL amyloidosis. The majority (79%) had cardiac involvement, 15% and 23% were Mayo stage 3A and 3B, respectively, and 54% had renal involvement. After the first VRD cycle, 71% of patients achieved a hematologic response (44% at least very good partial response [VGPR]). On intent to treat, 11 (32%) achieved a complete response (of whom 5 of 11 were minimal residual disease [MRD] negative at 10-5), 17 (50%) a VGPR, and 2 (7%) a partial response. The 12-month survival was 73%. Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; nonhematologic toxicities included rash (grade 3/4 [16%]), infections (grade ≥3 [12%]), constipation (grade ≥3 [9%]), and peripheral neuropathy (grade 2 [20%]); 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide, 38% required bortezomib dose reduction, and 12% discontinued bortezomib. We compared VRD to CyBorD in 68 patients matched for Mayo stage and baseline difference between involved minus uninvolved serum free light chain levels, and observed a trend for deeper response at 3 and 6 months with VRD. In conclusion, VRD can be an active regimen for newly diagnosed patients with AL amyloidosis able to induce very deep hematologic responses at the expense of increased toxicity.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bortezomib; Chromosome Aberrations; Dexamethasone; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Lenalidomide; Male; Middle Aged; Treatment Outcome
PubMed: 31648323
DOI: 10.1182/bloodadvances.2019000147