AL amyloidosis: advances in diagnosis and management.
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ABSTRACT:
SUBMITTER: Koh Y
PROVIDER: S-EPMC7386888 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
Publications
Light chain (AL) amyloidosis is a disease in which malignant plasma cell clones affect multiple organs including the heart and kidney. The mechanism for organ function deterioration in AL amyloidosis differs from multiple myeloma. Thus, not all agents used to treat multiple myeloma shows similar efficacy in AL amyloidosis. In AL amyloidosis, both hematologic and organ responses after treatment are important to improve the clinical outcome. Especially, improving heart function is one of the key a ...[more]
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Project description:AL amyloidosis is caused by the excessive production of nonfunctional immunoglobulins, leading to the formation of amyloid fibrils that damage vital organs, especially the heart and kidneys. AL amyloidosis presents with non-specific symptoms such as fatigue, weight loss, numbness, pain, and nephrotic syndrome. Consequently, diagnosis is often delayed, and patients typically present with advanced disease at diagnosis. The Pavia renal staging model stratifies patients based on their likelihood of progressing to dialysis. Treatment with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (i.e., Dara-CyBorD) was effective in inducing renal response in the landmark phase III ANDROMEDA trial and reducing early mortality. However, determining the most appropriate treatment regimen for relapsed or refractory cases remains a challenge due to various patient- and disease-related factors. Encouragingly, t(11:14) may be a positive indicator of therapy responses to the anti-BCL2 therapy venetoclax. Moreover, it is increasingly possible-for the first time-to clear AL amyloid fibrils from peripheral organs by leveraging novel anti-fibril immunotherapeutic approaches, although these medications are still under investigation in clinical trials. Given these advancements, this review provides a comprehensive overview of the current strategies for diagnosing, staging, treating, and monitoring AL amyloidosis, emphasizing renal involvement.
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Project description:AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.
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Project description:In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.
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Project description:BACKGROUND:Light chain (AL) amyloidosis is a rare, complex disease associated with significant morbidity and mortality. Delays in diagnosis are common and may have detrimental consequences on patients' prognosis. Too little is known regarding the patient journey to diagnosis. OBJECTIVE:The objective of this study was to describe the patient-reported journey to a correct diagnosis for AL amyloidosis. METHODS:Using a mixed-methods approach, data were collected from clinician (n = 4) and patient (n = 10) interviews and a survey of community-based patients with AL amyloidosis (n = 341). Data were used to document the patient experience between the onset of symptoms and the receipt of a diagnosis. RESULTS:Delays in diagnosis were common. Qualitative and quantitative data indicated that initial symptoms were varied and similar to other more prevalent diseases. Two themes regarding the journey to diagnosis emerged: (1) barriers to an early diagnosis; and (2) the emotional toll of the journey. Time to diagnosis was heavily influenced by how patients interpreted their initial symptoms, whether they sought early medical help, and challenges associated with making differential diagnoses. Survey results indicate that patients with primary cardiac involvement were more likely to receive a delayed diagnosis than those with primary kidney involvement. Patients described mixed emotions associated with the eventual diagnosis of AL amyloidosis. CONCLUSIONS:These data support a need for better early identification and support for patients seeking a diagnosis. Increasing clinician awareness may reduce the time to diagnosis. Additional research is needed to identify optimal diagnostic testing to reduce delays in treatment initiation and subsequent severe impacts on health.
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Project description: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.
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