AL amyloidosis: untangling new therapies.
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ABSTRACT:
SUBMITTER: Bal S
PROVIDER: S-EPMC8791171 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Systemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic amyloidosis, light-chain (AL) amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
| S-EPMC6142527 | biostudies-literature
Project description:IntroductionThe field of systemic amyloidosis is experiencing major advances in diagnostic and prognostic methods coupled with a growing availability in treatment options.Areas coveredTreatment of AL amyloidosis traditionally targeted the clonal plasma cells, in order to block further production of amyloidogenic light chains. Currently, a research focus is placed on targeting the already formed amyloid deposits using monoclonal antibodies against epitopes on such deposits. Encouraging results were obtained from the three investigated antibodies: NEOD001, 11-1F4 and anti-SAP, but further validation is required before these antibodies can be commercialized. In this paper, we review the current active clinical research in AL amyloidosis, which includes the monoclonal antibodies targeting amyloid deposits, daratumumab, Venetoclax, doxycycline, green tea, pomalidomide, carfilzomib and ixazomib.Expert opinionMonoclonal antibodies, targeting either the amyloid deposits or the plasma cell compartment will likely be integrated into routine treatment practice given their encouraging results and minimal toxicity in the fragile population of AL amyloidosis. Other therapeutic options hold promise to the field as well, but toxicity will likely challenge their routine use. Early recognition remains the best option for outcome enhancement.
| S-EPMC8460071 | biostudies-literature
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.
| S-EPMC7727541 | biostudies-literature
Project description:CD138-selected marrow plasma cells from newly diagnosed AL patients were studied for cyclin D1 expression. We identified patients whose plasma cells overexpressed cyclin D1 and compared them to those whose cells did not.
2010-09-15 | GSE24128 | GEO
Project description:CD138-selected marrow plasma cells from newly diagnosed AL patients were studied for cyclin D1 expression. We identified patients whose plasma cells overexpressed cyclin D1 and compared them to those whose cells did not. We compared two groups of AL patients based cyclin D1 expression being high or low.
2010-09-15 | E-GEOD-24128 | biostudies-arrayexpress
Project description: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 aspects in the treatment of AL amyloidosis. With recent advances in the understanding of the pathophysiologic mechanism of AL amyloidosis, novel treatment methods are under active trial. In this article, I have reviewed the advances in pathophysiology, diagnosis, risk stratification, and treatment of AL amyloidosis.
| S-EPMC7386888 | biostudies-literature
Project description:Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light-chain (AL) amyloidosis for over two decades with improving outcomes; however, the majority of patients are not candidates for this therapy at diagnosis. Novel agents such as immunomodulatory drugs, proteasome inhibitors, and immunotherapy with monoclonal antibodies targeting CD38 have been adopted from the multiple myeloma spheres with encouraging results. Herein, we discuss the role of daratumumab, a monoclonal antibody to CD38, in the treatment of AL amyloidosis. We focus on its mechanism of action, tolerability, and the current published data on its use in AL amyloidosis. Early data from phase I and phase II studies show that daratumumab is tolerated well in this population and induces rapid and deep responses. Phase III trials are currently accruing and we envision daratumumab becoming a key component in the treatment of AL amyloidosis in the future.
| S-EPMC6342668 | biostudies-literature
Project description:Amyloid light chain (AL) amyloidosis is a rare hematologic disorder characterized by the accumulation of a misfolded monoclonal immunoglobulin (Ig) light chain (LC) as fibrillar protein deposits. Current treatments, including cytotoxic chemotherapy and immunomodulatory therapy, are directed at killing the plasma cells that produce the LCs, but have significant toxicity for other cell types. We have designed small interfering RNAs (siRNAs) targeting the amyloidogenic LC messenger RNA (mRNA) in order to reduce expression of the amyloid precursor protein. Using nanomolar concentrations of siRNAs, we have inhibited synthesis of LC in transfected cells in vitro in a dose-dependent fashion. Furthermore, in an in vivo plasmacytoma mouse model of AL amyloidosis, we have demonstrated that these siRNAs can significantly reduce local production and circulating levels of LC. This model system highlights the therapeutic potential of siRNA for AL amyloidosis.
| S-EPMC3155733 | biostudies-literature
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.
| S-EPMC5845075 | biostudies-literature
Project description:Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.
| S-EPMC8130794 | biostudies-literature