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Current Hematologic Malignancy Reports Jun 2018Light-chain-associated (AL) amyloidosis is a rare disease with a poor prognosis. However, we have made recent strides in more accurate diagnosis and effective treatment.... (Review)
Review
PURPOSE OF REVIEW
Light-chain-associated (AL) amyloidosis is a rare disease with a poor prognosis. However, we have made recent strides in more accurate diagnosis and effective treatment. Here, we discuss the most recent updates and advancements during the past year in the diagnosis, prognostication, and management of AL amyloidosis both in the upfront and relapsed setting.
RECENT FINDINGS
New imaging modalities, such as cardiac magnetic resonance (CMR) and use of fluorine-labeled radiotracers, are emerging as an important diagnostic tool in conjunction with biomarkers in the diagnosis, prognosis, and monitoring of the effects of therapy. In addition, ongoing evaluation of plasma cell-directed therapeutics, including daratumumab, pomalidomide, and ixazomib, as well as promising targeted novel therapies, such as the monoclonal antibody NEOD001, are in development. In conclusion, incorporating the use of plasma cell-directed therapy and novel agents targeting the amyloid deposits itself hold enormous potential in achieving improved outcomes in AL amyloidosis.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Boron Compounds; Glycine; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Prognosis; Thalidomide
PubMed: 29951831
DOI: 10.1007/s11899-018-0450-1 -
Nephrology (Carlton, Vic.) Nov 2022Early symptoms of primary (AL) amyloidosis are non-specific. Any delay in diagnosis and treatment results in poor outcome despite increasing treatment options. We aimed...
AIM
Early symptoms of primary (AL) amyloidosis are non-specific. Any delay in diagnosis and treatment results in poor outcome despite increasing treatment options. We aimed to determine baseline risk factors that identify patients with poor kidney outcomes and overall survivals.
METHODS
We recruited all patients aged 18 years or above with biopsy-proven renal amyloidosis between years 2000 and 2019 in three Hong Kong regional hospitals. Patients' clinical and pathological parameters, treatment response, kidney outcomes and overall survivals were recorded and analysed.
RESULTS
Thirty-six cases of renal amyloidosis were recruited. Four cases were diagnosed to have multiple myeloma. Edema was the most common presenting symptom. The mean estimated glomerular filtration rate (eGFR) was 98.8 ml/min/1.73 m at presentation. Autologous stem cell transplant conferred the best renal outcomes as well as patients' survival. Twenty-two patients had 50% decrease in eGFR, 12 patients developed end-stage kidney disease (ESKD) and 22 patients died. Hypertension, diabetes mellitus, proteinuria and low eGFR were identified as independent baseline risk factors for ESKD. Proteinuria, hyperlipidemia, and cardiac involvement were independent baseline risk factors for death.
CONCLUSION
Amyloidosis, a rare disease with poor prognosis without treatment. Hypertension, diabetes mellitus, heavy proteinuria and low eGFR at diagnosis were associated with poor kidney outcome.
Topics: Amyloidosis; Diabetes Mellitus; Glomerular Filtration Rate; Hong Kong; Humans; Hypertension; Immunoglobulin Light-chain Amyloidosis; Kidney; Kidney Failure, Chronic; Proteinuria
PubMed: 36054582
DOI: 10.1111/nep.14089 -
British Journal of Haematology Dec 2020Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital... (Review)
Review
Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma cell disorder characterised by production and deposition of misfolded monoclonal light chains in vital organs with potential to cause irreversible organ damage. The treatment of AL amyloidosis has evolved along the lines of multiple myeloma (MM) owing to clonal plasma cells being at the root of both disease processes. Treatment with melphalan and autologous haematopoietic cell transplantation, as well as proteasome inhibitors and immunomodulatory agents, are the standard of care for AL amyloidosis. While these treatment modalities are highly effective against the neoplastic plasma cells, patients often relapse and those with advanced disease may be unable to tolerate these treatments due to side-effects. Immunotherapy with monoclonal antibodies, bispecific antibodies, antibody-drug conjugates and chimeric antigen receptor T cells have revolutionised the treatment armamentarium for MM. These novel immunotherapy agents are in the early phases of evaluation and clinical development for patients with AL amyloidosis. The present review aims to discuss the role of novel immunotherapies currently in development and their potential for use in the treatment of AL amyloidosis.
Topics: Antibodies, Bispecific; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Humans; Immunoconjugates; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Immunotherapy, Adoptive
PubMed: 32298469
DOI: 10.1111/bjh.16697 -
Hematology/oncology Clinics of North... Dec 2020Kidney involvement in immunoglobulin-related amyloidosis (AIg) is common. Although patients with renal-limited AIg tend not to have the high mortality that patients with... (Review)
Review
Kidney involvement in immunoglobulin-related amyloidosis (AIg) is common. Although patients with renal-limited AIg tend not to have the high mortality that patients with cardiac amyloidosis have, they do experience significant morbidity and impact on quality of life. The complexity of the pathogenesis remains incompletely understood. Models have been established to prognosticate and assess for the response to therapy. Patients with advanced renal impairment from immunoglobulin light chain amyloidosis still have poor renal prognosis, and better therapy is needed in order to preserve kidney function. Patients who develop end-stage renal disease can undergo renal replacement therapy with kidney transplantation.
Topics: Antibodies, Monoclonal; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Renal Replacement Therapy
PubMed: 33099424
DOI: 10.1016/j.hoc.2020.08.002 -
Orphanet Journal of Rare Diseases Sep 2020Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides... (Review)
Review
BACKGROUND
Immunoglobulin light chain (AL) amyloidosis is a rare, multi-systemic disorder characterized by two disease processes: an underlying plasma cell dyscrasia that provides the source of pathologic light chains, and the resulting organ dysfunction caused by deposition of amyloid light chain fibrils. There are no FDA approved treatments for AL amyloidosis; regimens developed for multiple myeloma are used off-label to treat the plasma cell disorder and no therapies are directed at organ deposition. Thus, an unmet medical need persists despite advances in disease management. A public-private partnership was recently formed between the Amyloidosis Research Consortium (ARC) and the US Food and Drug Administration (FDA) to bridge scientific gaps in drug development for the treatment of AL amyloidosis.
MAIN BODY
The inaugural Amyloidosis Forum was convened at FDA on 12 November 2019 and led by a multidisciplinary panel of physicians, health outcomes professionals, and representatives from the FDA, ARC, and pharmaceutical companies. Patients provided important perspectives on the pathway to diagnosis, challenges of rigorous treatment, and the burden of disease. The panel reviewed the epidemiology, pathobiology, and clinical features of AL amyloidosis. Hematologic characteristics, staging systems, and response criteria were examined with clear consensus that a "deep response" to plasma cell-directed treatments was critical to overall survival. Emphasis was placed on the heterogeneous clinical phenotypes of AL amyloidosis, including cardiovascular, renal, neurological, and gastrointestinal system manifestations that contribute to morbidity and/or mortality, but render challenges to clinical trial endpoint selection. FDA representatives discussed regulatory perspectives regarding demonstration of clinical benefits of investigational therapies in the context of a rare disease with multi-systemic manifestations. The panel also highlighted the potential importance of well-designed health-related quality of life instruments, quantification of system organ effects, the potential of advanced imaging technologies, and survival prediction models.
CONCLUSIONS
The Amyloidosis Forum identified a clear need for novel trial designs that are scientifically rigorous, feasible, and incorporate clinically meaningful endpoints based on an understanding of the natural history of the disease in an evolving therapeutic landscape. Future forums will delve into these issues and seek to include participation from additional stakeholders.
Topics: Amyloidosis; Drug Development; Humans; Immunoglobulin Light-chain Amyloidosis; Public-Private Sector Partnerships; Quality of Life
PubMed: 32993758
DOI: 10.1186/s13023-020-01525-2 -
Hematology. American Society of... Dec 2020In 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 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.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bortezomib; Disease Management; Humans; Immunoglobulin Light-chain Amyloidosis; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 33275753
DOI: 10.1182/hematology.2020006913 -
Muscle & Nerve Mar 2015Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques...
INTRODUCTION
Acquired and hereditary amyloidosis can cause peripheral neuropathy, but the mechanisms by which this occurs have not been established. Threshold tracking techniques allow in vivo assessment of the properties of the axonal membrane and may shed light on pathogenetic mechanisms underlying neuropathic disorders.
METHODS
We studied 10 subjects with primary amyloidosis using conventional nerve conduction studies and quantitative sensory, autonomic, and axonal excitability testing of median motor and sensory fibers.
RESULTS
As expected, subjects with amyloidosis had evidence of small- and large-fiber neuropathy on conventional testing. There was no significant difference in axonal excitability between subjects and controls apart from the stimulus required to activate sensory fibers.
CONCLUSIONS
Amyloid-related neuropathy does not produce a change in membrane potential as either a primary or secondary event. This suggests that ischemia and axonal compression are unlikely mechanisms for the neuropathy.
Topics: Action Potentials; Aged; Aged, 80 and over; Amyloidosis; Axons; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged
PubMed: 25381694
DOI: 10.1002/mus.24508 -
International Journal of Hematology May 2023Characteristics of AL amyloidosis across Asia are not well-described in the literature. Thus, we overviewed the incidence and disease characteristics of AL amyloidosis... (Review)
Review
BACKGROUND
Characteristics of AL amyloidosis across Asia are not well-described in the literature. Thus, we overviewed the incidence and disease characteristics of AL amyloidosis in Korea.
METHODS
We collected medical records of 302 AL amyloidosis patients and compared survival outcomes by predominant treatment strategy and at four time points: 1995-2003, 2004-2008, 2009-2013, and 2014-2018.
RESULTS
The median age was 62 years (36-83). One hundred forty-one patients were classified as stage III (26.3%) or IV (47.9%). The patients diagnosed between 2014 and 2018 survived longer than those diagnosed at other time points due to the introduction of bortezomib (p < 0.01). In addition, patients who received upfront ASCT survived longer than those who received salvage ASCT or chemotherapy alone (p < 0.01). However, most of the 85 patients who experienced early death within 6 months were older than 75 years, had BMI less than 20, and had a high disease burden.
CONCLUSIONS
The incidence of AL amyloid has increased and survival outcomes have improved gradually, most likely due to introduction of novel agents and upfront ASCT. However, not all patients are suitable for these potent treatment modalities, and avoiding early death within 6 months remains a challenge.
Topics: Humans; Middle Aged; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Transplantation, Autologous; Bortezomib; Republic of Korea; Hematopoietic Stem Cell Transplantation; Retrospective Studies; Treatment Outcome
PubMed: 36574171
DOI: 10.1007/s12185-022-03525-3 -
Clinical Lymphoma, Myeloma & Leukemia Sep 2019Immunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell disorder leading to the production and extracellular deposition of abnormal immunoglobulin light... (Review)
Review
Immunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell disorder leading to the production and extracellular deposition of abnormal immunoglobulin light chains called amyloid. The pathogenesis of the disorder is driven by an abnormal plasma cell clone producing excessive monoclonal immunoglobulin light chains, which undergo deposition in various organs of the body such as the heart, kidney, and gastrointestinal tract. The outcome of the disease remains poor, with significant morbidity and mortality associated with the organ dysfunction. The mainstay of therapy remains targeting the plasma cell clone to decrease or eliminate the production of the abnormal light chains. These therapies include agents such as proteasome inhibitors, immunomodulators, and use of autologous stem cell transplantation. Although current therapies offer potential for disease control and improvement in survival, they cannot reverse light chain deposits in the organs. Newer therapies targeting the light chain fibrils in the form of antibodies binding to the amyloid protein in the organ have recently been developed and have shown early efficacy in clinical trials. In this review, we outline the preclinical work, mechanisms of action, and the clinical efficacy of fibril-directed therapies for light chain amyloidosis.
Topics: Amyloid; Antibodies, Monoclonal; Biomarkers; Combined Modality Therapy; Disease Management; Heart Diseases; Humans; Immunoglobulin Light-chain Amyloidosis; Molecular Targeted Therapy; Prognosis; Treatment Outcome
PubMed: 31262668
DOI: 10.1016/j.clml.2019.03.029 -
Clinical Lymphoma, Myeloma & Leukemia May 2022With recent advances in novel chemotherapeutic agents and increasing use of autologous hematopoietic stem cell transplant, there has been a significant improvement in... (Review)
Review
With recent advances in novel chemotherapeutic agents and increasing use of autologous hematopoietic stem cell transplant, there has been a significant improvement in outcomes for patients with AL Amyloidosis. Daratumumab, with its excellent safety and efficacy profile, appears to be an ideal treatment option for patients with newly diagnosed as well as relapsed refractory AL amyloidosis. In this systematic review, we analyzed the published literature on the role of Daratumumab in pretreated relapsed and refractory AL-amyloidosis patients using PubMed, Embase, Cochrane, and clinicaltrials.gov databases. A total of 16 studies evaluated the role of Daratumumab as monotherapy (DMT) or in combination with other chemotherapeutic agents (DCT). DMT and DCT were associated with promising efficacy with hematologic and organ responses (cardiac/renal) seen in 50%-90% and 50%-80% of the patients, respectively. Daratumumab appeared to be well tolerated with no significant treatment-related adverse events as DMT or DCT.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunoglobulin Light-chain Amyloidosis; Neoplasm Recurrence, Local; Treatment Outcome
PubMed: 34879994
DOI: 10.1016/j.clml.2021.10.014