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Acta Haematologica 2020Amyloidosis is a group of complex diseases caused by extracellular deposition of pathological insoluble fibrillary protein in organs and tissues and may result in severe... (Review)
Review
Amyloidosis is a group of complex diseases caused by extracellular deposition of pathological insoluble fibrillary protein in organs and tissues and may result in severe organ dysfunction. Despite the etiological heterogeneity of systemic amyloidosis, the clinical manifestations of the different forms of amyloidosis largely overlap and depend upon the effected organ. The signs and symptoms that should raise suspicion for the potential diagnosis of amyloidosis are usually nonspecific; therefore, establishing the diagnosis is difficult, and early diagnosis requires clinical suspicion. Light chain (AL) amyloidosis may present with highly specific signs such as macroglossia and periorbital purpura, but these signs are insensitive. Amyloidosis is still underdiagnosed, even though treatments are now available and are effective in improving patient's survival and quality of life. Cardiac amyloidosis is the major determinant of survival, and the earlier it is detected the better the survival. All MGUS patients should be routinely screened for AL amyloidosis by a focused history and physical examination and routine assessment of urine albumin. The aim of this review is to provide clinicians with knowledge about the signs and symptoms that raise the suspicion of amyloidosis, bearing in mind the importance of early diagnosis of this disease.
Topics: Amyloidosis; Animals; Diagnosis, Differential; Disease Susceptibility; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Organ Specificity; Phenotype
PubMed: 32340017
DOI: 10.1159/000506617 -
Drugs Feb 2023Systemic light chain (AL) amyloidosis is caused by an usually small B cell clone that produces a toxic light chain forming amyloid deposits in tissue. The heart and... (Review)
Review
Systemic light chain (AL) amyloidosis is caused by an usually small B cell clone that produces a toxic light chain forming amyloid deposits in tissue. The heart and kidney are the major organs affected, but all others, with the exception of the CNS, can be involved. The disease is rapidly progressive, and it is still diagnosed late. Screening programs in patients followed by hematologists for plasma cell dyscrasias should be considered. The diagnosis requires demonstration in a tissue biopsy of amyloid deposits formed by immunoglobulin light chains. The workup of patients with AL amyloidosis requires adequate technology and expertise, and patients should be referred to specialized centers whenever possible. Stagings are based on cardiac and renal biomarkers and guides the choice of treatment. The combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (dara-CyBorD) is the current standard of care. Autologous stem cell transplant is performed in eligible patients, especially those who do not attain a satisfactory response to dara-CyBorD. Passive immunotherapy targeting the amyloid deposits combined with chemo-/immune-therapy targeting the amyloid clone is currently being tested in controlled clinical trials. Response to therapy is assessed based on validated criteria. Profound hematologic response is the early goal of treatment and should be accompanied over time by deepening organ response. Many relapsed/refractory patients are also treated with daratumumab combination, but novel regimens will be needed to rescue daratumumab-exposed subjects. Immunomodulatory drugs are the current cornerstone of rescue therapy, while immunotherapy targeting B-cell maturation antigen and inhibitors of Bcl-2 are promising alternatives.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Plaque, Amyloid; Bortezomib; Kidney; Cyclophosphamide
PubMed: 36652193
DOI: 10.1007/s40265-022-01830-z -
Seminars in Neurology Oct 2019Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations... (Review)
Review
Peripheral neuropathy occurs in the setting of both hereditary and acquired amyloidosis. The most common form of hereditary amyloidosis is caused by 1 of 140 mutations in the transthyretin (TTR) gene, which can lead to neuropathic hereditary transthyretin amyloidosis (hATTR; previously referred to as transthyretin familial amyloid polyneuropathy), whereas acquired immunoglobulin light chain (AL) amyloidosis is the most common acquired form. Patients typically present with a sensorimotor polyneuropathy, focal neuropathy such as carpal tunnel syndrome, or autonomic neuropathy. When neuropathy is the sole or dominant presenting symptom, the diagnosis is commonly delayed. With the advent of new drug therapies for AL amyloidosis and hATTR amyloidosis, including proteasome inhibitors, TTR silencers, and TTR protein stabilizers, the neurologist is uniquely positioned to diagnose neurologic manifestations of systemic amyloidosis, leading to earlier disease identification and treatment. This article reviews the epidemiology, clinical presentations, pathophysiology, diagnostic workup, and treatment of neuropathy in the setting of amyloidosis.
Topics: Amyloid Neuropathies, Familial; Humans; Immunoglobulin Light-chain Amyloidosis; Mutation; Nervous System Diseases; Prealbumin
PubMed: 31639841
DOI: 10.1055/s-0039-1688994 -
Blood May 2022The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a...
The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a presymptomatic stage, checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients, inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible.
Topics: Amyloidosis; Bortezomib; Humans; Immunoglobulin Light-chain Amyloidosis; Immunotherapy; Paraproteinemias
PubMed: 34517412
DOI: 10.1182/blood.2020008737 -
Nature Reviews. Disease Primers Oct 2018Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional... (Review)
Review
Systemic immunoglobulin light chain amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction. The disease is progressive and, accordingly, early diagnosis is vital to prevent irreversible organ damage, of which cardiac damage and renal damage predominate. The development of novel sensitive biomarkers and imaging technologies for the detection and quantification of organ involvement and damage is facilitating earlier diagnosis and improved evaluation of the efficacy of new and existing therapies. Treatment is guided by risk assessment, which is based on levels of cardiac biomarkers; close monitoring of clonal and organ responses guides duration of therapy and changes in regimen. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of amyloid light chain production in the majority of patients. However, effective therapies for patients with advanced cardiac involvement are an unmet need. Passive immunotherapies targeting clonal plasma cells and directly accelerating removal of amyloid deposits promise to further improve the overall outlook of this increasingly treatable disease.
Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Bacterial Agents; Doxycycline; Heart; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney; Quality of Life; Risk Factors
PubMed: 30361521
DOI: 10.1038/s41572-018-0034-3 -
Nephrology, Dialysis, Transplantation :... Sep 2019AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and... (Review)
Review
AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma-bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients.
Topics: Combined Modality Therapy; Humans; Immunoglobulin Light-chain Amyloidosis; Prognosis
PubMed: 30299492
DOI: 10.1093/ndt/gfy291 -
JAMA Jul 2020Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis...
IMPORTANCE
Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe.
OBJECTIVE
To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis.
EVIDENCE REVIEW
A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non-English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature.
FINDINGS
There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype.
CONCLUSIONS AND RELEVANCE
All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.
Topics: Algorithms; Benzoxazoles; Dexamethasone; Diagnosis, Differential; Gene Silencing; Heart Failure; Humans; Immunoglobulin Light-chain Amyloidosis; Liver Transplantation; Melphalan; Prognosis; Proteinuria; Stem Cell Transplantation
PubMed: 32633805
DOI: 10.1001/jama.2020.5493 -
Blood 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... (Review)
Review
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; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis
PubMed: 33270858
DOI: 10.1182/blood.2020006913 -
Oncotarget Apr 2023Systemic Light chain (AL) amyloidosis is a monoclonal plasma cell proliferative disorder characterized by deposition of amyloidogenic monoclonal light chain fragments... (Review)
Review
Systemic Light chain (AL) amyloidosis is a monoclonal plasma cell proliferative disorder characterized by deposition of amyloidogenic monoclonal light chain fragments causing organ dysfunction. It is a fatal disease and if not diagnosed and treated early can lead to organ failure and potentially death. The renal system along with the cardiovascular system are the most common organs involved but other organs such as gut and liver can be involved as well. The initial evaluation of patients requires confirming the diagnosis with tissue biopsy and staining with Congo red followed by confirmatory typing with mass spectrometry of the Congo red positive tissue. Then establishing the extent of the organs involvement by various staging and biomarkers testing. The treatment options and the tolerability of therapy depend on the disease staging, frailty, and co-morbidities. The autologous hematopoietic cell transplantation (HCT) after high dose melphalan therapy is an effective strategy which is usually done after initial bortezomib induction therapy. Unfortunately, most systemic AL amyloidosis patients are not candidate for HCT due to frailty, old age, multi-organ involvement, renal and heart failure at the time of diagnosis. While it is widely accepted that the patients need to be treated until they achieve complete hematologic response, the maintenance therapy after HCT is not well established in AL amyloidosis. In this review, we report the literature on the latest treatment updates of AL amyloidosis and the ongoing clinical trials highlighting the future treatments.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Congo Red; Frailty; Melphalan; Hematopoietic Stem Cell Transplantation; Paraproteinemias
PubMed: 37185672
DOI: 10.18632/oncotarget.28415 -
Blood Cancer Journal May 2021Amyloid 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... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents; Bortezomib; Disease Management; Humans; Immunoglobulin Light-chain Amyloidosis; Neoplasm Recurrence, Local; Stem Cell Transplantation; Transplantation, Autologous
PubMed: 34006856
DOI: 10.1038/s41408-021-00486-4