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Acta Haematologica 2020Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as... (Review)
Review
Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.
Topics: Combined Modality Therapy; Disease Management; Humans; Immunoglobulin Light-chain Amyloidosis; Treatment Outcome
PubMed: 32526750
DOI: 10.1159/000507724 -
American Journal of Hematology Sep 2018Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in... (Review)
Review
DISEASE OVERVIEW
Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light or heavy chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic dysfunction, peripheral/autonomic neuropathy, and "atypical multiple myeloma."
DIAGNOSIS
Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow, salivary gland, or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. The gold standard is laser capture mass spectroscopy.
PROGNOSIS
N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months.
THERAPY
All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include systolic blood pressure >90 mm Hg, troponin T < 0.06 ng/mL, age < 70 years, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Daratumumab appears to be highly active in AL amyloidosis. Antibodies designed to dissolve existing amyloid deposits are under study.
FUTURE CHALLENGES
Delayed diagnosis remains a major obstacle to initiating effective therapy.
EDUCATIONAL OBJECTIVES
Upon completion of this educational activity, participants will be better able to: Master recognition of clinical presentations that should raise suspicion of amyloidosis. Understand simple techniques for confirming the diagnosis and providing material to classify the protein subunit. Recognize that a tissue diagnosis of amyloidosis does not indicate whether the amyloid is systemic or of immunoglobulin light chain origin. Understand the roles of the newly introduced chemotherapeutic and investigational antibody regimens for the therapy of light chain amyloidosis.
Topics: Age Factors; Blood Pressure; Creatinine; Humans; Immunoglobulin Light-chain Amyloidosis; Mass Spectrometry; Prognosis; Stem Cell Transplantation; Survival Analysis; Troponin T
PubMed: 30040145
DOI: 10.1002/ajh.25149 -
JACC. Cardiovascular Imaging Apr 2023Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of...
BACKGROUND
Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined.
OBJECTIVES
This study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging.
METHODS
A total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype.
RESULTS
AL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL.
CONCLUSIONS
There is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient.
Topics: Humans; Predictive Value of Tests; Tomography, X-Ray Computed; Amyloid Neuropathies, Familial; Heart; Immunoglobulin Light-chain Amyloidosis; Phenotype; Cardiomyopathies
PubMed: 36648052
DOI: 10.1016/j.jcmg.2022.07.008 -
PloS One 2022Light chain (AL) amyloidosis is a form of systemic amyloidosis, causing organ dysfunction, mainly affecting the heart and kidney. Patient-tailored and risk-adapted...
Light chain (AL) amyloidosis is a form of systemic amyloidosis, causing organ dysfunction, mainly affecting the heart and kidney. Patient-tailored and risk-adapted decision making is critical in AL amyloidosis management. There is limited real-world evidence data from Argentina and Latin America regarding the treatment approaches for AL amyloidosis. This retrospective cohort study aimed to describe the treatment patterns and outcomes in adult patients (>18 years) diagnosed with AL amyloidosis at the Hospital Italiano in Buenos Aires, Argentina, using a 10-yearfollow-up data (June 1, 2010 to May 31, 2019) from the institutional registry of amyloidosis (IRA). The study population had a mean age of 63 years and 54.4% weremale. Heart and kidney were the most frequently affected organs. Of the 90 eligible patients included in the study, 70underwent treatment. Bortezomib-based regimen was the preferred first-line treatment (75.7% patients). Overall,54.4% of the patients presented a deep response (complete or very good partial response). Median overall survival (OS) was 5years, the 1-year OS and progression free survival rates were 80% (95% confidence interval [CI]: 68-87) and 80% (95%CI 68-87)), respectively. This study provides vital real-world evidence for the long-term treatment patterns and survival in a large cohort of AL amyloidosis patients in Argentina.
Topics: Adult; Humans; Middle Aged; Immunoglobulin Light-chain Amyloidosis; Bortezomib; Retrospective Studies; Argentina; Amyloidosis; Registries
PubMed: 36301970
DOI: 10.1371/journal.pone.0274578 -
F1000Research 2018Immunoglobulin (Ig) light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by misfolded Ig light chain deposition in vital organs of the body,... (Review)
Review
Immunoglobulin (Ig) light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by misfolded Ig light chain deposition in vital organs of the body, resulting in proteotoxicity and organ dysfunction. Owing to its diverse clinical presentations and a tendency to mimic common medical conditions, AL amyloidosis is often diagnosed late and results in dismal outcomes. Early referral to a specialized center with expertise in management of AL amyloidosis is always recommended. The availability of sensitive biomarkers and novel therapies is reforming our approach to how we manage AL amyloidosis. Treatment for patients with AL amyloidosis should be risk-adapted and customized on the basis of individual patient characteristics. In the future, approaches directed at amyloid fibril clearance in combination with agents that target plasma cells will be needed both to eradicate the malignant clone and to establish organ responses.
Topics: Animals; Humans; Immunoglobulin Light Chains; Immunoglobulin Light-chain Amyloidosis; Myeloablative Agonists
PubMed: 30228867
DOI: 10.12688/f1000research.15353.1 -
British Journal of Haematology May 2017
Topics: Amyloidosis; Humans; Immunoglobulin Light-chain Amyloidosis; Prognosis; Risk Assessment
PubMed: 28437006
DOI: 10.1111/bjh.14587 -
Hematology. American Society of... Dec 2017Systemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The... (Review)
Review
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.
Topics: B-Lymphocytes; Biomarkers; Disease-Free Survival; Humans; Immunoglobulin Light-chain Amyloidosis; Protein Folding; Survival Rate
PubMed: 29222231
DOI: 10.1182/asheducation-2017.1.1 -
Acta Haematologica 2020AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High-dose intravenous melphalan and autologous stem cell... (Review)
Review
AL amyloidosis is a systemic amyloidosis and is associated with an underlying plasma cell dyscrasia. High-dose intravenous melphalan and autologous stem cell transplantation was developed for the treatment of AL amyloidosis in the early 1990s and was prompted by its success in myeloma. This application has evolved significantly over the past three decades. This review provides a comprehensive assessment of eligibility criteria, stem cell collection, and mobilization strategies and regimens, risk-adapted melphalan dosing, role for induction and consolidation therapies as well as long-term outcome with respect to survival, hematologic response and relapse as well as organ responses following stem cell transplantation. Continued efforts to refine patient selection and management, and incorporate novel anti-plasma cell agents in combination or sequentially to further improve outcomes in AL amyloidosis are also discussed.
Topics: Combined Modality Therapy; Disease Management; Hematopoietic Stem Cell Mobilization; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Myeloablative Agonists; Organ Specificity; Peripheral Blood Stem Cell Transplantation; Postoperative Care; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome
PubMed: 32248194
DOI: 10.1159/000506498 -
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 -
Medicina 2022Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence.
INTRODUCTION
Immunoglobulin light chain (AL) amyloidosis is a rare disease. Treatment is challenging, justified in part by systemic compromise and limited scientific evidence.
OBJECTIVES
Develop evidencebased recommendations that allow adequate treatment of patients with amyloidosis AL.
METHODS
A list of PICO format questions focused on the effectiveness and safety of amyloidosis AL treatment was generated. PubMed, Cochrane and Epistemonikos were searched. The levels of evidence and grades of recommendation were based on the GRADE system.
RESULTS
11 recommendations were generated. In selected patients with amyloidosis AL, autologous hematopoietic stem cell transplantation (ASCT) is recommended after induction with bortezomibbased regimens and conditioning with melphalan, since it could deepen the hematological and organ response, its durability and improve survival. In patients not eligible for ASCT, first-line treatment with bortezomib-based regimens is recommended, since it is likely to achieve a higher rate of hematological and organ response and improve survival. In patients with a contraindication or inaccessibility to bortezomib, treatment with alkylating agents and corticosteroids is recommended, since they are likely to achieve haematological and organ response and improve survival.
DISCUSSION
These treatment recommendations are based on the available evidence and the experience of the panel of experts, in a scenario of limited available resources, according to developing countries.
Topics: Amyloidosis; Bortezomib; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin Light-chain Amyloidosis; Melphalan; Transplantation, Autologous; Treatment Outcome
PubMed: 35904916
DOI: No ID Found