Light Chain Amyloidosis Research Articles

Abstract 4131488: Artificial Intelligence-Enhanced Electrocardiogram for the Diagnosis of Cardiac Amyloidosis: A Systemic Review and Meta-analysis

Background: Diagnosis of cardiac amyloidosis (CA) is often delayed due to variability in clinical presentation. The electrocardiogram (ECG) is one of the most common and widely available tools for assessing cardiovascular diseases. Artificial intelligence (AI) models analyzing ECG have recently been developed to detect CA, but their pooled accuracy is yet to be evaluated. Aim: To meta-analyze the accuracy of AI-enhanced ECG in diagnosing CA. Methods: We searched the Scopus, MEDLINE, and Cochrane CENTRAL databases up until April 2024 for studies assessing AI-enhanced ECG diagnosis of CA. Studies reporting findings from derivation and validation cohorts were included. Studies combining other diagnostic modalities such as echocardiography were excluded. The outcome of interest was the area under the receiver operating characteristic curve (AUC) for overall CA and subtypes transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL). Analysis was done using RevMan 5.4.1 general inverse variance random effects model, pooling data for AUC and 95% confidence intervals (CI). Results: 5 studies comprising 7 cohorts met the eligibility criteria. The total derivation and validation cohorts were 8,639 and 3,843 respectively. The AUC were 0.89 (95% CI, 0.86-0.91) for cardiac amyloidosis, 0.90 (95% CI, 0.86-0.95) for ATTR amyloidosis and 0.80 (95% CI, 0.80-0.93) for AL amyloidosis. The forest plots can be found in the Figure 1. Conclusion: AI-enhanced ECG models effectively detect CA and may provide a useful tool for the early detection and intervention of this disease.

Abstract 4138014: Incidence and Association of Amyloidosis Found at Carpal Tunnel Release to Development of Cardiac Involvement

Background: Carpal tunnel syndrome (CTS) associated with transthyretin cardiac amyloidosis (ATTR-CA) may manifest 5 to 10 years prior to cardiac diagnosis. Transthyretin amyloidosis (ATTR) identification in the tenosynovium isolated during carpal tunnel release (CTR) may facilitate earlier ATTR-CA diagnosis and treatment. Hypothesis: Amyloid discovered at CTR will be associated with, and/or serve as a precursor for, cardiac involvement. Aim: We aimed to determine the frequency and type of amyloid found at CTR as well as the incidence of cardiac involvement and/or treatment indication. Methods: A retrospective analysis was conducted on a convenience sample of adults undergoing CTR from 01/05/2021 to 03/24/2023. Biopsy specimens with confirmed amyloid via Congo red staining were analyzed using mass spectrometry (MS) for subtyping. Patients with amyloid in tenosynovial tissue were offered cardiac evaluation with history and physical, electrocardiogram, B-type natriuretic peptide, troponin-I HS, echocardiogram, and TcPYP nuclear scintigraphy. Patients with light-chain amyloidosis (AL) were referred to oncology, while patients with ATTR were offered genetic testing. Results: A total of 578 patients underwent CTR with tenosynovial sample excision. Amyloid involvement by Congo red staining was found in 43 patients (7.4%), with a definitive subtype confirmed by MS in 30 patients (5.2%). Samples were insufficient to define subtypes in 13 patients. Sole ATTR was found in 27 patients (4.7%), both AL and ATTR were found in 1 patient, and sole AL was found in 2 patients. Of the 28 ATTR patients (the patient with both ATTR and AL included), 24 pursued genetic testing, revealing all had wild-type ATTR. Of these 28 patients, 21 underwent cardiac evaluation, for which 2 had cardiac involvement on TcPYP and started tafamidis therapy. The patients with concomitant ATTR and AL or sole AL did not have evidence of cardiac involvement, however, chemotherapy was initiated as indicated. Unfortunately, 1 patient with AL on CTR did not pursue an evaluation. Conclusion: Incidental amyloid tissue found at CTR is common and associated with occult involvement warranting therapy in a minority of cases. Future cardiac involvement is unknown, and this cohort will be followed to determine future incidence. A startling number of patients were found to have occult systemic AL discovered at CTR. These incidental diagnoses may trigger lifesaving interventions, which may otherwise go undiagnosed.

Antibody Aggregation: A Problem Within the Biopharmaceutical Industry and Its Role in AL Amyloidosis Disease.

Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings.

Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report

Systemic Amyloid Light Chain Amyloidosis With Repeated Syncope Due to Severe Orthostatic Hypotension Caused by Autonomic Neuropathy: A Case Report

Light chain amyloidosis with cuticular cysts as the initial symptom complicated with multiple myeloma: report of a case

Light chain amyloidosis with cuticular cysts as the initial symptom complicated with multiple myeloma: report of a case

Early minimal residual disease eradication in light chain amyloidosis generates deeper and faster cardiac response

Minimal residual disease (MRD) is of growing interest in light chain (AL) amyloidosis and is associated with higher rates of cardiac response. A new graded cardiac response criteria has been proposed for better assessment of cardiac improvement. We evaluated MRD status in 63 patients with cardiac AL amyloidosis using next generation flow cytometry (sensitivity ≥ 1*10–5) within four cycles after treatment initiation and cardiac response kinetics. All patients were treated with first-line proteasome inhibitor (100%) and predominantly bortezomib (87.3%). The overall early MRD negative rates were 33.3%. Patients who achieved early MRD negativity were less likely to harbor t(11;14) (21.1% vs 57.5%, P = 0.009). The MRD negative rates amongst patients in hematologic complete response were 66.7% (14/21), and in very good partial response 29.2% (7/24). Early MRD negativity was associated with a higher likelihood of achieving ≥ cardiac partial response (≥ CarPR) (66.7% vs 38.1%, P = 0.032) and ≥ cardiac very good partial response (≥ CarVGPR) (38.1% vs 11.9%, P = 0.023) throughout first-line therapy. The cumulative incidence curve of achieving ≥ CarPR (P = 0.034) and ≥ CarVGPR (P = 0.026) showed significant difference between early MRD negative and positive group. After a median follow-up time of 27.2 months, the median progression free survival was longer in early MRD negative group (not reached vs 31.3 months, P = 0.033). Early MRD eradication in cardiac AL amyloidosis generated deeper and faster cardiac organ response.

Diagnostic Value of Combined Light and Electron Microscopic Examination in Endomyocardial Biopsy in Patients with Cardiac Amyloidosis.

Despite advances in imaging techniques, endomyocardial biopsy remains the gold standard for confirming cardiac amyloidosis (CA) and defining the amyloid type. Electron microscopy may detect amyloid deposits with greater sensitivity than light microscopy; however, its capabilities have not been thoroughly investigated. Patients with pathologically diagnosed CA were prospectively enrolled. Myocardial specimens were collected from the right ventricular septum, and light and electron microscopy were performed on the samples to compare their efficacy in detecting amyloid deposits. Sixty-five patients were pathologically diagnosed with CA, including 13 with light-chain amyloidosis, 51 with transthyretin amyloidosis, and one with unclassified amyloidosis. Amyloid deposits were detected through both examinations in 60 (92.3%) of the 65 patients. However, they were detected through only light microscopy in two cases (3.1%) and only electron microscopy in three cases (4.6%). Patients with amyloid deposits detected through a single method had reduced thickness of the intraventricular septal wall (9.5 vs. 15.1 mm, p=0.001), lower left ventricular (LV) mass index (94 vs. 147 g/m2, p= 0.013), greater LV diastolic dimension (45 vs. 41 mm, p=0.044), lower LVEF (49% vs. 57%, p=0.004), lower mean pulmonary capillary wedge pressure (9 vs. 19 mmHg, p=0.021), and lower right atrial pressure (4 vs. 8 mmHg, p=0.043) than did those in whom they were detected using both methods. Concomitant use of electron microscopy may improve the detection rate of amyloid deposits and prevent CA misdiagnosis, especially in patients with atypical features such as mild hypertrophy or eccentric hypertrophy with LV systolic dysfunction.

Single-center analysis of cardiac amyloidosis using 99mTc-HMDP imaging for diagnosis and evaluation after tafamidis treatment.

This study aimed to evaluate the diagnostic performance of 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) imaging for cardiac amyloidosis and to demonstrate changes in cardiac uptake of 99mTc-HMDP after tafamidis treatment. Seventy-five patients with suspected cardiac amyloidosis who underwent 99mTc-HMDP imaging were included. We compared visual Perugini grades and semiquantitative heart-to-contralateral (H/CL) area ratios, myocardial maximum standardized uptake value (SUVmax), and peak of SUV (SUVpeak) between cardiac transthyretin amyloidosis (ATTR) and amyloid light-chain amyloidosis (AL). Comparison of interobserver reproducibility between H/CL ratios and myocardial SUVmax/SUVpeak was performed. H/CL ratio of 99mTc-HMDP and myocardial SUVmax/SUVpeak were compared before and after tafamidis administration for cardiac wild-type ATTR. Among 75 patients, 20 patients (26.7%) were visually positive based on Perugini grade. Fifteen and three patients were pathologically identified as cardiac ATTR and AL, respectively. ATTR group (n = 15) had significantly higher H/CL ratios of 99mTc-HMDP than AL group (n = 3) (P = 0.003). ATTR group (n = 15) had significantly higher myocardial SUVmax/SUVpeak of 99mTc-HMDP than AL group (n = 2) (P = 0.015). Myocardial SUVmax/SUVpeak had better interobserver reproducibility than H/CL ratios. After tafamidis treatment for cardiac wild-type ATTR, the decrease in myocardial SUVpeak was significant but not in H/CL ratios and myocardial SUVmax. H/CL ratio and SUVmax/SUVpeak in 99mTc-HMDP imaging were useful for diagnosing cardiac ATTR. Myocardial SUVpeak may be useful for monitoring changes in cardiac uptake after tafamidis treatment for cardiac ATTR.

A review of recent clinical trials to evaluate disease-modifying therapies in the treatment of cardiac amyloidosis.

Cardiac amyloidosis (CA) is a serious condition that results in infiltrative cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) that is caused by the extracellular deposition of amyloid fibrils within heart tissue. While many important features of CA have been known for years, its prevalence in elderly patients with HF is increasingly being recognized. Plasma cells produce monoclonal immunoglobulin light chains which results in the formation and aggregation of amyloid fibrils that are responsible for AL amyloidosis. CA is classified as originating from either transthyretin (ATTR) or light chain (AL) amyloidosis. ATTR CA may result from a genetic mutation in the TTR gene, which is inherited (ATTRv), or from age-related deposition from wild-type ATTR (ATTRwt). Cardiac involvement in AL amyloidosis is attributed to either of two mechanisms: the extracellular deposition of amyloid fibril in the myocardium, or direct cardiotoxicity from the fibril aggregates. Typing of amyloid fibrils, a critical determinant of therapy, has also improved with wider availability of laser capture and mass spectrometry of histologic specimens. Specific and accurate evaluation of CA is now possible using cardiac magnetic resonance imaging and bone scintigraphy tracers. Survival in CA has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilizers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise and may improve outcomes in systemic and cardiac amyloidoses. Treatment strategies for CA has recently undergone transformative changes, leading to some progress in outcomes for certain patients. Here, we discuss the basic features of CA as well as the emergence of novel, disease-modifying strategies that have been recently evaluated in clinical trials for the treatment of CA.

Warning values of serum total kappa/lambda ratio for M-proteinemia

BackgroundTo introduce the serum total kappa/lambda ratio (K/L) in humoral immunity testing reports to improve the detection rate of M-proteinemia.Methods156 M protein-positive and 5464 M protein-negative samples confirmed by serum immunofixation electrophoresis(sIFE) were accumulated from January 2021 to December 2023 in the First Affiliated Hospital of Soochow University and the contents of immunoglobulins (IgG, IgA, IgM, kappa and lambda) were tested by Beckman IMMAGE800. All the samples were divided into two groups by time: the modeling group and the validation group. The K/L values in the modeling group were analyzed by SPSS 27.0 to get the receiver operating characteristic curve (ROC). Furthermore, a more in-depth analysis was conducted to verify the reliability of the optimal cutoff values in the validation group. In addition, the levels of immunoglobulins of another group including 106 patients with definite diagnosis of monoclonal gammopathy ranging from January 2021 to June 2024 were traced back to improve the diagnostic efficiency.ResultsThe optimal cutoff values of K/L were 2.31 and 1.43 corresponding to K-type and L-type M-proteinemia respectively by ROC analysis. The sensitivity and specificity were validated as 76.14% and 77.42%. False positives were mainly found in samples with systemic sclerosis (36.84%), hypohepatia (28.71%) and sicca syndrome (27.27%). While false negatives were mainly found in IgA monoclonal gammopathy (38.39%) and IgM monoclonal gammopathy (28.57%). Combining with the detection rules of IgG, IgA and IgM, the sensitivities for the diagnosis of immunoglobulin light chain amyloidosis(AL) and monoclonal gammopathy of undetermined significance(MGUS) can be increased to 83.33% and 85%.ConclusionsK/L > 2.31 and K/L < 1.43 can be used as warning values for M-proteinemia. In addition, the content of the heavy chain in IgA- or IgM-type M-proteinemia may be considered to improve the detection rate.

Improving early mortality risk detection in light-chain cardiac amyloidosis patients with routine echocardiographic indicators and mayo staging

Abstract Background Light-chain cardiac amyloidosis (AL-CA) is a fatal cardiomyopathy caused by the deposition of monoclonal immunoglobulin light-chain in the cardiac fibers, conduction system, valves, and other parts of the heart. The Mayo 2004 staging system is widely used to assess the prognosis of AL-CA. Those in the highest-risk categories, Mayo 2004 stage IIIb, exhibit extremely poor responses to conventional treatment regimens, resulting in high early mortality rates. However, within the same stage, prognostic outcomes among patients can still vary significantly. Hence, a more detailed stratification of high-risk patients is crucial for pinpointing those at extreme risk. Objective To investigate whether conventional echocardiographic measurements can enhance the identification of high-risk patients with early mortality in AL-CA on the basis of existing risk stratification. Methods Continuous enrollment of patients diagnosed with AL-CA at our center from May 2020 to December 2022. Clinical data, echocardiography, and follow-up results of the patients were collected. Logistic regression analyses were used to identify risk factors for early mortality, with risk factor thresholds calculated using Receiver Operating Characteristic (ROC) curves. Kaplan-Meier survival analysis was employed to assess endpoint events. The diagnostic efficacy of the model was evaluated using the area under the ROC curve and the Integrated Discrimination Improvement (IDI). Results A total of 76 patients were included with an average age of 59±10 years. Among them, 51 were male (67.1%). The median follow-up duration was 10 months (ranging from 5 to 20 months). Early mortality, defined as death within 6 months, occurred in 20 patients (26.3%). Twenty-three patients were categorized under the Mayo 2004 stage IIIb (30.3%). The 6-month mortality rate for patients in the Mayo 2004 stage IIIb was 56.5%. The sensitivity of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity ratio divided left ventricular ejection fraction [(E/e’) /LVEF] in predicting early mortality in patients with AL-CA is 63%, and the specificity is 92%.When compared to the Mayo 2004 stage IIIb alone, (E/e')/LVEF≥0.5 combined with the Mayo 2004 stage IIIb had an area under the curve of 0.731 and 0.824, respectively, in the ROC curve. The IDI was 0.113 (95% CI: 0.013-0.213, P=0.026), representing an 11.3% enhancement in the predictive value of early mortality in AL-CA patients. Conclusion Routine echocardiography derived E/e' to LVEF ratio offered added prognostic value for early mortality beyond Mayo staging.Kaplan-Meier survival curve

Contemporary description of cardiac manifestations in ATTR amyloidosis: results from the multi-country OverTTuRe study

Abstract Background In transthyretin (ATTR) amyloidosis, amyloid fibrils accumulate in the myocardium, resulting in cardiac manifestations that can ultimately be fatal. The diverse presentation of this condition often results in prolonged diagnostic journeys for patients before they receive a definitive diagnosis of ATTR amyloidosis and treatment. Purpose To delineate the demographic and clinical characteristics of patients diagnosed with ATTR amyloidosis by cardiac manifestations, and to examine the duration from the first recorded cardiac manifestation to diagnosis. Methods OverTTuRe is a multi-country study generating real-world evidence from a cohort of patients identified as having ATTR amyloidosis between 2017-2022. Data were extracted from the US (Optum’s de-identified Clinformatics Data Mart Database) and Japan (Medical Data Vision Database). Additional analyses from European countries are ongoing. Patients aged ≥18 years with a recorded ICD-10 diagnosis code for ATTR amyloidosis (all phenotypes) or record for an ATTR-specific treatment were included. The index date was defined as first recorded date of diagnosis or ATTR-specific treatment. Patients with a diagnostic code or treatment indicative of secondary (AA) amyloidosis or light chain (AL) amyloidosis were excluded. Results 17,720 patients (median age: 75 years; 48.3% males) with ATTR amyloidosis were identified from the US and 4,690 from Japan (median age: 77 years; 57.0% males). Among individuals with 5 years of any available data prior to ATTR amyloidosis diagnosis (US: 9,147 [51.6%]; Japan: 2,600 [55.4%]), the most frequent initial cardiac manifestation ahead of ATTR amyloidosis was heart failure (US: 30.3%; Japan: 42.0%) followed by atrial fibrillation (21.9%) and cardiomyopathy (21.7%) in the US, and angina (21.6%) and atrial fibrillation (18.7%) in Japan. Among patients with 5 years of any available data before diagnosis plus cardiac manifestations, there were higher proportions of males than females and older individuals (Table). Median time from the earliest recording of any cardiac manifestation to the diagnosis of ATTR amyloidosis was 2.4 years (IQR: 0.9, 3.9) in the US and 1.2 years (IQR: 0.1, 3.2) in Japan. Median time to diagnosis increased with age and was similar across sexes in the US, whilst females in Japan had longer median time to diagnosis. Among the cardiac manifestations (heart failure, atrial fibrillation, cardiomyopathy, angina, aortic valve stenosis), 52.5% of patients in Japan had at least 2 manifestations, whilst in the US 59.4% of patients had more than 2 manifestations. Conclusions These findings highlight the prevalence of cardiac manifestations such as heart failure, in patients identified as having ATTR amyloidosis, particularly among men and elderly individuals. The observed delay in diagnosis of ATTR amyloidosis illustrates the importance of increased awareness to support early recognition and treatment to limit adverse clinical outcomes.

Cardiac magnetic resonance T1 imaging for the diagnosis of cardiac amyloidosis among patients with symptomatic heart failure

Abstract Background Cardiac amyloidosis (CA) is a significant cause of heart failure in elderly patients. However, specific signs in cardiac imaging are lacking, hence bone scintigraphy in combination with screening for monoclonal protein, or myocardial biopsy is required for the diagnosis. Cardiac magnetic resonance (CMR) imaging with T1 mapping is a promising diagnostic tool, which may allow to differentiate causes of left ventricular (LV) hypertrophy, particularly CA. Purpose The aim of this study was to test the diagnostic accuracy of T1 mapping for the diagnosis of CA in elderly patients with symptomatic heart failure and red flags for CA. Methods We prospectively enrolled 120 patients aged above 60 years with symptomatic heart failure NYHA II-IV, LV ejection fraction ≥ 40%, increased LV wall thickness of ≥ 12 mm end-diastolic on echocardiography, and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥ 1,000 ng/L, high-sensitivity cardiac troponin T (hs-cTnT) ≥ 14 ng/L). All patients underwent standardized quantitative CMR with a 3.0T scanner. 99mTc-DPD bone scintigraphy, blood screening for monoclonal protein, and, where applicable, cardiac biopsy, were performed as reference methods in all patients. Primary endpoint was diagnostic accuracy of native T1 mapping for the diagnosis of CA. Results 112 patients were included in the final analysis. Median age was 81.0 years (interquartile range 74.0–85.0 years), and 45% were female. CA was diagnosed in 38 patients (34%), of which 32 suffered from a Transthyretin (ATTR) and 6 patients from light chain (AL) amyloidosis. The areas under the receiver operating characteristic curves for native T1 were 0.713, 0.772, 0.836 for global, septal short-axis (SAX), and septal 4-chamber (4Ch) view measurements. The corresponding value of extracellular volume fraction (ECV) was 0.904 (Figure 1). Based on these results, we developed a new diagnostic algorithm for the diagnosis of CA including T1 septal 4Ch and ECV, with a sensitivity and positive predictive value of both 92.9% and a specificity and negative predictive value of 95.8% (Figure 2). Thereby, contrast application can be avoided in 33% of patients. A definite diagnosis could be provided in 81%. Conclusion CMR with T1 imaging provides a high diagnostic accuracy to diagnose CA in patients with symptomatic heart failure at risk for CA. These data may help to identify underlying causes in heart failure which require specific treatment. An earlier diagnosis of CA may improve outcome of these patients.Figure 1Figure 2

Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart.

Heart Failure with Preserved Ejection Fraction (HFpEF) is one of the most frequent causes of heart failure in the world's population (about 19-55%), and is commonly associated with a high rate of hospitalization (almost 70-80%) and with increased mortality (40-50% in a 5-year timeframe). The elderly are more often affected, with higher rates of hospitalizations than young people, and currently almost 70% of the population aged 65 years old has HFpEF. An increase in cardiomyocyte stiffness, thus resulting in diastolic dysfunction, increased filling pressures and heart failure with preserved ejection fraction are characteristics features of the disease. In addition, among the various causes of HFpEF, cardiac amyloidosis (CA) can provoke diastolic dysfunction and increased wall stiffness directly from intercellular deposition of insoluble proteic substances and their toxic activity. Totally, almost 30 different proteins are able to form deposits, but the most frequently involved are transthyretin and misfolded monoclonal immunoglobulin light chains, which bring to two clinical conditions called transthyretin amyloidosis (ATTR) and light-chain amyloidosis (AL). Although there has been increasing attention on ATTR-CA in recent years, the actual prevalence remains underestimated, especially in people of advanced age, as well as its real impact as a cause of HFpEF, and only data derived from autoptic exams are currently available. Moreover, CA itself often mimics HFpEF, and some conflicting data on the use of predictive scores are described in the literature. The close relationship between HFpEF and CA, especially in older population and the main pathophysiological mechanisms which bond these two conditions are described in this focused review. The need to screen red flags for ATTR-CA in elderly patients with HFpEF is urgently advised, because a prompt recognition of the disease can optimize the approach to the disease with an early therapeutic, life-saving choice.

Maintenance therapy promotes profound organ and haematologic response in light-chain amyloidosis patients not undergoing autologous stem cell transplantation

Background Evidence on maintenance therapy following frontline induction is sparse in primary light-chain amyloidosis (AL), especially for those who do not undergo autologous haematopoietic stem cell transplantation (ASCT). Methods We enrolled primary AL patients who achieved at least haematologic very good partial response (VGPR) by the 4th month at the frontline from December 2008 to June 2023 at Zhongshan Hospital, Fudan University. Those who followed maintenance therapy were identified as the maintenance group (n = 44), whereas those entering the observational phase were classified as the observational group (n = 24). Results After 7.2(interquartile range, 4.7–18.6) months of maintenance therapy, 9(20.5%), 14(31.8%) and 5 (11.4%) patients achieved improvement in haematologic, cardiac and renal response respectively. Five (11.4%) patients had minimal residual disease (MRD) response conversion from positive to negative based on maintenance therapy. In the observation group, none of the patients had haematologic response improvement, with 3(12.5%) and 1(4.2%) patient showing cardiac and renal response improvement during follow-up. Conclusion This study identified the clinical benefits of maintenance therapy in patients with AL who did not undergo ASCT in real-world practice.

Top 10 Clinical Pearls in Paraproteinemic Neuropathies.

Paraproteinemic neuropathies represent an important subset of peripheral neuropathies. Once identified, further evaluation into the paraproteinemic subtype, clinical exam pattern, and electrodiagnostic phenotype helps clarify if the paraproteinemia is coincidental or causal of the neuropathy, as not all paraproteinemias cause neuropathy. Of all paraproteinemias, immunoglobulin M (IgM)-associated peripheral neuropathy, or IgM neuropathy, is of particular importance as half of IgM neuropathies also harbor anti-myelin-associated glycoprotein antibodies, which produce a characteristic demyelinating pattern on nerve conduction testing. Immunoglobulin G and immunoglobulin A paraproteinemias are less strongly associated with peripheral neuropathy, except in the setting of multiple myeloma or osteosclerotic myeloma (POEMS syndrome), which have characteristic systemic features. In multiple myeloma, chemotherapy is more likely to result in neuropathy than the myeloma itself. Finally, the presence of systemic features (e.g., cardiomyopathy, nephropathy, recurrent carpal tunnel syndrome, and autonomic insufficiency) should raise concern for hereditary or acquired light (AL) chain amyloidosis. AL amyloidosis can occur in the setting of any light or heavy chain paraproteinemia. Central to the proper evaluation of paraproteinemic neuropathy is electrodiagnostic testing, which helps delineate axonal versus demyelinating paraproteinemic neuropathy, the latter often misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy.

Cardiovascular magnetic resonance-derived left atrioventricular coupling index as a novel prognostic marker for light-chain amyloidosis

BackgroundLeft atrioventricular coupling index (LACI) is a novel biomarker, and the prognostic value of LACI to predict cardiovascular events has been validated. The present study aimed to explore the prognostic value of LACI in patients with light-chain (AL) amyloidosis. MethodsWe prospectively enrolled 179 patients with AL amyloidosis who underwent cardiovascular magnetic resonance imaging between December 2011 and January 2020. LACI was defined as the ratio between the left atrial volume and the left ventricular volume at end-diastole. The primary endpoint was all-cause mortality. Receiver operating characteristic curve was used to identify the optimal cut-off of LACI in predicting all-cause mortality. Univariable and multivariable Cox proportional hazard models were used to assess the association of LACI and primary endpoint. ResultsDuring a median follow-up of 30 months, 118 (65.9 %) patients with all-cause mortality were documented. LACI was significantly higher in patients with primary endpoint compared to those without primary endpoint (55.4 %, interquartile range: 31.6 %–71.5 % vs. 39.4 %, interquartile range: 24.1 %–54.7 %, p = 0.001). The optimal cut-off for LACI to predict mortality was 49.3 %. In multivariate Cox regression analysis, LACI≥49.3 % (HR 1.907, 95 % CI 1.273–2.857, p = 0.002) was an independent predictor of all-cause mortality. On Kaplan-Meier analysis, patients at advanced Mayo stage (IIIa and IIIb) can be further risk stratified using LACI≥49.3 % (log-rank p = 0.035, p = 0.025). ConclusionThe LACI provides powerful independent prognostic value in AL amyloidosis. The LACI has incremental prognostic value to predict all-cause mortality over the Mayo stage in patients at the advanced Mayo stage.

Light Chain (AL) Amyloidosis for Nephrologists - Treatment Standard.

Amyloidosis is a group of complex diseases caused by the misfolding and aggregation of proteins into amyloid fibrils. AL amyloidosis is one of the most prevalent forms of amyloidosis, characterized by the gradual proliferation of light chains from plasma cell clones. A growing body of evidence has contributed to our understanding of its pathogenesis, presentation, and clinical course. Increased recognition of its clinical sequelae has increased the prevalence of AL amyloidosis. Renal involvement, seen in up to 70% of cases, is particularly challenging due to its impact on quality of life and access to treatment options. Thus, early recognition of its unique sequelae, appropriate staging, and a comprehensive understanding of treatment options balanced by their organ toxicities are crucial to managing this disease. We review the current treatment standards and discuss novel developments in the pathophysiology, diagnosis, outcome prediction, and management of AL amyloidosis for the Nephrologist.

An Atypical Cause of Kidney Amyloidosis: Combined Heavy and Light-Chain Amyloidosis

An Atypical Cause of Kidney Amyloidosis: Combined Heavy and Light-Chain Amyloidosis

Diagnosing AL and ATTR Amyloid Cardiomyopathy: A Multidisciplinary Approach.

Amyloidosis with cardiac involvement is a fatal disease leading to progressive heart failure. The most common forms of amyloidosis with cardiac involvement are light chain (AL) and transthyretin (ATTR) amyloidosis. To allow effective specific treatment for both forms, precise and early diagnosis is important. This review focuses on diagnostic approaches for AL and ATTR amyloidosis with cardiac involvement, including different strategies, the role of imaging and biomarkers and possible pitfalls.