Involvement In Light Chain Amyloidosis Research Articles

Hepatic Response and Progression Criteria in Light Chain Amyloidosis: A Multicenter Validation Study

Background: Liver involvement in light chain amyloidosis (AL) is seen in up to 20% of patients and is typically encountered as part of multi-organ involvement. Liver involvement is associated with a poor prognosis. The goal of this study was to assess the prognostic impact of the hepatic response criteria, which were published in 2005 and were not broadly assessed for their prognostic value. Patients and methods: Ten centers across the USA and Europe participated in this study.AL amyloidosis patients who were diagnosed between 2010 and 2015, had liver involvement with serum alkaline phosphatase (AP) >1.5 upper reference limit (URL), and achieved hematologic response to therapy were included in this study. Hepatic response was assessed at 6, 12, and 24 months from therapy initiation and at best response. Based on a receiver operation characteristic analysis, a 50% reduction in AP was set as the optimal cut point for discrimination of 5-year overall survival (OS) in the 12-months response assessment landmark (area under the curve 0.67). Therefore, hepatic response was defined as a reduction in AP >50% from baseline value in addition to AP normalization, regardless of AP percentage reduction. Hepatic progression was defined as >50% increase in serum AP. OS was assessed from therapy initiation until death or last follow-up and was plotted using the Kaplan-Meier method. The log-rank test used to compare survival between groups. For fixed-time point survival analysis, patients who died before the landmark were excluded. Hepatic response at a fixed time points, when missing, was imputed based on available data from adjacent time points (imputation of hepatic response was performed in 15%, 23%, and 22% of evaluable patients at 6-, 12-, and 24-month landmarks, respectively). Multivariate Cox proportional models were set to determine independent prognostic factors for OS using variables with p-value <0.1 in a univariate analysis. P-values <0.05 were considered significant. Results: One hundred and sixteen patients (n=116) are included. The median age was 60 years, and the median serum AP was X2.6 URL. Concomitant kidney involvement was present in 63.8% of patients, while coexisting heart involvement was seen in 56% of patients. Hematologic VGPR or better was achieved in 69% of patients. AP decrease deepened with time, with a median reduction at 6-, 12-, 24-months and best response being 22%, 34%, 53%, and 56%, respectively. Overall, 65% of patients (n=75) achieved hepatic response, of whom 71 patients based on reduction in AP >50% and 4 patients for reaching AP within normal reference but not meeting >50% reduction in AP (40- 46% reduction in AP). The median time to hepatic response was 13.8 months, longer for patients undergoing autologous stem cell transplantation (ASCT) as their primary therapy compared to non-transplant therapies (24 vs 12.6 months, P=0.1). With a median follow-up of 105 months, 42 patients died (36.2% of the study cohort). The 2-, 5- and 10-year OS rates were 83%, 67%, and 61%, respectively. Achievement of hepatic response as early as 12 months and at best response was associated with a longer survival (Figure). Hepatic response was an independent prognostic factor in a multivariate analysis, after adjusting for other known prognostic factors (age, cardiac stage, hematologic response, and primary therapy). Predictors of hepatic response include higher baseline AP level, lower total bilirubin, hematologic ≥VGPR, and cardiac and renal responses, when applicable. Hepatic progression was borderline associated with inferior OS (5-year OS 47% vs 70% among non-progressors, P=0.08). Conclusions: Hepatic response and progression measured by the change in alkaline phosphatase are prognostic in AL amyloidosis. These criteria are independent of other prognostic markers, and thus may have clinical implications for patients' care.

116 A CASE REPORT OF ISOLATED CARDIAC LIGHT CHAIN AMYLOIDOSIS WITHOUT HEART FAILURE: AN UNDER-RECOGNISED PRESENTATION

Abstract Background Cardiac involvement in light-chain amyloidosis (AL) usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is un uncommon scenario characterised by a challenging diagnostic and therapeutic work-up. Case Summary A 57-year-old asymptomatic man presented for an incidental finding of myocardial necrosis at the ECG performed for newly-diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinesia with normal LV systolic function with ‘apical sparing’ pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic work-up was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed and the patients was timely started on chemotherapy. Discussion The diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flow-chart have to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.

Cardiac involvement in light chain amyloidosis: a case report.

Cardiac involvement in light chain amyloidosis: a case report.

Kidney Involvement in Light Chain Amyloidosis

Systemic amyloidoses are complex diseases caused by the misfolding of autologous protein. Immunoglobulin light chain (AL) amyloidosis is caused by usually small plasma cell clone synthesizing light chains undergoing conformational changes that lead to their aggregation and deposition in tissues. Although the presence of heart involvement is the most important prognostic determinant, the kidney is involved in 70% of patients. Renal involvement results in significant morbidity, and renal failure limits the therapeutic options. The clinical presentation of kidney involvement is characterized by nephrotic syndrome and progressive renal failure. Diagnosis relies on the identification and accurate typing of amyloid deposits at the abdominal fat pad aspirate or with renal biopsy. Refined diagnostic and staging systems based on biomarkers have helped in assessing prognoses and evaluating responses to therapy, which has considerably improved the management of these conditions. In addition, the availability of nove...

Usefulness of Diastolic Myocardial Stiffness Assessed by Diastolic Wall Strain in Assessing Cardiac Involvement in Light-chain Amyloidosis

Usefulness of Diastolic Myocardial Stiffness Assessed by Diastolic Wall Strain in Assessing Cardiac Involvement in Light-chain Amyloidosis

Autologous Stem Cell Transplantation Improves Survival For High Risk Cardiac Amyloidosis

Cardiac involvement in light chain amyloidosis (AL) predicts poor prognosis and is associated with higher treatment related mortality and morbidity during autologous stem cell transplantation (ASCT). We studied the outcomes of AL patients with cardiac involvement undergoing ASCT at our center between January 2002 and December 2012.Out of a total of 264 AL patients, 53 patients had cardiac involvement according to the International Consensus Criteria (Gertz M et al. AJH 2005) and 27 underwent ASCT. Cardiac staging was assessed using the Revised Prognostic Staging System for Light Chain Amyloidosis (Kumar S et al, JCO 2012). Hematologic and cardiac responses were evaluated before and at 1 year after ASCT using the guidelines established by the 10th International Symposium on Amyloid and Amyloidosis (Gertz M et al. AJH 2005).The median age of the patients was 53 years (range 36-74) with a median duration from diagnosis to ASCT of 6 months (range 3-95). The estimated median follow up for the entire cohort was 41 months (range 6-173). Twenty-four patients (89%) had an additional organ involvement, besides heart. Cardiac stage ≥3 was seen in 14 patients. The median troponin-T, Troponin-I, BNP and NT-proBNP levels and free light chain difference (FCL-diff) were 0.054 ng/ml, 0.05 ng/ml, 376 pg/ml, 1888 pg/ml, and 116.4 mg/l respectively (table1). Twenty-four patients (89%) received induction chemotherapy and 22 of those (81%) received novel chemotherapy agents. Eighteen patients (66.6%) achieved at least PR prior to ASCT. Four patients (14.8%) received reduced doses melphalan conditioning (140-180 mg/m2). One-year transplant related mortality (TRM) was 3.7% (1 patient died at day 11 post-transplant due to cardiac event). At 1-year post ASCT, overall HR was seen in 24 patients (89%) (CR=26% and PR=63%) while 3 patients (11%) had cardiac responses. At the time of last follow up, 17 patients (63%) were alive. The median overall survival (OS) from diagnosis and from ASCT was 58 months (95% CI; 46-69) and 46 months (95% CI; 36-55) respectively (figure1). The median progression free survival (PFS) was 25 months (95% CI; 6-44). Cumulative incidence of hematologic relapse at 3 year was 38.5% (95%CI 23.7-62.5). Cardiac progression at last follow up was seen in 1 patient (3.7%). Negative factors affecting OS included lack of induction therapy prior to ASCT and NT-proBNP more than 5000 pg/ml. We conclude that ASCT is well tolerated in patients with high-risk cardiac amyloidosis and the incorporation of induction therapy can improve overall outcomes of these patients. [Display omitted] Table1Patient CharacteristicsBaseline characteristicsTotal (N=27)Interquartile rangeMedian age (year)5336-71Gender: male (%)20 (74.1)Median time from diagnosis to transplant, (month)63-95Receive induction chemotherapy (%)24 (88.9)Receive novel induction chemotherapy (%)22 (81.5)Light chain type (%)-Kappa-Lambda.6 (22.2) 21 (77.8)Other organ involvement (%)24 (88.9)History of cardiac complications prior ASCT (%)17 (63)History of cardiac complications after ASCT (%)20 (74.1)ICU admission prior ASCT (%)3 (11.1)Cardiac event prior ASCT (%)17 (62.9%)Median FLC-diff (mg/l) (N=15)116.415-1168Median EF (%) (N=19)6030-82Median IVS (mm.) (N=14)1.350.7-2.1Median Troponin-T (ng/ml) (N=20)0.0190.01-0.22Median Troponin-I (ng/ml) (N=19)0.060.03-9.09Median BNP (pg/ml) (N=23)37615.2-1782Median NT-proBNP (pg/ml) (N=12)1888.519-9911Median serum calcium (mg/dl)9.27-11Median serum albumin (g/dl)3.92.4Median Creatinine (mg/dl)1.01-9Median B2 microglobulin (mg/l)3.151-15Median 24-hr urine protein (mg)574120-36006Median serum M protein (g/dl)0.50-4Median LDH (IU/l)377146-770Median BM plasma cell (%)110-58Cardiac stage at diagnosis.Stage 11Stage 25Stage 36Stage 48Cardiac stage at transplant.Stage 13Stage 25Stage 34Stage 46 Disclosures:No relevant conflicts of interest to declare.

Respiratory muscle weakness and inefficient ventilation in heart failure due to light-chain amyloidosis

Background. Cardiac involvement in light-chain amyloidosis (AL) frequently results in heart failure with dyspnoea. In heart failure due to ischemic or idiopathic etiology, respiratory muscle dysfunction and ventilatory inefficiency contribute to symptoms and are independent prognostic predictors. However, in patients with AL, respiratory muscle function has not been elucidated.Methods. In 46 consecutive male patients with AL, lung function, maximal inspiratory (Pimax) and expiratory (Pemax) mouth occlusion pressures, cardiopulmonary exercise testing, echocardiography, and cardiac biomarkers were prospectively studied.Results. Pimax and Pemax were reduced, P0.1 did not differ between controls and AL. Pimax and Pemax were reduced in AL with congestive heart failure compared with asymptomatic patients (median (range) 5.4 (2.3–12.4) kPa vs 10.4 (6.5–14.0) kPa; p < 0.05). Respiratory muscle weakness occurred in systolic and diastolic LV dysfunction. Pimax was associated with peak exercise oxygen uptake, respiratory inefficiency, wall thickness, and N-terminal pro-brain natriuretic peptide.Conclusions. Respiratory muscle dysfunction and ventilatory inefficiency correlates well with intraventricular septum thickness and peak oxygen uptake and are present even in patients with diastolic dysfunction. Respiratory muscle dysfunction might contribute to dyspnea and exercise limitation and appears to represent a marker of cardiac impairment even in diastolic heart failure. Further studies of Pimax as a potential non-invasive prognostic marker are needed.