A Novel Prognostic Staging System for Light Chain Amyloidosis (AL) Incorporating Markers of Plasma Cell Burden and Organ Involvement.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2797-2797 ◽  
Author(s):  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Suzzane Hayman ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Plasma Cell ◽  
Light Chain ◽  
Cardiac Involvement ◽  
Troponin T ◽  
Prognostic Score ◽  
Staging System ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
The Impact

Abstract Abstract 2797 Poster Board II-773 Background: Primary systemic amyloidosis (AL) is characterized by deposition of light chain derived amyloid fibrils in multiple organs leading to varying degree of dysfunction. Cardiac involvement is a common feature of AL, and when significant is highly predictive of poor outcome. The currently used prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro B-type Natriuretic peptide (NT-ProBNP) and is effective at predicting outcome in patients with AL. However, this is driven primarily by the degree of cardiac involvement and does not take into account the degree of plasma cell burden and its impact on the disease course. It is possible that some of the heterogeneity in outcome can be explained by the plasma cell characteristics rather than the degree of the end organ damage. Methods: We examined the baseline clinical and laboratory data from 2119 patients with AL who were seen at our institution with in 90 days of their diagnosis. The data were collected from a prospectively maintained data base, and additional testing was done for free light chain levels (FLC) on stored sera from patients seen before the routine introduction of FLC testing. Cox proportional hazards analysis was performed to estimate the prognostic values of different variables. Results: We first examined the impact of plasma cell clone related characteristics namely, difference between involved and uninvolved FLC (FLC-Diff), bone marrow plasma cell (BMPC) %, plasma cell labeling index (PCLI), beta 2 microglobulin (B2M), and presence of circulating plasma cells, on overall survival (OS) from diagnosis. All variables were dichotomized into high and low based on their median value (FLC-diff: 20 mg/dL, BMPC: 10%, PCLI as a continuous variable, B2M: 3 mg/dL and circulating cells: absent or present). While all were found to be prognostic for OS in univariate analysis; in a multivariate analysis incorporating a stepwise selection only B2M and FLC-diff were significant. We then used these two variables along with the cTnT and NT-ProBNP that are used in the current model to develop a staging system. The median values for all four variables were used for developing the scores. Patients were assigned a score of 1 for presence of each characteristic (FLC difference > 20 mg/dL, troponin-T > 0.02, NT-ProBNP > 1000, and B2M > 3) or 0 if the value was at or below the cutoff. The scores were added to obtain a composite prognostic score that grouped the 370 patients (who had all the variables available for analysis) into 5 groups with very different OS (4.4, 9.3, 24.4, 43, and not reached for stages 4, 3, 2, 1, and 0 respectively; Figure A). However, since the NT-ProBNP did not have independent impact on survival in a multivariable model incorporating all the four variables, we also examined a system that only included FLC-diff, cTnT and B2M. This system again allowed grouping of patients (n=450 with all three variables available) into four distinct groups with divergent outcome with OS of 4.6, 10.5, 36.8, and not reached for stages 3, 2, 1, and 0 respectively; (Figure B). Conclusion: Incorporation of plasma cell related measurements into the existing staging system using cardiac biomarkers allows better risk stratification of patients with AL amyloidosis. The system using FLC, B2M and troponin has the advantage of easily available laboratory values and can be widely adopted. Addition of NT-ProBNP into the system allows better refinement of the intermediate risk groups. This system will allow upfront risk stratification and development of risk-adapted therapies for patients with AL. Disclosures: Gertz: Genzyme: Research Funding.

scholarly journals Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements

2012 ◽  
Vol 30 (9) ◽  
pp. 989-995 ◽  
Author(s):  
Shaji Kumar ◽  
Angela Dispenzieri ◽  
Martha Q. Lacy ◽  
Suzanne R. Hayman ◽  
Francis K. Buadi ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Plasma Cell ◽  
Light Chain ◽  
Troponin T ◽  
Cell Clone ◽  
Staging System ◽  
Cell Labeling ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Long Term Outcome

Purpose Cardiac involvement predicts poor prognosis in light chain (AL) amyloidosis, and the current prognostic classification is based on cardiac biomarkers troponin-T (cTnT) and N-terminal pro–B-type natriuretic peptide (NT-ProBNP). However, long-term outcome is dependent on the underlying plasma cell clone, and incorporation of clonal characteristics may allow for better risk stratification. Patients and Methods We developed a prognostic model based on 810 patients with newly diagnosed AL amyloidosis, which was further examined in two other datasets: 303 patients undergoing stem-cell transplantation, and 103 patients enrolled onto different clinical trials. Results We examined the prognostic value of plasma cell–related characteristics (ie, difference between involved and uninvolved light chain [FLC-diff], marrow plasma cell percentage, circulating plasma cells, plasma cell labeling index, and β2 microglobulin). In a multivariate model that included these characteristics as well as cTnT and NT-ProBNP, only FLC-diff, cTnT, and NT-ProBNP were independently prognostic for overall survival (OS). Patients were assigned a score of 1 for each of FLC-diff ≥ 18 mg/dL, cTnT ≥ 0.025 ng/mL, and NT-ProBNP ≥ 1,800 pg/mL, creating stages I to IV with scores of 0 to 3 points, respectively. The proportions of patients with stages I, II, III and IV disease were 189 (25%), 206 (27%), 186 (25%) and 177 (23%), and their median OS from diagnosis was 94.1, 40.3, 14, and 5.8 months, respectively (P < .001). This classification system was validated in the other datasets. Conclusion Incorporation of serum FLC-diff into the current staging system improves risk stratification for patients with AL amyloidosis and will help develop risk-adapted therapies for AL amyloidosis.

Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2455-2461 ◽  
Author(s):  
Arnt V. Kristen ◽  
Evangelos Giannitsis ◽  
Stephanie Lehrke ◽  
Ute Hegenbart ◽  
Matthias Konstandin ◽  
...  
Keyword(s):  
Light Chain ◽  
Cardiac Involvement ◽  
Troponin T ◽  
Interventricular Septum ◽  
High Sensitivity ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Blood Levels ◽  
Al Amyloidosis ◽  
Light Chain Amyloidosis

Abstract Cardiac biomarkers provide prognostic information in light-chain amyloidosis (AL). Thus, a novel high-sensitivity cardiac troponin T (hs-TnT) assay may improve risk stratification. hs-TnT was assessed in 163 patients. Blood levels were higher with cardiac than renal or other organ involvement and were related to the severity of cardiac involvement. Increased sensitivity was not associated with survival benefit. Forty-seven patients died during follow-up (22.3 ± 1.0 months). Nonsurvivors had higher hs-TnT than survivors. Outcome was worse if hs-TnT more than or equal to 50 ng/L and best less than 3 ng/L. Survival of patients with hs-TnT 3 to 14 ng/L did not differ from patients with moderately increased hs-TnT (14-50 ng/L), but was worse if interventricular septum was more than or equal to 15 mm. Discrimination according to the Mayo staging system was only achieved by the use of the hs-TnT assay, but not by the fourth-generation troponin T assay. Multivariate analysis revealed hs-TnT, NT-proBNP, and left ventricular impairment as independent risk factors for survival. hs-TnT and NT-proBNP predicted survival, even after exclusion of patients with impaired renal function. Plasma levels of the hs-TnT assay are associated with the clinical, morphologic, and functional severity of cardiac AL amyloidosis and could provide useful information for clinicians on cardiac involvement and outcome.

scholarly journals The Impact of Longitudinal Strain on Haematological and Cardiac Response and Survival in Patients with Systemic AL Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-40
Author(s):  
Oliver C Cohen ◽  
Andreia Ismael ◽  
Richa Manwani ◽  
Sriram Ravichandran ◽  
Steven Law ◽  
...  
Keyword(s):  
Longitudinal Strain ◽  
Cardiac Involvement ◽  
Troponin T ◽  
Staging System ◽  
Stage I ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
International Consensus ◽  
The Uk ◽  
The Impact

Background: Cardiac involvement is the major determinant of prognosis in systemic AL amyloidosis. The extent is assessed by cardiac biomarker-based staging system using N-terminal pro-brain natriuretic peptide (NT-proBNP) and Troponin T. Longitudinal strain evaluates the global and regional function of the left ventricle (LV) and may be preferable to both LV ejection fraction and NT-proBNP, which is limited by its sensitivity to changes in fluid balance, in determining prognosis. This is the first report of a large cohort of uniformly treated prospectively followed patients assessing the utility of changes in longitudinal function by 2-D strain (LS%), impairment of which is a hallmark of amyloidosis. Methods: 915 newly diagnosed patients seen at the UK National Amyloidosis Centre (February 2010 - August 2017) were studied. All patients underwent comprehensive assessments including echo-cardiogram at baseline and each follow up visit. Results: 628/915 (68.6%) patients had cardiac involvement. Mayo stage I, II, IIIa and IIIb in 144 (15.7%), 302 (33.0%) 344 (37.6%) and 125 (13.7%) respectively. Impairment of LS% correlated significantly with increasing Mayo stage (p&lt;0.0001 between LS% for each Mayo stage). At 12 months, only patients with complete haematological responses (CR) had significant improvement in LS% (overall p=0.04; regional baso-lateral p=0.007, and baso-septal p=0.007). The median overall survival (OS) of the whole cohort was 61 months; survival of Mayo stage I and II patients was not reached whilst OS in Mayo stage IIIa and IIIb patients was 30 and 4 months respectively. Patients with cardiac involvement were stratified into 3 baseline LS% groups (≤17%; 10.3-16.9%; and ≥10.2%) with poor baseline LS% being associated with shorter OS (p&lt;0.0001). These groups predicted survival independently of Mayo stage. OS was superior in patients who achieved a minimum absolute improvement in LS% of 1.5% when analysed at either 12 (not reached vs. 72 months, p=0.008) and 24 (not reached vs. 80 months, p&lt;0.0001) months from diagnosis. Patients achieving a LS% response (1.5%) improvement survived longer than those achieving a traditional cardiac response alone or no cardiac response at both 12 and 24 months (p&lt;0.0001). Conclusion: Longitudinal strain is an informative functional marker that is independent of Mayo staging in predicting outcomes in patients with cardiac AL amyloidosis which can be incorporated in prognostic staging for these patients. Improvement in LS% was observed in patients who achieved a CR, and a value of 1.5% was associated with superior outcomes over and above achieving a cardiac response by international consensus criteria. An absolute improvement in LS% should be considered a criterion for cardiac response in AL amyloidosis. Disclosures Wechalekar: Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel; Celgene: Honoraria.

scholarly journals Development and validation of a survival staging system incorporating BNP in patients with light chain amyloidosis

Blood ◽  
2019 ◽  
Vol 133 (3) ◽  
pp. 215-223 ◽  
Author(s):  
Brian Lilleness ◽  
Frederick L. Ruberg ◽  
Roberta Mussinelli ◽  
Gheorghe Doros ◽  
Vaishali Sanchorawala
Keyword(s):  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Light Chain ◽  
Cardiac Involvement ◽  
Staging System ◽  
Stage I ◽  
Stage Iiib ◽  
Stage Ii ◽  
Al Amyloidosis ◽  
Derivation Cohort

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) is caused by misfolded light chains that form soluble toxic aggregates that deposit in tissues and organs, leading to organ dysfunction. The leading determinant of survival is cardiac involvement. Current staging systems use N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T and I (TnT and TnI) for prognostication, but many centers do not offer NT-proBNP. We sought to derive a new staging system using brain natriuretic peptide (BNP) that would correlate with the Mayo 2004 staging system and be predictive for survival in AL amyloidosis. Two cohorts of patients were created: a derivation cohort of 249 consecutive patients who had BNP, NT-proBNP, and TnI drawn simultaneously to create the staging system and a complementary cohort of 592 patients with 10 years of follow-up to determine survival. In the derivation cohort, we found that a BNP threshold of more than 81 pg/mL best associated with Mayo 2004 stage and also best identified cardiac involvement. Three stages were developed based on a BNP higher than 81 pg/mL and a TnI higher than 0.1 ng/mL and compared with Mayo 2004 with high concordance (κ = 0.854). In the complementary cohort, 25% of patients had stage I, 44% had stage II, 15% had stage III, and 16% had stage IIIb disease with a median survival not reached in stage I, 9.4 years in stage II, 4.3 years in stage III, and 1 year in stage IIIb. This new Boston University biomarker scoring system will allow centers without access to NT-proBNP the ability to appropriately stage patients with AL amyloidosis. This trial was registered at www.clinicaltrials.gov as #NCT00898235.

Diagnostic score of cardiac involvement in AL amyloidosis

2019 ◽  
Vol 21 (5) ◽  
pp. 542-548 ◽  
Author(s):  
Martin Nicol ◽  
Mathilde Baudet ◽  
Stephanie Brun ◽  
Stephanie Harel ◽  
Bruno Royer ◽  
...  
Keyword(s):  
Cardiac Involvement ◽  
Troponin T ◽  
Characteristic Curve ◽  
Global Longitudinal Strain ◽  
Left Ventricular ◽  
Cardiac Biomarkers ◽  
Blood Levels ◽  
Al Amyloidosis ◽  
Derivation Cohort ◽  
Diagnostic Score

Abstract Aims  Early diagnosis of cardiac involvement is a key issue in the management of AL amyloidosis. Our objective was to establish a diagnostic score of cardiac involvement in AL amyloidosis and to compare it with the current consensus criteria [i.e. left ventricular hypertrophy &gt;12 mm and N-terminal pro b-type natriuretic peptide (NT-proBNP) &gt;332 ng/L]. Methods and results  We carried out a prospective and multicenter study on AL amyloidosis patients who underwent cardiac evaluation including clinical examination, electrocardiography (ECG), cardiac biomarkers, transthoracic echocardiography (TTE), and cardiac magnetic resonance imaging (CMR). Cardiac involvement was based on CMR and/or endomyocardial biopsy. In a derivation cohort of 114 patients (82 with cardiac involvement), the highest diagnostic accuracy was observed with NT-proBNP and troponin blood levels, TTE-derived global longitudinal strain (LS), and apical to basal LS gradient. By using multivariate analysis, we established a diagnostic score including global LS ≥−17% (1 point), apical/(basal + median) LS ≥0.90 (1 point), and troponin T &gt;35 ng/L (1 point). A score &gt;1 was associated with sensitivity of 94% and specificity of 97%, an area under the curve of 0.98 [95% confidence interval (CI) 0.93–0.99] as well as a net reclassification index of 0.39 (95% CI 0.28–0.46) when compared with consensus criteria. In a validation cohort of 73 AL amyloidosis patients, the area under the receiver operating characteristic curve of the diagnostic score was 0.97 (95% CI 0.90–0.99). Conclusion  Combining T troponin blood levels and two echo-derived strain parameters leads to very high accuracy for diagnosing cardiac involvement in AL amyloid patients.

scholarly journals The Effect of Cytogenetic Abnormalities on Organ Involvement and Survival in Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1833-1833
Author(s):  
Michael Ozga ◽  
Qiuhong Zhao ◽  
Don M. Benson ◽  
Patrick Elder ◽  
Nita Williams ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Kidney Involvement ◽  
The Impact

Introduction: Systemic light chain amyloidosis (AL) is a clonal plasma-cell neoplasm that carries a poor prognosis. Efforts are being made at recognizing this disease earlier and developing better prognostic tools as AL is frequently diagnosed at an advanced stage. Cytogenetic analysis and its prognostic relevance have been well studied in multiple myeloma (MM), a related disorder, but remain relatively unknown and less widely reported in AL literature. Previous studies have demonstrated that AL amyloidosis exhibits an increased incidence of translocation t(11;14). However, with an extensive array of fluorescence-in-situ hybridization (FISH) probes now available, multiple other cytogenetic abnormalities are being identified in AL at diagnosis. In addition, it is well known that cardiac involvement in AL is an independent negative prognostic factor for these patients; however, the implications of cytogenetics for these high-risk patients remains largely unexplored. Finally, with the advent of novel non-transplant therapy options for AL patients, we look to evaluate the relevance of daratumumab in this setting. As such, the present study aims to a) determine the most relevant FISH abnormalities in AL patients and establish their importance as independent prognostic factors for response to therapy and in survival, b) assess the impact of cytogenetics on the survival of cardiac AL patients, and c) determine the effect of daratumumab on the survival of patients with AL. Methods: A retrospective chart review was performed on 140 consecutive AL patients treated at The Ohio State University. This cohort included 20 patients who received daratumumab. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS), and Kaplan Meier curves were used to calculate PFS and OS. Results: The median age at diagnosis was 62 years (range: 33-88) and 55% were male. Median number of organs involved was 2, and 49% and 65% had cardiac and kidney involvement, respectively. Chromosomal abnormalities were detected in 86 (61%) patients. Translocation t(11;14) was the most prevalent (44%) aberration followed by hyperdiploidy (43%). We observed a statistically significant relationship between several FISH abnormalities and increased plasma cell burden (PC) (≥10%), including gain (+) 5p/5q (p=0.025), del13q (0.009), +11q (p<0.001), and hyperdiploidy (p<0.001). In addition, hyperdiploidy was associated with worsening of PFS (p=0.019) and OS (p=0.032) (Figure 1A). In multivariable analysis, hyperdiploidy was confirmed to be a poor prognostic marker after adjusting for other confounding variables. In patients with cardiac involvement, hyperdiploidy was also associated with worsening of PFS (p=0.0497) and OS (p=0.006) (Figure 1B). Del 13q was found to be associated with cardiac involvement (p=0.01) but showed no prognostic impact on survival. Conversely, survival benefit was seen among these patients with cardiac involvement who had no FISH abnormalities at diagnosis, both in terms of OS and PFS (p=0.019 and p=0.042, respectively). In addition, the overall presence of t(11;14) did not have any prognostic impact on OS (p=0.76) or PFS (p=0.41). However, on further stratification, we did observe a marginal difference in PFS (p=0.09) among four groups (Figure 1C), and more specifically, patients with presence of only t(11;14) did worse compared to those patients with normal FISH in terms of PFS (p=0.021). This potentially suggests that patients with t(11;14) only are at risk for earlier progression. Finally, we evaluated the efficacy of daratumumab, and observed a median OS of 6.1 years and median PFS 2.6 years. Of note, presence of gain 1q was associated with a trend toward better response to daratumumab. 100% of patients (5/5) with gain 1q achieved a hematologic partial response (PR) or better versus only 60% of patients without +1q. Conclusion: Our findings reveal the effect of hyperdiploidy on PC tumor burden, overall survival, and its importance within the high-risk cardiac AL patient population. The results with daratumumab in our patient subset with gain 1q is intriguing in its own right but identification of the mechanism by which the effect of this mutation is abrogated merits further exploration as its use only continues to grow. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau.

Soluble ST2 (sST2) Is a Novel Valuable Prognostic Marker Among Patients With Immunoglobulin Light Chain (AL) Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3095-3095 ◽  
Author(s):  
Angela Dispenzieri ◽  
Amy K. Saenger ◽  
Shaji K. Kumar ◽  
Morie A. Gertz ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Research Funding ◽  
Troponin T ◽  
High Sensitivity ◽  
Staging System ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Prognostic Information ◽  
Soluble St2 ◽  
Staging Systems

Abstract The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of <7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p<0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p<0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p<0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p<0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.

scholarly journals Amyloidosis and Plasma Cell Dyscrasias: A Single Institution Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5463-5463
Author(s):  
Poornima Ramadas ◽  
Ajay Tambe ◽  
Mijung Lee
Keyword(s):  
Mass Spectrometry ◽  
Plasma Cell ◽  
Light Chain ◽  
Cardiac Involvement ◽  
False Negative ◽  
Protein Electrophoresis ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Negative Mass ◽  
High Clinical Suspicion

Background: Amyloidosis is the extracellular tissue deposition of small molecular subunits of proteins as fibrils. AL Amyloidosis is a complication of underlying plasma cell dyscrasia with an associated monoclonal paraprotein. It can occur in association with multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) or non-Hodgkin lymphoma. While isolated organ involvement can be seen, many patients (pts) have multiorgan involvement. Our aim was to explore the trend of amyloidosis associated with plasma cell dyscrasia, treatment and outcome at our institution. Methods: After IRB approval, we reviewed medical records of adult pts ≥ 18 years with a histological diagnosis of amyloid and had evidence of monoclonal gammopathy, between January 1st, 2010 and June 30th, 2019. We reviewed age at diagnosis, gender, work up for paraproteinemia, site of biopsy, technique used for identification of amyloid, imaging studies, treatment and outcome. Results: We found a total of 33 pts with biopsy proven amyloid and evidence of a monoclonal paraprotein. 23 (69.6%) were males and 10 (30.3%) were females. Age ranged from 39 to 89 years with a median age of 62; 3 (9%) being <50 years. 7 (21.2%) were diagnosed with multiple myeloma and one pt each was diagnosed with diffuse large B cell lymphoma and WM. Monoclonal paraprotein was IgG Kappa in 10 (30.3%), IgG lambda in 5 (15%), IgA lambda in 3 (9%), IgA kappa in one, IgM lambda in 3 (9%), IgM Kappa in one, kappa light chain in 5 (15.1%), lambda light chain in 3 (9%), one had both IgG lambda and IgM kappa and no paraprotein was documented in one pt. Serum protein electrophoresis with immunofixation was positive in 22 (66.6%), Urine protein electrophoresis and immunofixation was positive in 16 (48.4%). Most common initial site of amyloid identification by biopsy was kidney in 12 (36.3%). Diagnosis was from abdominal fat pad in 8 (24.2%), lung in 4 (12.1%), bone marrow, heart and skin in 2 each (6%) and liver, colon and bone in 1 each (3%). Positive immunohistochemistry (IHC) stain demonstrating light chain restriction was seen in 23 (69.6%) and out of this only 11 (33%) underwent further evaluation with mass spectrometry. One patient with positive IHC had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. IHC was not performed in 8 (24.2%) and identification was only based on Congo red staining. IHC was negative in 2 (6%) despite evidence of a monoclonal paraprotein. Involvement of kidney was identified in 14 (42.4%) with isolated kidney involvement in 2 (6%). Cardiac involvement was identified in 17 (51.5%) either by biopsy, imaging findings and/or pro-BNP and troponin levels and isolated cardiac disease was noted in 3 (9%). 6 (18.1%) had lung involvement, which was the only disease site in 4 (12.1%). Neuropathy was noted in 10 (30.3%). One had only a single bony site involved. 21 (63.6%) were treated with disease related therapy for amyloidosis, one patient underwent radiation to site of isolated bone disease and the remaining patients were either observed or died before therapy was initiated. 7 (21%) underwent Autologous stem cell transplant for amyloidosis. At the time of data cut off, 21 (63.6%) were alive and 12 (36.3%) were deceased. Amyloidosis was the documented cause of death in 10 pts and of this 9 pts had cardiac involvement. Conclusion: AL Amyloidosis is an uncommon disorder and patients should undergo further diagnostic evaluation if suspicious symptoms with an underlying monoclonal gammopathy. In our study, we noted a male predominance and IgG Kappa was the most common monoclonal paraprotein. As immunohistochemistry has a greater chance of false positive and false negative results, mass spectrometry is the preferred method for identification of amyloid. However, this technique is not widely available which restricts it's use in clinical practice. In our study, we identified one patient with positive IHC who had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. We also identified two patients with negative IHC despite evidence of a monoclonal paraprotein and this may be either a false negative IHC or the amyloid being unrelated to the monoclonal paraprotein. 9/10 pts who died of amyloidosis had cardiac involvement. Disclosures No relevant conflicts of interest to declare.

scholarly journals Predictors of cardiac involvement and survival in patients with primary systemic light-chain amyloidosis: roles of the clinical, chemical, and 3-D speckle tracking echocardiography parameters

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Changhui Lei ◽  
Xiaoli Zhu ◽  
David H. Hsi ◽  
Jing Wang ◽  
Lei Zuo ◽  
...  
Keyword(s):  
Light Chain ◽  
Cardiac Troponin ◽  
Speckle Tracking ◽  
Cardiac Involvement ◽  
Speckle Tracking Echocardiography ◽  
Troponin T ◽  
Al Amyloidosis ◽  
Cardiac Troponin T ◽  
3D Measurements ◽  
Staging Systems

Abstract Background Light-chain (AL) amyloidosis is the most common type of systemic amyloidosis with poor prognosis. Currently, the predictors of cardiac involvement and prognostic staging systems are primarily based on conventional echocardiography and serological biomarkers. We used three-dimensional speckle tracking echocardiography (STE-3D) measurements of strain, hypothesizing that it could detect cardiac involvement and aid in prediction of mortality. Methods We retrospectively analysed 74 consecutive patients with biopsy-proven AL amyloidosis. Among them, 42 showed possible cardiac involvement and 32 without cardiac involvement. LV global longitudinal strain (GLS), global radial strain, global circumferential strain and global area strain (GAS) measurements were obtained. Results The GLS and GAS were considered significant predictors of cardiac involvement. The cut-off values discriminating cardiac involvement were 16.10% for GLS, 32.95% for GAS. During the median follow-up of 12.5 months (interquartile range 4–25 months), 20 (27%) patients died. For the Cox proportional model survival analysis, heart rate, cardiac troponin T, NT-proBNP levels, E/e’, GLS, and GAS were univariate predictors of death. Multivariate Cox model showed that GLS ≤ 14.78% and cardiac troponin T ≥ 0.049 mg/l levels were independent predictors of survival. Conclusions STE-3D measurements of LV myocardial mechanics could detect cardiac involvement in patients with AL amyloidosis; GLS and cardiac biomarkers can provided prognostic information for mortality prediction.

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