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.

Frequency of Amyloid Subtyping Among Patients with Immunoglobulin Light-Chain Amyloidosis Referred for High-Dose Chemotherapy and Autologous Stem Cell Transplant

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5601-5601
Author(s):  
Andrew J. Cowan ◽  
David G. Coffey ◽  
Teresa S. Hyun ◽  
Pamela S. Becker ◽  
Damian J. Green ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Plasma Cell ◽  
Light Chain ◽  
Congo Red ◽  
Plasma Cell Dyscrasia ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Immunoglobulin Light Chain ◽  
Organ Systems

Abstract Background: The amyloidoses comprise a heterogeneous group of diseases characterized by misfolding of amyloidogenic proteins and subsequent deposition as amyloid fibrils. To date, over 30 proteins are known to be amyloidogenic (Sipe Amyloid 2014). Immunoglobulin light chain (AL) amyloidosis, a plasma cell dyscrasia, is the most common subtype. The standard diagnostic algorithm in AL amyloidosis is to obtain a biopsy of a clinically involve organ, and once Congo red positivity is confirmed, perform subtyping analyses with immunohistochemistry or mass spectrometry. Accurate subtyping of amyloidosis is essential to appropriate treatment, as misdiagnosis occurs in up to 10% of patients and may lead to inappropriate administration of chemotherapy (Comenzo Blood 2006; Lachmann NEJM 2002). We sought to determine the patterns of amyloid subtyping among patients with a diagnosis of AL amyloidosis referred to a tertiary referral center for HDM/SCT. Methods: Sequential patients with confirmed amyloidosis, age ≥ 18 years who underwent HDM/SCT between 2001 and 2014 at the Fred Hutchinson Cancer Research Center and University of Washington Medical Center were eligible. Presence of a Congo red-positive biopsy for each patient referred for transplant was confirmed and the pathology reports and medical records were reviewed to determine if subtyping was performed, and which modality was used. Results: Fifty-one patients with AL amyloidosis were referred for transplant; of these, 45 proceeded with HDM/SCT. The organ systems most commonly involved were renal in 34/51, and gastrointestinal in 5/51. Of the biopsies, subtyping was performed in 35 (68.6%), and no subtyping was performed in 16 patients (31.3%). Immunofluorescence was the most common modality used for subtyping in 33 biopsies (94.2%) and laser capture/mass spectrometry (LC/MS) was used in 2 patients (5.7%). All patients had evidence of a clonal plasma cell dyscrasia by bone marrow biopsy and peripheral blood testing. Of the patients without subtyping, 8 (50%) were diagnosed before 2008. Discussion: Misdiagnosis of amyloidosis due to a lack of appropriate subtyping is a well-described and ongoing problem for patients with amyloidosis. These data suggest that definitive subtyping is still not routinely performed in the evaluation of amyloidosis. At our center, efforts to standardize the evaluation of Congo-red positive biopsies using definitive typing are underway. Disclosures Gopal: Seattle Genetics: Research Funding.

Renal Pathologic Spectrum in an Autopsy Series of Patients With Plasma Cell Dyscrasia

2004 ◽  
Vol 128 (8) ◽  
pp. 875-879 ◽  
Author(s):  
Guillermo A. Herrera ◽  
Lija Joseph ◽  
Xin Gu ◽  
Aubrey Hough ◽  
Bart Barlogie
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Renal Infarction ◽  
Light Chain Deposition Disease ◽  
Renal Lesions ◽  
Cast Nephropathy ◽  
Plasma Cell Dyscrasias ◽  
Light Chain Deposition

Abstract Context.—Renal dysfunction in plasma cell dyscrasias is common. It is the second most common cause of death in patients with myeloma. Objective.—We evaluated 77 sequential autopsies performed on patients dying from complications of plasma cell dyscrasias during an 11-year period at the University of Arkansas for Medical Sciences. These consisted of 15% of all the autopsies performed during this time. Design.—The kidneys were evaluated by light microscopy using hematoxylin-eosin–stained sections as well as Congo red and thioflavin T stains when amyloidosis was in the differential diagnosis. Immunofluorescence was performed on selected cases. Results.—The most common lesion identified was cast nephropathy (30%). Other findings included acute tubulopathy, AL-amyloidosis, light chain deposition disease, tubulointerstitial nephritis associated with monotypic light chain deposits, thrombotic microangiopathy, renal infarction, fungal infection, and plasma cell tumor nodules. Autolysis, an expected finding in autopsy evaluations, was significant in 25 cases. Conclusions.—Renal lesions are heterogeneous in these patients. In some cases, combined pathologic lesions were noted. Myeloma cast nephropathy predominated among all the renal lesions noted.

Monoclonal antibody therapeutics as potential interferences on protein electrophoresis and immunofixation

2016 ◽  
Vol 54 (6) ◽  
Author(s):  
Maria Alice V. Willrich ◽  
Paula M. Ladwig ◽  
Bruna D. Andreguetto ◽  
David R. Barnidge ◽  
David L. Murray ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Mass Measurement ◽  
Protein Electrophoresis ◽  
Plasma Cell Dyscrasia ◽  
Monoclonal Gammopathies ◽  
Flight Mass Spectrometry ◽  
Immunofixation Electrophoresis ◽  
Plasma Cell Dyscrasias ◽  
Monoclonal Proteins

AbstractThe use of therapeutic recombinant monoclonal antibodies (mAbs) has triggered concerns of mis-diagnosis of a plasma cell dyscrasia in treated patients. The purpose of this study is to determine if infliximab (INF), adalimumab (ADA), eculizumab (ECU), vedolizumab (VEDO), and rituximab (RITU) are detected as monoclonal proteins by serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE).Pooled normal sera were spiked with various concentrations (ranging from trough to peak) of INF, ADA, ECU, VEDO and RITU. The peak concentration for VEDO and RITU was also added to samples with known monoclonal gammopathies. All samples were analyzed by SPEP (Helena Laboratories) and IFE (Sebia); sera containing peak concentrations of mAbs were reflexed to electrospray-time-of-flight mass spectrometry (AbSciex Triple TOF 5600) for the intact light chain monoclonal immunoglobulin rapid accurate mass measurement (miRAMM).For all mAbs tested, no quantifiable M-spikes were observed by SPEP at any concentration analyzed. Small γ fraction abnormalities were noted on SPEP for VEDO at 300 μg/mL and RITU at 400 μg/mL, with identification of small IgG κ proteins on IFE. Using miRAMM for peak samples, therapeutic mAbs light chain accurate masses were identified above the polyclonal background and were distinct from endogenous monoclonal gammopathies.MAbs should not be easily confounded with plasma cell dyscrasias in patients undergoing therapy except when a SPEP and IFE are performed within a couple of days from infusion (peak). In ambiguous cases the use of the miRAMM technology could precisely identify the therapeutic mAb distinct from any endogenous monoclonal protein.

scholarly journals A Novel Mass Spectrometry Method to Identify the Serum Monoclonal Light Chain Component and Infer Organ Involvement in Systemic Light Chain Amyloidosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4445-4445 ◽  
Author(s):  
Faye Sharpley ◽  
Richa Manwani ◽  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
Helen Lachmann ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mass ◽  
Light Chain ◽  
Mass Spectra ◽  
Amyloid Fibrils ◽  
Cardiac Involvement ◽  
Small Sample ◽  
Organ Involvement ◽  
Light Chains ◽  
Al Amyloidosis

Abstract Introduction Light chain (AL) amyloidosis is caused by progressive organ dysfunction due to the deposition of structurally abnormal monoclonal light chains (LC) as amyloid fibrils. Serial free light chain measurement is the cornerstone of AL diagnosis but is limited by current methods which measure normal polyclonal and abnormal monoclonal LCs. Since each individual monoclonal LC has a unique amino acid sequence, mass spectrometry (MS) has the ability to detect serum monoclonal LCs. We report a novel MS method for monoclonal LC detection in AL amyloidosis. Methods Twenty patients with systemic AL amyloidosis, diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC), were randomly selected. This included 16 newly diagnosed patients, 2 patients in a complete haematological remission (CR) post-treatment and 2 patients with no amyloidosis (acting as negative controls). All patients had detailed baseline assessments of organ function and serum FLC measurements. Organ involvement was defined according to the international amyloidosis consensus criteria. Magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free k) and free lambda light chains (anti-free l). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute free light chains in monomeric form. Mass spectra were acquired on a Microflex LT/SH smart matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF-MS; Bruker, GmbH). Results The median number of organs involved was 2 (range 1-4); cardiac involvement was most common in 70% (14/20) patients, followed by renal 40% (8/20), autonomic and soft tissue in 15% (3/20) and peripheral nerve involvement in 5% (1/20). No patients had liver involvement. The median N-terminal pro b-type natriuretic peptide (NT-proBNP) and cardiac troponin T were 3761.5 (range 245-25348 ng/L) and 35.5 (8-170 ng/L) respectively. The median presenting serum albumin was 37 (19-45 g/L) and eGFR 62 (10-100 mls/min). The amyloid deposits were typed as AL lambda in 14(70%), kappa in 2(10%) patients and amyloid of uncertain type in two cases (10%). The median involved FLC was kappa 76 mg/L (range 71-440) and lambda 185 mg/L (44-1023), with difference involved to uninvolved (dFLC) 118 mg/L (33-1015). An intact monoclonal protein was present in 70% (14/20). In all cases, MS correctly identified the presence and type of monoclonal LC, identifying a monoclonal lambda in 14/14 (100%) and a monoclonal kappa in 2/2 (100%); the two patients where a clear monoclonal component could not be identified were patients whose amyloid fibrils failed to be typed by immunohistochemistry or MS. The assay also confirmed normal polyclonal expression of both kappa and lambda LCs in the two control samples. In the two lambda patients in a CR, the MS method identified monoclonal lambda LC expression; in one of these patients next-generation sequencing (NGS) confirmed minimal residual disease (MRD). A clear shift in the LC mass spectra was seen relating to the specific pattern of organ involvement: in patients with renal amyloid the monoclonal LC predominantly displayed a "heavy" molecular mass, (with a mean molecular mass of 11596+/- 436 daltons), whereas in patients with cardiac involvement the monoclonal LC mainly exhibited a "light" mass (with a mean molecular mass of 11443 +/- 102 daltons). Conclusion This small study shows that monoclonal light chains can be accurately detected by MS and be concordant to the tissue amyloid type. A monoclonal LC was detected in 2 patients in serological "CR" - in one case presence of persistent disease was demonstrated by NGS-MRD. Even in this small sample size, there appears to be a marked difference in LC mass for patients with cardiac ("light" LC) vs. renal ("heavy" LC) involvement, raising the interesting possibility that "heavy" LC are trapped by the glomerulus causing renal AL but are unable to penetrate the tight cardiac capillary gap junctions, and vice versa. The unique molecular location of LC on MS offers the possibility of exploiting this technique as a tool to detect amyloidogenic FLC and potentially predict organ involvement in patients with gammopathies. We plan to expand this study to a large cohort of patients to confirm these findings and assess the impact on survival and organ response outcomes. Figure 1 Figure 1. Disclosures Wechalekar: Janssen: Honoraria.

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.

Macroglossia – Not Always AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5007-5007 ◽  
Author(s):  
Andrew J Cowan ◽  
Martha Skinner ◽  
J. Mark Sloan ◽  
John L Berk ◽  
Carl J O'Hara ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Bone Marrow ◽  
Plasma Cell ◽  
Light Chain ◽  
Plasma Cells ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Immuno Electron Microscopy ◽  
Congo Red Staining

Abstract Abstract 5007 Introduction: Amyloidosis is characterized by extracellular deposition of abnormal insoluble fibrillar proteins. The two most frequent systemic amyloidoses are the light-chain (AL amyloidosis) and familial transthyretin (ATTR) forms. Clinical presentations often vary between the two types. Macroglossia is viewed as pathognomic of AL amyloidosis, and has not previously been described in patients with hereditary TTR amyloidosis. Here, we describe two cases of systemic amyloidosis with macroglossia in which immuno-electron microscopy diagnosed ATTR in one and AL in the other. Case Presentations: A 61 year old woman presented initially to her general internist with weight loss, difficulty swallowing, and tongue numbness. Her clinical exam revealed macroglossia and peripheral neuropathy. Tongue and axillary lymph node biopsies demonstrated amyloid deposits by Congo red staining. There was no evidence of renal, cardiac or other vital organ involvement. She had no evidence of a plasma cell dyscrasia with negative serum and urine immunofixation electrophoresis, normal serum free light chain concentration and ratio as well as polytypic plasma cells in the bone marrow. Immuno-electron microscopy using gold-labeled antibodies was performed on the tongue biopsy. The fibrils were immunoreactive with anti-TTR but not anti-kappa, anti-lambda, or anti-AA antibodies. DNA sequencing identified a known amyloidogenic T60A TTR mutation in exon 3 of chromosome 18, confirming the diagnosis of ATTR with amyloidotic polyneuropathy and macroglossia. The second case involved a 59 year old man with renal insufficiency. He complained of fatigue, weight loss, and tongue swelling. Physical examination was significant for macroglossia and submandibular gland enlargement. Tongue biopsy demonstrated amyloid deposits by Congo red staining. As in the previous case, markers of plasma cell dyscrasia with clonal plasma cells in the bone marrow, blood, and urine were absent. Immuno-electron microscopy of the tongue biopsy documented antibody reactivity to lambda light chain and not TTR, kappa light chain or AA proteins, confirming the diagnosis of AL amyloidosis. He subsequently underwent treatment with high dose intravenous melphalan followed by stem cell transplantation achieving a good clinical response sustained for 2 years to date. Discussion: While macroglossia is thought to be pathognomonic of AL amyloidosis, we report a case of macroglossia with fibrillar ATTR amyloid deposits diagnosed by immuno-electron microscopy. This is contrasted with a clinical presentation consistent with AL in which routine laboratory testing failed to identify evidence of a plasma cell dyscrasia. In both cases, electron microscopy demonstrated immunoreactivity for the fibrils of a single pathogenic protein. The first case was confirmed by DNA sequencing, and the second had a typical response to anti-plasma cell chemotherapy, in spite of the lack of identifiable markers of disease. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

2018 ◽  
Vol 49 (1) ◽  
pp. 9-14
Author(s):  
Monika Adamska ◽  
Anna Komosa ◽  
Tatiana Mularek ◽  
Joanna Rupa-Matysek ◽  
Lidia Gil
Keyword(s):  
Differential Diagnosis ◽  
Light Chain ◽  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Diagnosis And Treatment ◽  
Diagnostic Approach ◽  
Al Amyloidosis ◽  
Delay In Diagnosis ◽  
Light Chain Amyloidosis ◽  
Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

scholarly journals Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4375-4375 ◽  
Author(s):  
Faye Amelia Sharpley ◽  
Hannah Victoria Giles ◽  
Richa Manwani ◽  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Residual Disease ◽  
Renal Involvement ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Accurate Identification ◽  
Monoclonal Protein ◽  
Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

scholarly journals Conventional Therapy for Amyloid Light-Chain Amyloidosis

2020 ◽  
Vol 143 (4) ◽  
pp. 365-372
Author(s):  
Paolo Milani ◽  
Giovanni Palladini
Keyword(s):  
Stem Cell ◽  
Plasma Cell ◽  
Light Chain ◽  
Cell Clone ◽  
Alkylating Agents ◽  
Proteasome Inhibitors ◽  
Response Rates ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Conventional Chemotherapy

The vast majority of patients with light-chain (AL) amyloidosis are not eligible for stem cell transplant and are treated with conventional chemotherapy. Conventional regimens are based on various combinations of dexamethasone, alkylating agents, proteasome inhibitors, and immunomodulatory drugs. The choice of these regimens requires a careful risk stratification, based on the extent of amyloid organ involvement, comorbidities, and the characteristics of the amyloidogenic plasma cell clone. Most patients are treated upfront with bortezomib and dexamethasone combined with cyclophosphamide or melphalan. Cyclophosphamide does not compromise stem cell mobilization and harvest and is more manageable in renal failure. Melphalan can overcome the effect of t(11;14), which is associated with lower response rates and shorter survival in subjects treated with bortezomib and dexamethasone, or in combination with cyclophosphamide. Lenalidomide and pomalidomide are the mainstay of rescue treatment. They are effective in patients exposed to bortezomib, dexamethasone, and alkylators, but deep hematologic responses are rare. Ixazomib, alone or in combination with lenalidomide, increases the rate of complete responses in relapsed/refractory patients. Conventional chemotherapy regimens will represent the backbone for future combinations, particularly with anti-plasma-cell immunotherapy, that will further improve response rates and outcomes.

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