This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dispenzieri, A. Articles by Jaffe, A. S. Search for Related Content PubMed PubMed Citation Articles by Dispenzieri, A. Articles by Jaffe, A. S.

Serum Cardiac Troponins and N-Terminal Pro-Brain Natriuretic Peptide: A Staging System for Primary Systemic Amyloidosis

From the Division of Hematology and Internal Medicine, the Division of Biostatistics, the Division of Cardiovascular Diseases and Internal Medicine, the Division of Laboratory Genetics and Laboratory Medicine and Pathology, the Department of Surgery, and the Division of Clinical Biochemistry and Immunology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Address reprint requests to Angela Dispenzieri, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: dispenzieri.angela{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Primary systemic amyloidosis (AL) is a multisystemic disorder resulting from an underlying plasma cell dyscrasia. There is no formal staging system for AL, making comparisons between studies and treatment centers difficult. Our group previously identified elevated serum cardiac troponin T (cTnT) as the most powerful predictor of overall survival. Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL.

PATIENTS AND METHODS: Two hundred forty-two patients with newly diagnosed AL who were seen at the Mayo Clinic between April 1979 and November 2000, and who had echocardiograms and stored serum samples at presentation were eligible for this retrospective review. NT-proBNP measurements were performed on 242 patients in whom cTnT and cardiac troponin I (cTnI) had been previously run. Two prognostic models were designed using threshold values of NT-proBNP and either cTnT or cTnI (NT-proBNP < 332 ng/L, cTnT < 0.035 µg/L, and cTnI < 0.1 µg/L). Depending on whether NT-proBNP and troponin levels were both low, were high for only one level, or were both high, patients were classified as stage I, II, or III, respectively.

RESULTS: Using the cTnT+NT-proBNP model 33%, 30%, and 37% of patients were stages I, II, and III, respectively, with median survivals of 26.4, 10.5, and 3.5 months, respectively. The alternate cTnI+NT-proBNP model predicted median survivals of 27.2, 11.1, and 4.1 months, respectively.

CONCLUSION: Stratification of AL patients into three stages is possible with two readily available and reproducible tests setting the stage for more consistent and reliable cross comparisons of therapeutic outcomes.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Primary systemic amyloidosis (AL) is a plasma cell dyscrasia typically associated with short survival. However, prognosis is highly variable, making estimation of survival problematic. This obstacle complicates the ability to evaluate new therapies and to adequately inform patients of their prognosis. The extent of cardiac involvement is the most important determinant of clinical outcome.^1-8 Other adverse predictors of survival include increased number of organ systems involved, time to referral center,^9-13 bone marrow plasmacytosis greater than 30%, circulating plasma cells in the peripheral blood, elevated bone marrow plasma cell labeling index, Howell Jolly bodies on peripheral-blood film, and increased beta₂-microglobulin.²

Recently, blood levels of cardiac troponins and N-terminal pro-brain natriuretic peptide (NT-proBNP) have been shown to provide potent prognostic information in patients with AL.^14,15 We and others have developed algorithms to help predict survival based on these measurements. Cardiac troponins T (cTnT) and I (cTnI) are highly specific and sensitive markers of cardiac injury. Their high concentration in myocardium, high release ratio, and prolonged elevation after injury allows detection of even subtle myocyte damage.¹⁶ ProBNP is a 108-amino acid propeptide made by myocytes in response to increased wall stress. It is produced predominantly in the left ventricle, and when released, it is thought to be cleaved into two fragments, the active brain natriuretic peptide (amino acids 77 to 108) and a leader sequence known as NT-proBNP (amino acids 1 to 76). NT-proBNP has been shown to be a sensitive indicator of cardiac abnormalities.

A simple yet robust way of stratifying patients that would predict survival would be helpful. We recently published two prognostic models based on cardiac troponin values.¹⁴ Although reproducible, these models are cumbersome. Cognizant of this limitation and of the NT-proBNP data reported by Palladini et al¹⁵ in patients with AL, we sought to develop a simpler model based on these two cardiac markers. The desired characteristics of this model were that it could be easily applied by clinicians, potentially allow for comparisons of outcomes across data sets, and be used to help inform patients of their prognosis.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Study Population
Between April 1979 and November 2000, there were 261 patients with AL seen at the Mayo Clinic within 30 days of diagnosis who had echocardiograms performed within 30 days of presentation and serum samples stored within 7 days of presentation but who did not undergo peripheral-blood stem-cell transplantation at the Mayo Clinic. cTnT and cTnI measurements were performed on all 261 patients.¹⁴ NT-proBNP measurements were performed on 242 of these 261 patients. All but two patients had follow-up through April 2001. The diagnosis of AL was made as previously described.¹³ The study was approved by the Mayo Foundation Institutional Review Board. All patients provided written consent for review of their medical records.

The definition of an involved organ was based on a positive biopsy of that organ or by accepted surrogate measurements. Renal involvement included a urine albumin greater than or equal to 0.5 g/24 hours or a creatinine of greater than or equal to 2 mg/dL. Cardiac involvement required a history of congestive heart failure, positive cardiac biopsy, cardiac interventricular septum more than 12 mm in the absence of uncontrolled hypertension, or left ventricular ejection fraction (LVEF) less than 55%. Hepatic involvement was defined as alkaline phosphatase greater than 1.5 times the institutional normal or hepatomegaly greater than 5 cm below the right costal margin. Peripheral neuropathy with no other identified cause was sufficient to document peripheral nerve involvement. Soft tissue, autonomic, pulmonary, and gastrointestinal involvement were not counted as organ involvement because of the relative lack of clinical significance for soft tissue involvement and the difficulties and subjectivity in diagnosing the other involvements.

Laboratory Methods
Serum samples, stored at –20°C, were thawed and analyzed immediately after thawing. Assays for cTnT and cTnI were performed with sensitive second- and third-generation assays with reagents provided by Roche Diagnostics (Indianapolis, IN) and Dade (Newark, DE).^14,17 The cTnT assay has a limit of detection of less than 0.01 µg/L and coefficients of variability of 10% at 0.035 µg/L and 20% at 0.015 µg/L (Roche).¹⁷ The value of 0.035 µg/L is the lowest value that meets the European Society of Cardiology/American College of Cardiology criteria for precision.¹⁸ The cTnI assay (Dade) has a limit of detection of 0.03 µg/L and a coefficient of variability of 10% at the upper limit of the normal range of 0.06 µg/L.¹⁸ The results of serum levels of cTnT and cTnI in this cohort have been previously reported.¹⁴ NT-proBNP levels were measured with electrochemiluminescence sandwich immunoassay on an Elecsys System 2010 (Roche). The detection limit is 5 ng/L. Serum NT-proBNP levels are higher in women and increase with age. Upper reference limits (97.5 percentiles of healthy subjects) in men and women are 87 and 150 ng/L, respectively, in subjects less than 50 years old and 220 and 331.5 ng/L, respectively, in individuals more than 50 years old (data from Roche from 712 normal subjects). Precision with this assay is excellent, but substantial biologic variability exists, especially at higher values.¹⁹

Statistical Analysis
A multivariate model was constructed incorporating cTnT, which resulted in an idealized cTnT risk score that was calculated as follows: r = 3.19 cTnT + 0.52 urine M spike + 0.025 age + 0.34 ejection fraction, where cTnT and urine M spike are the actual values expressed in µg/L and g/24 hours, respectively; age is number of years when less than 65 years old but 65 years for those 65 years and older; and ejection fraction is 1 when less than 55% and 0 when 55% or higher. The overall risk score yields values ranging between 0.77 to 5.2.¹⁴ The following similar idealized model was independently designed for cTnI: r = 0.399 cTnI + 0.497 ejection fraction + 0.0247 age + 0.338 septal thickness + 0.373 urine M spike. The assignment of values for the variables is the same as for the cTnT model with the following exceptions: cTnI and septal thickness variables are each assigned a value of 1 if 0.1 ng/mL or more than 15 mm, respectively, and 0 for less than 0.1 ng/mL or 15 mm, respectively. The maximum value of this risk score is 3.18.¹⁴ The model including cTnT was substantially more robust than the model with cTnI.

Thresholds for NT-proBNP were explored for best fit. The upper reference limit for normal women older than 50 years (331.5 ng/L) proved to be the best fit with the highest hazard ratio (HR; 2.05; 95% CI, 1.56 to 2.71).

We compared differences between groups using the rank sum and Kruskal-Wallis tests. Fisher's exact test was used to test differences in categoric variables. Survival curves were constructed according to the Kaplan-Meier method. We identified predictors of survival in univariate and multivariate Cox proportional hazards models and calculated the relative hazards and 95% CIs using univariate and multivariate Cox proportional hazards regression models. Multivariate analyses were performed with the use of a stepwise forward regression model with an entry probability for each variable set at .05. All analyses were performed using Statview Software (SAS, Cary, NC).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The patient characteristics of the 242 patients separated by the proposed staging system are listed in Table 1. The median age was 64 years, with 24% of patients under age 55 years. Sixty-five percent of the patients were male. Seventy-six percent of the patients had clonal lambda plasma cell dyscrasia. Median values of cTnT, cTnI, and NT-proBNP were 0.02 µg/L, 0.11 µg/L, and 580 ng/L. The median LVEF and septal thickness were 58% and 14 mm, respectively. The median number of organs involved was two. Two hundred twenty-two patients (92%) have died. The median overall survival time was 9.2 months, with only 25% of patients alive at 30 months. Their overall survival was comparable to the 310 patients presenting to the Mayo Clinic within 30 days of their AL diagnosis during the same time period who did not have cardiac biomarkers measured.¹⁴

View larger version (18K): [in this window] [in a new window]   Fig 1. Overall survival is superior if serum cardiac troponin T (cTnT) level is less than 0.035 µg/L. MS, median survival.

View larger version (18K): [in this window] [in a new window]   Fig 2. Overall survival is superior if serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level is less than 332 ng/L. MS, median survival.

View larger version (14K): [in this window] [in a new window]   Fig 3. Survival according to stage. Thresholds for cTnT, cTnI, and NT-proBNP are < 0.035 µg/L, < 0.1 µg/L, and < 332 ng/L, respectively. (A) cTnT+NT-proBNP stage (stage I-t, both < threshold; stage II-t, either threshold; and stage III-t, both threshold). (B) cTnI+NT-proBNP stage (stage I-i, both < threshold; stage II-i, either threshold; and stage III-i, both threshold). cTnT, cardiac troponin T; cTnI, cardiac troponin I; NT-proBNP, N-terminal pro-brain natriuretic peptide; MS, median survival.

The two new staging systems (including either cTnT or cTnI levels) were in agreement for the majority of cases. Regardless of whether cTnT or cTnI was used, there was concordant stage classification in 72% of patients (rho, 0.80; P < .0001). For the 68 patients with discordant stage assignment, the cTnI system upstaged 46 patients relative to the cTnT system and downstaged 22 patients. Twenty-eight of the stage I-t patients were classified as stage II-i. Eighteen of the stage II-t patients were classified as stage III-i. Seven of the stage II-t patients were classified as stage I-i, and 15 of the stage III-t patients were classified as stage II-i.

The relationship between these biochemical cardiac markers and other prognostic factors was evaluated, and the results of the multivariate analysis are listed in Table 3. cTnT, NT-proBNP, LVEF, serum albumin level, and urine monoclonal protein were independent predictors of survival. Age, interventricular wall thickness, and number of organs involved by amyloid were no longer significant in the multivariable analysis. cTnI was not an independent variable once cTnT was in the model. An alternate model incorporating cTnI as a separate variable (without cTnT) is also shown. The correlation coefficients between NT-proBNP and cTnT, cTnI, interventricular septal thickness, and LVEF were 0.62 (P < .0001), 0.31 (P < .0001), 0.40 (P < .0001), and –0.48 (P < .0001), respectively.

The troponin+NT-proBNP staging systems add information above and beyond the historical cardiac risk factors. Once patients were stratified by the cTnT+NT-proBNP staging system, the clinical and echocardiographic diagnosis of presence or absence of cardiac involvement added little to prognosis (Table 4). Seventeen additional patients who were not suspected of cardiac involvement by either standard echocardiographic or clinical grounds were stage II-t or III-t. The survival of these 17 patients was inferior to the 33 patients who were not suspected of cardiac involvement based on standard predictors but who were stage I-t (16.9 v 30.1 months, respectively; P = .03). Moreover, the 47 stage I-t patients who had echocardiographic or clinical features consistent with cardiac involvement had a markedly superior median survival (26.4 months) than patients with clinical or echocardiographic suspicion and elevated biomarkers (median survival, 5.4 months; P < .0001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
We previously demonstrated that cardiac troponins are the most powerful predictors of survival in patients with primary systemic AL.¹⁴ Subsequently, Palladini et al¹⁵ described NT-proBNP as being prognostic in amyloid patients as well. We now demonstrate that troponins and NT-proBNP are independent predictors of survival in patients with AL and can be incorporated into simple prognostic staging systems. NT-proBNP is elevated in a larger number of patients than cTnT, potentially reflecting other noncardiac processes such as volume overload or right ventricular stress caused by pulmonary disease.²⁰

Palladini et al¹⁵ described a threshold value of 152 pmol/L (1,266 ng/L) as being 93% sensitive and 90% specific for detecting cardiac involvement based on clinical and echocardiographic findings. We found that a lower threshold (332 ng/L, the upper limit of normal for women older than 50 years) provided a better cutoff point (ie, a higher HR for mortality). Their concept of sensitivity and specificity in the context of determining cardiac involvement by amyloid uses circular logic. The gold standard for cardiac involvement is the heart biopsy, a test performed in a minority of patients (33 patients in the present study). Most experts would agree that in the absence of an endomyocardial biopsy, the most valuable test for cardiac involvement is the echocardiogram. Echocardiogram provides quantitative information, but coexisting hypertensive heart disease, coronary artery disease, and/or valvular abnormalities may confound its interpretation. Finally, given the variable course of the disease and the relatively slow rate of change of echocardiographic findings in these patients, it is not surprising that we found that echocardiography is less predictive of survival, which is the end point of choice in patients with amyloid. The risk of death in patients with primary systemic AL can be accurately stratified with our models using two simple measurements, serum troponins (preferably cTnT over cTnI) and NT-proBNP. Adding LVEF strengthens the prediction but adds another degree of complexity. The difference in concordance values between our original cTnT model¹⁴ versus the proposed staging system is 0.70 v 0.66, a relatively small sacrifice for simplicity. Although our staging systems do not directly supply information about renal, hepatic, or nervous system involvement, they predict survival because cardiac involvement is the primary determinant of prognosis.

The systems we propose can be used to stratify patients in randomized clinical trials and to compare outcomes between therapeutic interventions when randomized clinical trials are not available. This is especially important in a disease with a low prevalence, where studies reporting treatment efficacy are often small and not randomized.^11,21-29 Although not ideal, comparisons between studies can help to better understand the disease. Because organ response is delayed and evaluated with surrogate markers, survival is an important but potentially confounded end point. Often, to be included in a series, a patient must be fit enough both to travel to the tertiary center^12,13 and to meet protocol eligibility criteria for the therapy.³⁰ Better descriptors are required to define the patients reported from different centers, and our models could serve to provide this information.

Historically, the dominant organ involved and the numbers of organs involved have been used to stratify patients. Although conceptually appealing for a staging system, designating the number and or types of organs involved by amyloid is a challenging exercise fraught with subjectivity.^9,10,15,21 Because most major organs are not routinely biopsied, surrogate measurements are used to define functional involvement. Furthermore, histologic evidence of amyloid does not indicate the degree of involvement. Renal involvement is the most straightforward to characterize, in that patients have significant albuminuria. Even so, heart failure and pulmonary edema can result in modest proteinuria. Defining cardiac involvement has been even more challenging because different institutions use different criteria. Among the definitions for cardiac involvement are interventricular septal thickness more than 12 mm or more than 15 mm, diastolic dysfunction, LVEF less than 50% or less than 60%, low voltage ECG, low anterior forces on ECG, cardiac rhythm disturbances, unexplained fatigue, and the presence of interstitial edema or pleural effusions.^10,15,27 In patients in their seventh and eighth decades of life, distinguishing amyloid from hypertensive cardiomyopathy or age-related rhythm disturbances may be formidable. Moreover, differentiating between the capillary leak into the pulmonary vasculature from severe nephrotic syndrome and true heart failure may also pose problems.

Thus, we propose a staging system based on objective, easily reproducible, biochemical criteria. The International Prognostic Indices introduced to the field of lymphoma and myelodysplastic syndrome have revolutionized the interpretation and stratification of studies.^31-33 The same should hold true for patients with AL. The staging systems we suggest use simple, readily available blood tests and should be easily generalizable. Although models combining cTnT and LVEF or NT-proBNP and LVEF seem roughly comparable to troponin+NT-proBNP (data not shown), we advocate the use of our model, which is based on two inexpensive, objective, and reproducible biochemical tests. Although we did not measure brain natriuretic peptide levels and, therefore, cannot comment on the ability to translate our findings for those without access to NT-proBNP assay, there is a good correlation between brain natriuretic peptide levels and NT-proBNP levels, both from a laboratory³⁴ and a clinical standpoint.³⁵ Our models meet the criteria needed for a prognostic index for staging and stratifying patients with AL. Confirmatory studies from other data sets are required. The fact that our prognostic index holds true in AL patients undergoing peripheral-blood stem-cell transplantation supports the utility of our system.³⁶

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Carol Shipman for her years of work managing the database and Tara Phelps for collecting and storing the serum samples. We thank Joseph P. McConnell for running the troponin I assays. Roche (Indianapolis, IN) provided reagents for the NT-proBNP measurements. Dade (Newark, DE) and Roche provided reagents for the second- and third-generation troponin assays, respectively.

	NOTES

 
Supported in part by grant Nos. CA 62242 (R.A.K) and CA 91561 (A.D.) from the National Cancer Institute and the Robert A. Kyle Hematology Malignancies Fund, Mayo Foundation.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Cueto-Garcia L, Reeder GS, Kyle RA, et al: Echocardiographic findings in systemic amyloidosis: Spectrum of cardiac involvement and relation to survival. J Am Coll Cardiol 6:737-743, 1985[Abstract]

2. Gertz MA, Kyle RA: Amyloidosis: Prognosis and treatment. Semin Arthritis Rheum 24:124-138, 1994[CrossRef][Medline]

3. Klein AL, Hatle LK, Taliercio CP, et al: Prognostic significance of Doppler measures of diastolic function in cardiac amyloidosis: A Doppler echocardiography study. Circulation 83:808-816, 1991[Abstract/Free Full Text]

4. Tei C, Dujardin KS, Hodge DO, et al: Doppler index combining systolic and diastolic myocardial performance: Clinical value in cardiac amyloidosis. J Am Coll Cardiol 28:658-664, 1996[Abstract]

5. Patel AR, Dubrey SW, Mendes LA, et al: Right ventricular dilation in primary amyloidosis: An independent predictor of survival. Am J Cardiol 80:486-492, 1997[CrossRef][Medline]

6. Kyle RA, Greipp PR, O'Fallon WM: Primary systemic amyloidosis: Multivariate analysis for prognostic factors in 168 cases. Blood 68:220-224, 1986[Abstract/Free Full Text]

7. Kyle RA, Gertz MA: Cardiac amyloidosis. Int J Cardiol 28:139-141, 1990[CrossRef][Medline]

8. Dubrey SW, Cha K, Anderson J, et al: The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement. QJM 91:141-157, 1998[Abstract/Free Full Text]

9. Moreau P, Leblond V, Bourquelot P, et al: Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: A report on 21 patients. Br J Haematol 101:766-769, 1998[CrossRef][Medline]

10. Gertz MA, Lacy MQ, Dispenzieri A, et al: Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med 113:549-555, 2002[CrossRef][Medline]

11. Sanchorawala V, Wright DG, Seldin DC, et al: An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant 28:637-642, 2001[CrossRef][Medline]

12. Kyle RA, Gertz MA, Greipp PR, et al: Long-term survival (10 years or more) in 30 patients with primary amyloidosis. Blood 93:1062-1066, 1999[Abstract/Free Full Text]

13. Kyle RA, Gertz MA: Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 32:45-59, 1995[Medline]

14. Dispenzieri A, Kyle RA, Gertz MA, et al: Survival in patients with primary systemic amyloidosis and raised serum cardiac troponins. Lancet 361:1787-1789, 2003[CrossRef][Medline]

15. Palladini G, Campana C, Klersy C, et al: Serum N-terminal pro-brain natriuretic peptide is a sensitive marker of myocardial dysfunction in AL amyloidosis. Circulation 107:2440-2445, 2003[Abstract/Free Full Text]

16. Jaffe AS, Ravkilde J, Roberts R, et al: It's time for a change to a troponin standard. Circulation 102:1216-1220, 2000[Free Full Text]

17. Miller WL, Wright RS, McGregor CG, et al: Troponin levels in patients with amyloid cardiomyopathy undergoing cardiac transplantation. Am J Cardiol 88:813-815, 2001[CrossRef][Medline]

18. Apple FS, Wu AH, Jaffe AS: European Society of Cardiology and American College of Cardiology guidelines for redefinition of myocardial infarction: How to use existing assays clinically and for clinical trials. Am Heart J 144:981-986, 2002[CrossRef][Medline]

19. Wu AH, Smith A, Wieczorek S, et al: Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. Am J Cardiol 92:628-631, 2003[CrossRef][Medline]

20. Raymond I, Groenning BA, Hildebrandt PR, et al: The influence of age, sex and other variables on the plasma level of N-terminal pro brain natriuretic peptide in a large sample of the general population. Heart 89:745-751, 2003[Abstract/Free Full Text]

21. Comenzo RL, Sanchorawala V, Fisher C, et al: Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM+G-CSF or G-CSF alone to treat AL (amyloid light chain) amyloidosis. Br J Haematol 104:553-559, 1999[CrossRef][Medline]

22. Gertz MA, Kyle RA: Phase II trial of alpha-tocopherol (vitamin E) in the treatment of primary systemic amyloidosis. Am J Hematol 34:55-58, 1990[Medline]

23. Gertz MA, Kyle RA: Phase II trial of recombinant interferon alfa-2 in the treatment of primary systemic amyloidosis. Am J Hematol 44:125-128, 1993[Medline]

24. Gertz MA, Lacy MQ, Lust JA, et al: Phase II trial of high-dose dexamethasone for previously treated immunoglobulin light-chain amyloidosis. Am J Hematol 61:115-119, 1999[CrossRef][Medline]

25. Gertz MA, Lacy MQ, Lust JA, et al: Phase II trial of high-dose dexamethasone for untreated patients with primary systemic amyloidosis. Med Oncol 16:104-109, 1999[Medline]

26. Saba N, Sutton D, Ross H, et al: High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant 24:853-855, 1999[CrossRef][Medline]

27. Sanchorawala V, Wright DG, Seldin DC, et al: Low-dose continuous oral melphalan for the treatment of primary systemic (AL) amyloidosis. Br J Haematol 117:886-889, 2002[CrossRef][Medline]

28. Gertz MA, Lacy MQ, Dispenzieri A, et al: A multicenter phase II trial of 4'-iodo-4'deoxydoxorubicin (IDOX) in primary amyloidosis (AL). Amyloid 9:24-30, 2002[Medline]

29. Merlini G, Ascari E, Amboldi N, et al: Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: Inhibition of amyloidogenesis. Proc Natl Acad Sci U S A 92:2959-2963, 1995[Abstract/Free Full Text]

30. Dispenzieri A, Lacy M, Kyle RA, et al: Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol 19:3350-3356, 2001[Abstract/Free Full Text]

31. Shipp MA: Prognostic factors in aggressive non-Hodgkin's lymphoma: Who has "high-risk" disease? Blood 83:1165-1173, 1994[Abstract/Free Full Text]

32. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339:1506-1514, 1998[Abstract/Free Full Text]

33. Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079-2088, 1997[Abstract/Free Full Text]

34. Masson S, Vago T, Baldi G, et al: Comparative measurement of N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in ambulatory patients with heart failure. Clin Chem Lab Med 40:761-763, 2002[CrossRef][Medline]

35. Hammerer-Lercher A, Neubauer E, Muller S, et al: Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta 310:193-197, 2001[CrossRef][Medline]

36. Dispenzieri A, Gertz MA, Kyle RA, et al: Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplant. Blood (in press)

Submitted March 3, 2004; accepted June 22, 2004.

This article has been cited by other articles:

				A. Biolo, S. Ramamurthy, L. H. Connors, C. J. O'Hara, H. K. Meier-Ewert, P. T. Soo Hoo, D. B. Sawyer, D. S. Seldin, and F. Sam Matrix Metalloproteinases and Their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition Circ Heart Fail, November 1, 2008; 1(4): 249 - 257. [Abstract] [Full Text] [PDF]

				F.-U. Sack, A. Kristen, H. Goldschmidt, P. A. Schnabel, T. Dengler, A. Koch, and M. Karck Treatment options for severe cardiac amyloidosis: heart transplantation combined with chemotherapy and stem cell transplantation for patients with AL-amyloidosis and heart and liver transplantation for patients with ATTR-amyloidosis Eur. J. Cardiothorac. Surg., February 1, 2008; 33(2): 257 - 262. [Abstract] [Full Text] [PDF]

				E. Kastritis, A. Anagnostopoulos, M. Roussou, S. Toumanidis, C. Pamboukas, M. Migkou, A. Tassidou, I. Xilouri, S. Delibasi, E. Psimenou, et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone Haematologica, October 1, 2007; 92(10): 1351 - 1358. [Abstract] [Full Text] [PDF]

				D. H. Vesole, W. S. Perez, M. Akasheh, C. Boudreau, D. E. Reece, C. N. Bredeson, and Plasma Cell Disorders Working Committee of the Cen High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation for Patients With Primary Systemic Amyloidosis: A Center for International Blood and Marrow Transplant Research Study Mayo Clin. Proc., July 1, 2006; 81(7): 880 - 888. [Abstract] [Full Text] [PDF]

				A. M. S. Muller, A. Geibel, H. P. H. Neumann, A. Kuhnemund, A. Schmitt-Graff, J. Bohm, and M. Engelhardt Primary (AL) Amyloidosis in Plasma Cell Disorders Oncologist, July 1, 2006; 11(7): 824 - 830. [Abstract] [Full Text] [PDF]

				M. A. Gertz Monitoring organ response in amyloidosis Blood, May 15, 2006; 107(10): 3814 - 3814. [Full Text] [PDF]

				G. Palladini, F. Lavatelli, P. Russo, S. Perlini, V. Perfetti, T. Bosoni, L. Obici, A. R. Bradwell, G. M. D'Eril, R. Fogari, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL Blood, May 15, 2006; 107(10): 3854 - 3858. [Abstract] [Full Text] [PDF]

				S. V. Rajkumar, A. Dispenzieri, and R. A. Kyle Monoclonal Gammopathy of Undetermined Significance, Waldenstrom Macroglobulinemia, AL Amyloidosis, and Related Plasma Cell Disorders: Diagnosis and Treatment Mayo Clin. Proc., May 1, 2006; 81(5): 693 - 703. [Abstract] [Full Text] [PDF]

				L. Babuin and A. S. Jaffe Troponin: the biomarker of choice for the detection of cardiac injury Can. Med. Assoc. J., November 8, 2005; 173(10): 1191 - 1202. [Abstract] [Full Text] [PDF]

				R. H. Falk Diagnosis and Management of the Cardiac Amyloidoses Circulation, September 27, 2005; 112(13): 2047 - 2060. [Full Text] [PDF]

				R. L. Comenzo Light chains ahoy: pirating Thal/Dex for AL too Blood, April 1, 2005; 105(7): 2625 - 2625. [Full Text] [PDF]

				H. J. B. Goodman, P. N. Hawkins, A. Dispenzieri, M. A. Gertz, R. A. Kyle, and J. Mehta The role of PBSCT in treatment of AL amyloidosis is far from settled Blood, November 1, 2004; 104(9): 2991 - 2994. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dispenzieri, A. Articles by Jaffe, A. S. Search for Related Content PubMed PubMed Citation Articles by Dispenzieri, A. Articles by Jaffe, A. S.