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Prognostication of survival using cardiac troponins and N-terminal pro-brain natriuretic peptide in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation

Angela Dispenzieri, Morie A. Gertz, Robert A. Kyle, Martha Q. Lacy, Mary F. Burritt, Terry M. Therneau, Joseph P. McConnell, Mark R. Litzow, Dennis A. Gastineau, Ayalew Tefferi, David J. Inwards, Ivana N. Micallef, Stephen M. Ansell, Luis F. Porrata, Michelle A. Elliott, William J. Hogan, S. Vincent Rajkumar, Rafael Fonseca, Philip R. Greipp, Thomas E. Witzig, John A. Lust, Steven R. Zeldenrust, Denise S. Snow, Susan R. Hayman, Christopher G. A. McGregor and Allan S. Jaffe

Article Figures & Data

Figures

  • Figure 1.

    Survival according to circulating cardiac biomarkers. (A) Troponin T (cTnT). (B) Troponin I (cTnI). (C) N-terminal pro-brain natriuretic peptide (NT-proBNP).

  • Figure 2.

    Survival according to risk scores or stage. (A) The cTnT Idealized Risk Score. Risk scores 3 through 5 were merged due to low numbers of patients in higher risk groups. Score 3, n = 6; score 4, n = 0; and score 5, n = 1. See “Patients and methods” for calculation. (B) The cTnI Idealized Risk Score. Risk scores 2 and 3 were merged because there were only 3 patients in the score 3 category. See “Patients and methods” for calculation. (C) cTnT/NT-proBNP Staging System. Stage I-t is when both are below threshold. Stage II-t is when either is greater than or equal to threshold value. Stage III-t is when both are greater than or equal to threshold value. Threshold values for cTnT and NT-proBNP are less than 0.035 μg/L and less than 332 ng/L, respectively. (D) cTnI/NT-proBNP Staging System. Stage I-i is when both are below threshold. Stage II-i is when either is greater than or equal to threshold value. Stage III-i is when both are greater than or equal to threshold value. Threshold values for cTnI and NT-proBNP are less than 0.1 μg/L and less than 332 ng/L, respectively.

Tables

  • Table 1.

    Patient characteristics

    CharacteristicMedian (range)Cut-offPercent
    Male NA NA 54
    Age, y 55 (35-71) > 60 28
    Serum albumin, g/L 29 (10-44) < 20 25
    Diagnosis to transplantation, months 4.2 (1.3-75) ≥ 12 12
    Creatinine, μM/L [mg/dL] 97 (53-247) > 150 10
    [1.1 (.6-2.8)] [>1.7]
    Creatinine clearance, mL/s [mL/min] 1.22 (0.33-2.10) [73 (20-126)] 1.00 [< 60] 31
    Alkaline phosphatase, IU/L (UNL 300) 186 (85-2789) > 1.5 UNL 17
    β2-microglobulin, nM/L [μg/mL] 201.4 [2.37] (85-858 [1-10.1]) ≥ 229.5 [2.7] 31
    Serum M spike, g/L 10 (0-26) ≥ 20 6
    Urine total protein, g/24 hours 3.7 (0.02-26.2) ≥ 3 57
    Urine M spike, g/24 hours 0.17 (0-2.2) ≥ 1 10
    Bone marrow plasma cells, % 6 (.4-49) > 30 5
    Bone marrow plasma cell labeling index, % 0 (0-2.4) > 1 7
    Interventricular septal thickness, mm 12 (7-25) > 15 15
    Left ventricular ejection fraction, % 65 (28-84) < 55 11
    Organ systems involved, n 2 (1-3) ≥ 3 19
    Troponin T, μg/L 0.01 (0-1) ≥ 0.03 14
    Troponin I, μg/L* 0.07 (0-4.31) ≥ 0.1 44
    NT-proBNP, ng/L 323 (0-35001) ≥ 332 48
    Melphalan conditioning
        Mel 200 mg/m2 NA NA 54
        Mel 140 mg/m2/TBI NA NA 12
        Mel 140 mg/m2 NA NA 24
        Mel 100 mg/m2 NA NA 9
    • n = 98 except where stated.

      UNL indicates upper normal limit; NA, not applicable.

    • * n = 65.

    • n = 63.

  • Table 2.

    Probability of death by 3 months, using univariate logistic regression

    CharacteristicOdds ratio95% CIP
    cTn1 greater than or equal to 0.1 μg/L 9.8 1.1-87.1 .04
    β2-microglobulin greater than or equal to 229.5 nM/L 6.2 1.5-26.0 .01
    Creatinine greater than or equal to 150 μM (1.7 mg/dL) 5.0 1.0-23.5 .04
    No. of organs involved 3.6 1.4-9.2 .008
    Albumin greater than or equal to 30 g/L 0.1 0.02-1.0 .06
    Alkaline phosphatase greater than or equal to 1.5 normal 3.8 10.9-15.5 .06
    cTnT greater than or equal to 0.035 μg/L 3.0 0.7-13.3 .1
    NT-proBNP greater than or equal to 332 ng/L 3.1 0.5-17.3 .2
    NT-proBNP greater than or equal to 1266 ng/L16 2.0 0.4-10.2 .4
    LV EF greater than 50% .3 0-1.7 .2
    IVS greater than 15 mm 1.4 0.3-7.6 .7
    Age greater than 60 y 1.10 0.3-4.5 .9
    • LV EF indicates left ventricular ejection fraction; IVS, interventricular septum.

  • Table 3.

    Predictors for overall survival

    PredictorHazard ratio (95% CI)P
    Univariate
        Troponin T greater than or equal to 0.035 μg/L 4.4 (1.7-10.9) .002
        Troponin I greater than or equal to 0.1 μg/L 4.9 (1.6-15.1) .006
        NT-proBNP greater than or equal to 332 ng/L 3.8 (1.2-12) .02
        cTnT Idealized Risk Score* 2.2 (1.4-3.3) .0003
        cTnI Idealized Risk Score 2.8 (.8-9.4) .09
        cTnT/NT-proBNP stage 3.1 (1.5-6.2) .001
        cTnI/NT-proBNP stage 3.8 (1.7-8.4) .001
        β2-microglobulin greater than 2.7 U/L 3.8 (1.5-9.5) .004
        Organ systems involved, no. 3.5 (1.9-6.5) < .0001
        Serum creatinine 2.3 (1.0-5.5) .05
        Melphalan intensity, high dose 0.5 (0.2-1.1) .08
        Left ventricular EF less than or equal to 50% 1.4 (0.3-6) .7
        IVS greater than or equal to 15 mm 1.8 (0.6-5.0) .3
        Age greater than 60 y 1.0 (0.4-2.5) .99
        Female gender 1.2 (0.5-2.9) .7
        Time to transplantation 0.8 (0.8-1.0) .06
        Serum M spike 1.0 (0.5-1.9) .99
        Bone marrow plasmacytosis less than 30% 1.1 (0.1-8.4) .9
        Bone marrow plasma cell labeling index 1.9 (0.8-4.2) .1
    Multivariate model 1
        cTnT/NT-proBNP stage 2.3 (1.1-4.7) .02
        β2-microglobulin, U/L 2.4 (1.5-3.8) .0005
    Multivariate model 2
        cTnI/NT-proBNP stage 3.2 (1.4-7.4) .007
        β2 microglobulin, U/L 2.4 (1.4-3.9) .0006
    • EF indicates ejection fraction; IVS, interventricular septum.

    • * See “Patients and methods” for equation. If risk levels 3 through 5 are collapsed into one level: HR 3.8, 95% CI 1.5-9.6, P = .004.

    • See “Patients and methods” for equation. If levels 2 and 3 are collapsed into one level: HR 6.6, 95% CI .9-49.6, P = .07.

    • Stage I is when troponin (either cTnT or cTnI) and NT-proBNP are both below threshold. Stage II is when troponin (either cTnT or cTnI) or NT-proBNP is greater than or equal to threshold value. Stage III is when troponin (either cTnT or cTnI) and NT-proBNP are both greater than or equal to threshold value. Threshold values for cTnT, cTnI, and NT-proBNP are < 0.035 μg/L, < 0.1 μg/L, and < 332 ng/L. Suffix (-t or -i) used depending on whether the troponin measured is cTnT or cTnI.

  • Table 4.

    Prognostic markers in patients who underwent transplantation and in those who did not

    SCT N = 98No SCT17N = 242
    Characteristic and cut-off%Median survival, mos.%Median survival, mos.
    cTnT
        Less than 0.035 μg/L 86 NR 56 17
        Greater than or equal to 0.035 μg/L 14 26.1 44 3.7
        cTnI*
        Less than 0.10 μg/L 57 NR 46 16.4
        Greater than or equal to 0.10 μg/L 43 66.1 54 5.9
    NT-proBNP
        Less than 332 ng/L 52 NR 40 20.0
        Greater than or equal to 332 ng/L 48 66.1 60 5.8
    Ejection fraction
        Less than 50% 92 NR 68 14.0
        Greater than or equal to 50% 8 NR 32 3.9
    Septal thickness
        Less than or equal to 15 mm 76 NR 67 12.3
        Greater than 15 mm 24 NR 33 4.3
    cTnT Idealized Risk Score
        1 11 NR 11 23.4
        2 82 NR 52 16.4
        3-5 7 26.1 38 2.9
    cTnI Idealized Risk Score*
        1 23 NR 11 17.0
        2 72 NR 52 11.1
        3 5 66.1 32 2.2
    cTnT/NT-proBNP stage§
        I-t 49 NR 33 26.4
        II-t 38 NR 30 10.5
        III-t 13 8.4 37 3.5
    cTnI/NT-proBNP stage§
        I-i 35 NR 24 27.2
        II-i 38 NR 38 11.1
        III-i 27 21.6 38 4.1
    • NR indicates not reached.

    • * For TnI, only 65 transplantation patients had levels measured.

    • For NT-proBNP, 63 transplantation patients had levels measured

    • See “Patients and methods” for calculations.

    • § See Table 3 for definitions.