Biomarkers in AL Amyloidosis
Abstract
:1. Introduction
2. Current Prognostic Staging Systems and Biomarkers
3. Other Markers of Organ-Related Dysfunction Associated with Prognosis
3.1. Markers of Cardiac Dysfunction
Cardiac Imaging
Cardiac Echocardiography
Cardiac Magnetic Resonance (MRI)
3.2. Markers of Renal Dysfunction
4. Tumor-Related Biomarkers
4.1. Serum FLC
4.2. Bone Marrow Plasma Cell Burden:
4.3. Immunophenotyping
4.4. Cytogenetics of the Plasma Cell Clone
4.5. Immunoparesis
5. Prognosis and Response to Treatment
6. Novel biomarkers
6.1. New Prognostic Biomarkers for Survival
6.1.1. D-dimers
6.1.2. Von Willebrand Factor (vWF)
6.1.3. Red Cell Distribution Width (RDW)
6.1.4. Soluble Suppression of Tumorigenicity 2 (sST2)
6.1.5. Osteopontin
6.1.6. Flow-Mediated Dilatation (FMD)
6.2. New Prognostic Biomarkers for Renal Outcome
6.2.1. Growth Differentiation Factor-15 (GDF-15)
6.2.2. Soluble Urokinase-Type Plasminogen Receptor (suPAR)
6.2.3. Galectin-3 (Gal-3)
7. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Markers and Cutoffs | Stages | Median OS, Months | HR for OS | |
---|---|---|---|---|
Cardiac | ||||
Mayo 2004 [6] | NT-proBNP > 332 ng/L BNP > 81 ng/L cTnT > 0.035 ng/mL (cTnI > 0.01 ng/mL) | I: no marker above the cutoff | 130 | Reference |
II: one marker above the cutoff | 54 | 2.3 | ||
III: both markers above the cutoff | 10 | 6.4 | ||
European modification [7] | Like Mayo 2004 Mayo III is divided into two groups NT-proBNP > 8500 ng/L (or BNP 700 ng/L) | I | 130 | Reference |
II | 54 | 2.4 | ||
IIIa: both markers above the cutoff and NT-proBNP < 8500 ng/L | 24 | 4.2 | ||
IIIb: Mayo stage III and NT-proBNP > 8500 ng/L | 4 | 11.3 | ||
Cardiac + Tumor-related | ||||
Mayo 2012 [8] | NT-proBNP > 1800 ng/L | I: no marker above cutoff | 130 | Reference |
cTnT > 0.25 ng/mL | II: 1 marker above cutoff | 72 | 1.8 | |
dFLC > 180 mg/L | III: 2 markers above cutoff | 24 | 3.7 | |
IV: 3 markers above cutoff | 6 | 7.1 | ||
Renal | Risk of Dialysis | |||
Palladini et al. 2014 [9] | eGFR < 50 mL/min/1.73 m2 | I: both eGFR and proteinuria below cutoff | 0% risk of dialysis at 3 years | |
proteinuria > 5 g/24 h | II: either eGFR below or proteinuria above the cutoffs | 7% risk of dialysis at 2 years | ||
III: both eGFR below and proteinuria above the cutoff | 60% risk of dialysis at 2 years |
Biomarkers | Thresholds | Prognostic Significance | Reference Number | |
---|---|---|---|---|
NT-proBNP | serum | >152/>332/>18,000/>2736 pg/ML >8500 pg/ml | Adverse OS in MVA Adverse OS in MVA | [6,7,8,28] |
BNP | Serum | >81 pg/mL >700 pg/mL | Equivalent to NT-proBNP > 332 pg/mL Equivalent to NT-proBNP > 8500 pg/mL | [29] |
cTnT | Plasma Serum | Continuous or >0.03/≥0.035 μg/L | Adverse OS in MVA | [5,6,8] |
cTnI | Plasma Serum | Continuous or >70/>100 ng/L | Adverse OS in MVA | [5,6,28] |
hs-cTnT | Plasma serum | Continuous or ≥14/5054/ >77 ng/L | Adverse OS in MVA | [28,30,31] |
Ejection fraction | Echo (LVEF) | EF continuous or <45%/50% | Adverse OS in MVA | [5,6,30] |
LV longitudinal function | Echo (GLS) | GLS < −11.8% GLS 17% | Adverse OS in MVA discriminated survivors from non-survivors and added prognostic value within each cardiac staging system | [32,33] |
LV septum thickness | Echo | >15 mm | Adverse OS in MVA | [5,6] |
NYHA class | >2 | Adverse OS in MVA | [28] | |
Atrial arrhythmia | ECG | Presence | Adverse OS in MVA | [25,34] |
Systolic blood pressure | <100 mmHg | Adverse OS in MVA | [7] | |
Uric acid | Serum | >8 mg/dL | Adverse OS in MVA | [35] |
Albumin-to creatinine ratio | 3600 mg/gr 3600 mg/gr 220 mg/mmol | Adverse RS Adverse RS Adverse EFS | [36,37,38] | |
Albumin | cont or ≤30 g/L | [6,9] | ||
Proteinuria | >5 g/24 h | [6,9] | ||
EGFR | <50 mL/min | Adverse OS in MVA Adverse RS in MVA | [9,25] |
Factor/Biomarker | Thresholds or Adverse Factors | Prognostic Signfiicance | Reference | |
---|---|---|---|---|
Bone marrow | BM cytology or histology | ≥10% | MVA adverse OS and PFS | Kourelis 2013 [48] Tovar 2018 [49] |
≥20% | MVA adverse OS | Muchtar 2019 [50] | ||
BM-MCF | >1%, ≥2.5%, MFC automated profile | MVA adverse OS and PFS | Puig 2019 [51] | |
BM MCF | >1% clonal PC | MVA adverse OS and PFS | Paiva 2011 [52] | |
≥2.5% clonal PC | MVA adverse OS and PFS | Muchtar 2017 [53] | ||
CBPCs | > 5 × 106/L or >1% | Adverse OS (limited MVA) | Pardanani 2003 [54] | |
M protein | Urine | Continuous or >1 g/24 h | MVA adverse OS | Dispenzieri 2003 [5] Dispenzieri 2004 [6] |
FLC | Serum iFLC | >125 mg/L | MVA adverse OS | Palladini 2010 [28] |
>152 mg/L and continuous | MVA adverse OS | Dispenzieri 2006 [55] | ||
dFLC | > 50 mg/L | MVA adverse OS, more frequent and severe heart involvement | Dittrich 2017 [18] Milani 2017 [56] | |
>196 mg/L, λ > 182/κ > 294 mg/L | MVA for OS and more frequent and severe heart involvement | Kumar 2010 [21] | ||
>180 mg/L | MVA for OS | Kumar et al. 2012 [8] J Sachchithanantham 2017 [22] | ||
Immuno-paresis | HLC immunoassay | Severe HLC immunosuppression (≥2 Ig isotypes suppressed by >50% below normal levels) | Cardiac involvment in landmark analysis at 6 months MVA OS | Sachchithanantham 2017 [22] |
Ig nephelometry | Number of IgGs under the LLN and average relative difference of uninvolved IgGs from the LLN | MVA in OS | Muchtar 2017 [57] | |
Any chromosomal aberration | FISH/BM | Presence | Increased plasmacytosis, cardiac involvment, adverse OS in MVA | Hammons 2018 [58] |
Adverse OS in MVA, cardiac involvement | Warsame 2015 [59] | |||
t(11;14) | FISH/BM | Presence | Adverse OS when BMPC ≤ 10% | Warsame 2015 [59] |
Favorable OS after HDM/daratumumab | Bochtler 2016 [60] Kimmich 2020 [61] | |||
Adverse OS in MVA | Bochlter 2015 [38] | |||
Adverse OS in MVA for bortezomib based regimens | Muchtar 2017 [62] | |||
Gain of 1q21 | FISH/BM | Presence | Adverse OS and EFS in MVA for M-dex | Bochtler 2014 [63] |
Adverse OS and EFS in UVA for daratumumab | Kimmich 2020 [61] | |||
Deletion of 17p | FISH/BM | >50% cells | Trend towards short OS | Wong 2018 [64] |
Trisomies | FISH/BM | presence | Adverse OS in MVA | Muchtar 2017 [62] |
Adverse OS when BMPC > 10% | Warsame 2015 [59] |
Biomarkers | Thresholds | Prognostic Significance | Reference Number | |
---|---|---|---|---|
GDF-15 | Serum | 4000 pg/mL 7575 pg/mL 2300 pg/mL | Adverse RS MVA and Adverse OS MVA Adverse OS MVA | [81] [81] [82] |
suPAR | Serum | 7.2 at 6 months | Adverse RS | [83] |
Gal-3 | Serum | 11 ng/mL 20.24 ng/mL | Adverse OS in UVA Adverse OS MVA | [84] [85] |
Osteopontin | Serum | >426 ng/mL | Adverse OS in MVA no significant predictive value | [86] [82] |
vWF | Serum | ≥230.0 U/dL | Adverse OS MVA | [87] |
D-dimer | Serum | D-dimer ≥ 1 μg/mL vs. <0.5μg/mL and vs. <1.0 but >0.5 μg/mL | Increased risk of mortality in MVA | [88] |
RDW | Serum | RDW ≥ 13.8 | Adverse OS MVA Also in subgroup with no cardiac involvement | [89] |
sST2 | Serum | >32.6 ng/mL ≥30 ng/mL | Adverse OS in MVA and 1-year survival Adverse OS in MVA | [82] [84] |
Myocardial contraction fraction | MRI | MCF ≤ 56.6% | Adverse OS in MVA | [45] |
LV longitudinal axis strain | MRI | LAS < −7% | Adverse OS in MVA | [45] |
ECV | MRI | >0.45 | Higher mortality | [47] |
FMD | Doppler | ≥4.5% | Adverse OS in MVA | [90] |
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Fotiou, D.; Theodorakakou, F.; Kastritis, E. Biomarkers in AL Amyloidosis. Int. J. Mol. Sci. 2021, 22, 10916. https://doi.org/10.3390/ijms222010916
Fotiou D, Theodorakakou F, Kastritis E. Biomarkers in AL Amyloidosis. International Journal of Molecular Sciences. 2021; 22(20):10916. https://doi.org/10.3390/ijms222010916
Chicago/Turabian StyleFotiou, Despina, Foteini Theodorakakou, and Efstathios Kastritis. 2021. "Biomarkers in AL Amyloidosis" International Journal of Molecular Sciences 22, no. 20: 10916. https://doi.org/10.3390/ijms222010916