Plasma biomarkers for posttransplantation outcomes
| Protein . | Study year . | No. of patients in the study . | Association direction . | Diagnosis time point (median day post-HSCT) . | Prognostic time point (median day post-HSCT) . | References . |
|---|---|---|---|---|---|---|
| aGVHD | ||||||
| 4-protein panel (sIL-2Ra, TNFR1, HGF, IL-8) | 2009 | 42 + 282* + 142* | Increased | 28 | ND | 60 |
| ST2 | 2013 | 20 + 381* + 673† + 75† | Increased | 28 | 14 | 53 |
| 2015 | 328 + 164* + 300* | Increased | 28 | ND | 64 | |
| 2015 | 74* + 76* | Increased | 28 | Not significant | 63 | |
| 2016 | 211 (independent cohort following validation) | Increased | 28 | ND | 54 | |
| 2017 | 620 + 309† + 358† | Increased | ND | 7 | 56 | |
| TIM3 | 2013 | 20 + 127* + 22* | Increased | 28 | ND | 72 |
| 2015 | 74* + 76* + 167† | Increased | 28 | 14 | 63 | |
| 2016 | 211 (independent cohort following validation) | Increased | 28 | ND | 54 | |
| IL-6 | 2014 | 53 (1 cohort but subsequently validated) | Increased (3-14) then decreased | 30 | 7-14 | 66 |
| 2015 | 74* + 76* | Increased | 28 | Not significant | 63 | |
| GI specific | ||||||
| Reg3α | 2011 | 20 + 871* + 143* | Increased | 28 | ND | 69 |
| TIM3 | 2013 | 20 + 127* + 22* | Increased | 28 | ND | 72 |
| Liver specific | ||||||
| Reg3α > HGF and KRT18 | 2007 | 55 + 826* + 128* | Increased | 28 | ND | 71,73 |
| 2011 | ||||||
| Skin specific | ||||||
| (Elafin) | 2010 | 20 + 492* | Increased | 28 | ND | 67 |
| 2015 | 59 | Increased in skin | 28 | ND | 68 | |
| Late aGVHD | ||||||
| AREG-to-EGF ratio | 2016 | 105 + 50* | Increased | 160 | ND | 79 |
| cGVHD | ||||||
| (sBAFF) | 2007 | 104 | Increased | 480 | NA | 103 |
| 2008 | 80 (Pediatric) | Increased | 171 (early), 429 (late) | NA | 104 | |
| 2014 | 35 + 109* + 211* | Increased, and not validated in independent cohort | 154, 256 (early), 619 (late) | NA | 105 | |
| 2016 | 23 + 198* + 83* | Increased | 203, 174 | NA | 86 | |
| 2017 | 341 | Increased/decreased number | 189 | NA | 83 | |
| CXCL9 | 2014 | 35 + 109* + 211* | Increased | 154, 256 (early), 619 (late) | NA | 105 |
| 2016 | 53 + 211* + 180† | Increased | 210, 203 | 100 | 55 | |
| 2016 | 23 + 198* + 83* | Increased, and not validated in independent cohort | 203, 174 | NA | 86 | |
| 2016 | 26 + 83* | Increased | 132 | NA | 29 | |
| 2016 | 211† | Increased | NA | 100, 180, 365 (time-dependent analysis) | 54 | |
| CXCL10 | 2016 | 23 + 198* + 83* | Increased | 203, 174 | NA | 86 |
| 2016 | 26 + 83* | Increased | 132 | NA | 29 | |
| 4-protein panel (CXCL9, ST2, OPN, MMP3) | 2016 | 53 + 211* + 180† | Increased | 210, 203 | 100 | 55 |
| (MMP3) | 2016 | 76 (BOS) | Increased | 531 | NA | 85 |
| (CCL15) | 2018 | 211* + 792† | Increased at onset but not prognostic | 203 | 100 | 89 |
| SOS | ||||||
| ST2, ANG2, HA, VCAM1 L-Ficolin | 2015 | 40 + 45* + 35* | All increased but L-Ficolin that was decreased | 14 | NA | 90 |
| HA, VCAM1 L-Ficolin | 2015 | 26† + 24† | All increased but L-Ficolin that was decreased | NA | 0 | 90 |
| L-Ficolin | 2017 | 211 | Decreased | 28 | NA | 54 |
| TMA and aGVHD | ||||||
| ST2 | 2017 | 95† + 110† + 107† | Increased | NA | 14 | 91 |
| EASIX | 2017 | 239 + 141* + 173* + 89* | Increased (significant only in reduced-intensity conditioning) | 30-44 | ND | 93 |
| Protein . | Study year . | No. of patients in the study . | Association direction . | Diagnosis time point (median day post-HSCT) . | Prognostic time point (median day post-HSCT) . | References . |
|---|---|---|---|---|---|---|
| aGVHD | ||||||
| 4-protein panel (sIL-2Ra, TNFR1, HGF, IL-8) | 2009 | 42 + 282* + 142* | Increased | 28 | ND | 60 |
| ST2 | 2013 | 20 + 381* + 673† + 75† | Increased | 28 | 14 | 53 |
| 2015 | 328 + 164* + 300* | Increased | 28 | ND | 64 | |
| 2015 | 74* + 76* | Increased | 28 | Not significant | 63 | |
| 2016 | 211 (independent cohort following validation) | Increased | 28 | ND | 54 | |
| 2017 | 620 + 309† + 358† | Increased | ND | 7 | 56 | |
| TIM3 | 2013 | 20 + 127* + 22* | Increased | 28 | ND | 72 |
| 2015 | 74* + 76* + 167† | Increased | 28 | 14 | 63 | |
| 2016 | 211 (independent cohort following validation) | Increased | 28 | ND | 54 | |
| IL-6 | 2014 | 53 (1 cohort but subsequently validated) | Increased (3-14) then decreased | 30 | 7-14 | 66 |
| 2015 | 74* + 76* | Increased | 28 | Not significant | 63 | |
| GI specific | ||||||
| Reg3α | 2011 | 20 + 871* + 143* | Increased | 28 | ND | 69 |
| TIM3 | 2013 | 20 + 127* + 22* | Increased | 28 | ND | 72 |
| Liver specific | ||||||
| Reg3α > HGF and KRT18 | 2007 | 55 + 826* + 128* | Increased | 28 | ND | 71,73 |
| 2011 | ||||||
| Skin specific | ||||||
| (Elafin) | 2010 | 20 + 492* | Increased | 28 | ND | 67 |
| 2015 | 59 | Increased in skin | 28 | ND | 68 | |
| Late aGVHD | ||||||
| AREG-to-EGF ratio | 2016 | 105 + 50* | Increased | 160 | ND | 79 |
| cGVHD | ||||||
| (sBAFF) | 2007 | 104 | Increased | 480 | NA | 103 |
| 2008 | 80 (Pediatric) | Increased | 171 (early), 429 (late) | NA | 104 | |
| 2014 | 35 + 109* + 211* | Increased, and not validated in independent cohort | 154, 256 (early), 619 (late) | NA | 105 | |
| 2016 | 23 + 198* + 83* | Increased | 203, 174 | NA | 86 | |
| 2017 | 341 | Increased/decreased number | 189 | NA | 83 | |
| CXCL9 | 2014 | 35 + 109* + 211* | Increased | 154, 256 (early), 619 (late) | NA | 105 |
| 2016 | 53 + 211* + 180† | Increased | 210, 203 | 100 | 55 | |
| 2016 | 23 + 198* + 83* | Increased, and not validated in independent cohort | 203, 174 | NA | 86 | |
| 2016 | 26 + 83* | Increased | 132 | NA | 29 | |
| 2016 | 211† | Increased | NA | 100, 180, 365 (time-dependent analysis) | 54 | |
| CXCL10 | 2016 | 23 + 198* + 83* | Increased | 203, 174 | NA | 86 |
| 2016 | 26 + 83* | Increased | 132 | NA | 29 | |
| 4-protein panel (CXCL9, ST2, OPN, MMP3) | 2016 | 53 + 211* + 180† | Increased | 210, 203 | 100 | 55 |
| (MMP3) | 2016 | 76 (BOS) | Increased | 531 | NA | 85 |
| (CCL15) | 2018 | 211* + 792† | Increased at onset but not prognostic | 203 | 100 | 89 |
| SOS | ||||||
| ST2, ANG2, HA, VCAM1 L-Ficolin | 2015 | 40 + 45* + 35* | All increased but L-Ficolin that was decreased | 14 | NA | 90 |
| HA, VCAM1 L-Ficolin | 2015 | 26† + 24† | All increased but L-Ficolin that was decreased | NA | 0 | 90 |
| L-Ficolin | 2017 | 211 | Decreased | 28 | NA | 54 |
| TMA and aGVHD | ||||||
| ST2 | 2017 | 95† + 110† + 107† | Increased | NA | 14 | 91 |
| EASIX | 2017 | 239 + 141* + 173* + 89* | Increased (significant only in reduced-intensity conditioning) | 30-44 | ND | 93 |
This table includes only proteins that have been discovered with a large-scale proteomics platform, are identifiable, and that have reached the point of validation as biomarkers with the same reproducible assay in at least 2 independent cohorts of sufficient sample sizes from different institutions according to the 2014 NIH consensus on biomarkers criteria. Candidate biomarkers of interest that have not met these criteria are indicated in parentheses.
ANG2, angiopoietin-2; AREG, amphiregulin; BOS, bronchiolitis obliterans syndrome; EASIX, Endothelial Activation and Stress Index; EGF, epidermal growth factor; HA, hyaluronic acid; HGF, hepatocyte growth factor; MMP3, matrix metalloproteinase 3; NA, not applicable; ND, not done; OPN, osteopontin; sBAFF, soluble B-cell–activating factor; TIM3, T-cell immunoglobulin mucin-3; TNFR1, tumor necrosis factor receptor-1.
Patient number in validation cohort 1 and cohort 2.
Prognostic cohort.