Candidate aGVHD biomarkers with diagnostic and prognostic significance identified based on GVHD pathology and proteomics discovery
| Protein . | Study . | No. of patients in the study . | Target organ . | Diagnosis end point . | Association direction* . | Prognostic end point . | Predictive end point . |
|---|---|---|---|---|---|---|---|
| Based on GVHD pathology | |||||||
| Albumin | Rezvani 201176 | 401 | Systemic/GI tract/renal | ND | ↓ | 2 y NRM, 6 mo OS in RIC patients | aGVHD 3-4 in RIC patients |
| CRP | Schots 200264 | 96 | Systemic | All TRC | ↑ | Day 100 NRM | TRC |
| Pihush 200666 | 350 | Systemic | All TRC | ↑ | ND | TRC | |
| CXCL10 | Piper 200770 | 34 | Systemic | aGVHD 0-4 | ↑ | ND | aGVHD 0-4 by day 100 |
| HGF | Okamoto 200171 | 38 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Harris 201278 | 826 + 128† | GI tract | aGVHD 0-4 | ↑ | 6 mo NRM | ND | |
| IL-2Rα | Miyamoto 199654 | 30 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Foley 199853 | 36 | Systemic | aGVHD 0-4, sepsis, VOD | ↑ | ND | ND | |
| Shaiegan 200656 | 39 | Systemic | aGVHD 2-3 | ↔ | ND | ND | |
| August 201162 | 62 | Systemic | ND | ↑ | ND | Prospective study aGVHD 3-4 by day 60 | |
| IL-6 | Malone 200765 | 147 | Systemic | aGVHD 0-4 by day 100 | ↑ | ND | ND |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | ND | |
| Pihush 200666 | 350 | Systemic | All TRC | ↑ | ND | TRC | |
| IL-8 | Uguccioni 199367 | 30 | Systemic | aGVHD 0-4, rejection, liver fibrosis in thalassemic patients | ↑ | ND | ND |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | TRC | |
| IL-10 | Liem 199891 | 46 | Systemic | aGVHD 2-4, cGVHD, infection, relapse | ↑ | ND | ND |
| IL-12 | Mohty 200568 | 113 | Systemic | aGVHD 2-4 in RIC patients | ↑ | ND | ND |
| IL-18 | Fujimori 200090 | 37 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Shaiegan 200656 | 39 | Systemic | aGVHD 2-3 | ↑ | ND | ND | |
| KRT18 | Luft 200772 | 55 | GI tract | GI GVHD vs non-GVHD-enteritis | ↑ | Response to GVHD treatment | ND |
| Luft 201175 | 48 | Systemic | Refractory GVHD | ↑ | ND | ND | |
| Harris 201278 | 826 + 128† | GI tract | GI GVHD | ↑ | 6 mo NRM | ND | |
| REG3α | Harris 201278 | 826 + 128† | GI tract | GI GVHD | ↑ | 6 mo NRM, response to GVHD treatment | ND |
| Syndecan-1 | Seidel 200355 | 60 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| TNFα | Holler 199060 | 56 | Systemic | All TRC | ↑ | ND | ND |
| Abdallah 199758 | 80 | Systemic | All TRC, aGVHD 0-1 vs 2-4 | ↔ | ND | ND | |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | ND | |
| TNFR1 | Choi 200859 | 438 | Systemic | ND | ↑ | ND | aGVHD 2-4, 1 year NRM |
| Kitko 200859 | 82 (children) | Systemic | ND | ↑ | ND | aGVHD 2-4, 1 year NRM | |
| August 201162 | 62 | Systemic | ND | ↑ | ND | Prospective study aGVHD 3-4 by day 60 | |
| Tryptophan metabolites | Landfried 201174 | 51 | Systemic | ND | ↑ | 6 mo NRM | ND |
| Based on proteomics discovery | |||||||
| Peptides set | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | Presence vs Absence | ND | ND |
| Srinivasan 200630 | 34 | Systemic | aGVHD | Presence vs Absence | ND | ND | |
| Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND | |
| Weissinger 200777 | 33 + 141† | Systemic | aGVHD 2-4 | Presence vs Absence | ND | ND | |
| Proteins set | Wang 200534 | 9 | Systemic | aGVHD vs pre-HSCT | Presence vs Absence | ND | ND |
| Albumin | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | Presence vs Absence | ND | ND |
| Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND | |
| CCL8 | Hori 200869 | 14 | Systemic | Murine model discovery, Validation human serum: aGVHD 0-4 | Presence vs Absence | ND | ND |
| Collagen α-1 | Weissinger 200777 | 33 + 141† | Systemic | aGVHD 2-4 | ↓ while collagen chain III was ↑ | ND | ND |
| Elafin | Paczesny 201084 | 20 + 492† | Skin | Skin aGVHD 0-4 vs non-GVHD rashes | ↑ | NRM, OS | ND |
| HGF | Paczesny 2009 (in a panel)2 | 42 + 282† + 142† | Systemic/GI tract | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| IL-2Rα | Paczesny 2009 (in a panel)2 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| IL-8 | Paczesny 20092 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| Lactoferrin | Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND |
| Leukotriene A4 hydrolase | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | ↑ | ND | ND |
| REG3α | Ferrara 201138 | 20 + 871† + 143† | GI tract | GI-GVHD vs non-GVHD enteritis | ↑ | NRM, OS | ND |
| SLPI | Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND |
| TNFR1 | Paczesny 20092 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| Protein . | Study . | No. of patients in the study . | Target organ . | Diagnosis end point . | Association direction* . | Prognostic end point . | Predictive end point . |
|---|---|---|---|---|---|---|---|
| Based on GVHD pathology | |||||||
| Albumin | Rezvani 201176 | 401 | Systemic/GI tract/renal | ND | ↓ | 2 y NRM, 6 mo OS in RIC patients | aGVHD 3-4 in RIC patients |
| CRP | Schots 200264 | 96 | Systemic | All TRC | ↑ | Day 100 NRM | TRC |
| Pihush 200666 | 350 | Systemic | All TRC | ↑ | ND | TRC | |
| CXCL10 | Piper 200770 | 34 | Systemic | aGVHD 0-4 | ↑ | ND | aGVHD 0-4 by day 100 |
| HGF | Okamoto 200171 | 38 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Harris 201278 | 826 + 128† | GI tract | aGVHD 0-4 | ↑ | 6 mo NRM | ND | |
| IL-2Rα | Miyamoto 199654 | 30 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Foley 199853 | 36 | Systemic | aGVHD 0-4, sepsis, VOD | ↑ | ND | ND | |
| Shaiegan 200656 | 39 | Systemic | aGVHD 2-3 | ↔ | ND | ND | |
| August 201162 | 62 | Systemic | ND | ↑ | ND | Prospective study aGVHD 3-4 by day 60 | |
| IL-6 | Malone 200765 | 147 | Systemic | aGVHD 0-4 by day 100 | ↑ | ND | ND |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | ND | |
| Pihush 200666 | 350 | Systemic | All TRC | ↑ | ND | TRC | |
| IL-8 | Uguccioni 199367 | 30 | Systemic | aGVHD 0-4, rejection, liver fibrosis in thalassemic patients | ↑ | ND | ND |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | TRC | |
| IL-10 | Liem 199891 | 46 | Systemic | aGVHD 2-4, cGVHD, infection, relapse | ↑ | ND | ND |
| IL-12 | Mohty 200568 | 113 | Systemic | aGVHD 2-4 in RIC patients | ↑ | ND | ND |
| IL-18 | Fujimori 200090 | 37 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| Shaiegan 200656 | 39 | Systemic | aGVHD 2-3 | ↑ | ND | ND | |
| KRT18 | Luft 200772 | 55 | GI tract | GI GVHD vs non-GVHD-enteritis | ↑ | Response to GVHD treatment | ND |
| Luft 201175 | 48 | Systemic | Refractory GVHD | ↑ | ND | ND | |
| Harris 201278 | 826 + 128† | GI tract | GI GVHD | ↑ | 6 mo NRM | ND | |
| REG3α | Harris 201278 | 826 + 128† | GI tract | GI GVHD | ↑ | 6 mo NRM, response to GVHD treatment | ND |
| Syndecan-1 | Seidel 200355 | 60 | Systemic | aGVHD 0-4 | ↑ | ND | ND |
| TNFα | Holler 199060 | 56 | Systemic | All TRC | ↑ | ND | ND |
| Abdallah 199758 | 80 | Systemic | All TRC, aGVHD 0-1 vs 2-4 | ↔ | ND | ND | |
| Schots 200361 | 84 | Systemic | All TRC | ↑ | 1 y NRM | ND | |
| TNFR1 | Choi 200859 | 438 | Systemic | ND | ↑ | ND | aGVHD 2-4, 1 year NRM |
| Kitko 200859 | 82 (children) | Systemic | ND | ↑ | ND | aGVHD 2-4, 1 year NRM | |
| August 201162 | 62 | Systemic | ND | ↑ | ND | Prospective study aGVHD 3-4 by day 60 | |
| Tryptophan metabolites | Landfried 201174 | 51 | Systemic | ND | ↑ | 6 mo NRM | ND |
| Based on proteomics discovery | |||||||
| Peptides set | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | Presence vs Absence | ND | ND |
| Srinivasan 200630 | 34 | Systemic | aGVHD | Presence vs Absence | ND | ND | |
| Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND | |
| Weissinger 200777 | 33 + 141† | Systemic | aGVHD 2-4 | Presence vs Absence | ND | ND | |
| Proteins set | Wang 200534 | 9 | Systemic | aGVHD vs pre-HSCT | Presence vs Absence | ND | ND |
| Albumin | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | Presence vs Absence | ND | ND |
| Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND | |
| CCL8 | Hori 200869 | 14 | Systemic | Murine model discovery, Validation human serum: aGVHD 0-4 | Presence vs Absence | ND | ND |
| Collagen α-1 | Weissinger 200777 | 33 + 141† | Systemic | aGVHD 2-4 | ↓ while collagen chain III was ↑ | ND | ND |
| Elafin | Paczesny 201084 | 20 + 492† | Skin | Skin aGVHD 0-4 vs non-GVHD rashes | ↑ | NRM, OS | ND |
| HGF | Paczesny 2009 (in a panel)2 | 42 + 282† + 142† | Systemic/GI tract | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| IL-2Rα | Paczesny 2009 (in a panel)2 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| IL-8 | Paczesny 20092 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
| Lactoferrin | Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND |
| Leukotriene A4 hydrolase | Kaiser 200440 | 35 | Systemic | aGVHD 0-4, sepsis | ↑ | ND | ND |
| REG3α | Ferrara 201138 | 20 + 871† + 143† | GI tract | GI-GVHD vs non-GVHD enteritis | ↑ | NRM, OS | ND |
| SLPI | Imanguli 200731 | 41 | Systemic | 1 month post-HSCT vs pre-HSCT | ↑ | ND | ND |
| TNFR1 | Paczesny 20092 | 42 + 282† + 142† | Systemic | aGVHD 0-4 vs no GVHD | ↑ | NRM, OS | ND |
ND indicates not done; OS, overall survival; RIC, reduced intensity conditioning; TRC, transplantation-related complications, major complications, including aGVHD, microangiopathic hemolytic anemia, VOD, pneumonitis, and infection; and VOD, veno-occlusive disease.
↑, plasma protein increased; ↓, plasma protein decreased; and ↔, plasma protein unchanged.
Validation on independent sets of patients.