Abstract
Chronic graft-versus-host disease (cGVHD) is the most important long-term complication of allogeneic hematopoietic cell transplantation (HCT). As cGVHD is a fibroproliferative disorder, assessment of plasma biomarkers known to be associated with fibrosis and ECM turnover may provide a novel platform for risk stratification and prognostication. Among ECM biomarkers, we focused this analysis on TGFβ due to its significant profibrotic and immunomodulating properties. Plasma samples were prospectively obtained at the time of cGVHD onset, and ECM biomarkers were assayed simultaneously using a lab-derived (non-commercial) Luminex bead-based assay. TGFβ values at cGVHD diagnosis were available for 112 of 158 consecutive adult patients (pts) who had received HCT at the University of Michigan from 2007 to 2010. All characteristics (except for age) were assessed at the time of cGVHD diagnosis. TGFβ was evaluated in tertiles. The first (N=38), second (N=37), and third (N=37) tertiles are described as low, intermediate, and high TGFβ groups. Median time from cGVHD diagnosis to NRM was 8 (range 4-14), 25 (range 24-37), and 12 months (range 7-17) in the 3 TGFβ groups, respectively. The 2-years cumulative incidence of NRM was equally high in the low (25%) and high (23%) TGFβ groups compared with the intermediate group (0%, Figure 1). cGVHD was the predominant cause of NRM in the 3 groups. The 2-years actuarial progression-free survival was higher in the intermediate group (83%) compared with the low (55%, HR=4.6, P 0.005) or high (66%, HR=2.9, P 0.06) TGFβ groups. The median time from transplant to cGVHD diagnosis was comparable across the 3 groups (Table). Patients in the low TGFβ group were more likely to exhibit common adverse prognostic factors in cGVHD including higher prevalence of poor performance status (P 0.02), low platelet count (P 0.02), low eosinophil count (P 0.02), and moderate to severe lung involvement (P 0.01). These pts also tended to be more likely to have a history of grade III-IV acute GVHD and to present with quiescent cGVHD. The severity of cGVHD skin, liver, or gastrointestinal involvement did not differ across the 3 groups. Remarkably, the prevalence of being on steroids was comparable in pts with low (21%) and intermediate (19%) TGFβ values despite significant differences in the rate of NRM between these 2 groups. In contrast, 8% of pts in the high TGFβ group were on steroids. We could not identify any clinical characteristics distinguishing pts in the intermediate TGFβ group. Age, gender, disease status at transplant, type of conditioning regimen, type of GVHD prophylaxis, donor type, and stem cell source did not differ across the 3 TGFβ groups. Among the ECM markers evaluated, low TGFβ levels were correlated with low levels of surfactant protein-D, chemokine (C-C motif) ligand 2, and detectable IL-13Rα ; and with high levels of collagen, Tenascin-C, and metalloproteinase-2 and -9. Collectively these data indicate that extreme (low and high) TGFβ values at cGVHD diagnosis are associated with significantly faster NRM rate. Different pathologic mechanisms may account for the association with NRM in these 2 groups as suggested by the distinct clinical and biomarkers profiles of the low TGFβ group. The independent prognostic value of TGFβ in cGVHD is analyzed through multivariate analysis.
| TGFβ Group | ||||
|---|---|---|---|---|
| Low | Intermediate | High | P | |
| Characteristics (assessed at cGVHD diagnosis, except age) | N=38 | N=37 | N=37 | Low vs. Other |
| TGFβ values, median (range) | 6K (800-11K) | 22K (12K-34K) | 46K (35K-105K) | |
| Age at transplant, yrs median (range) | 52 (19-67) | 52 (22-66) | 54 (18-68) | 0.1 |
| Days from HCT to cGVHD diagnosis, median (range) | 162 (37-485) | 176 (52-547) | 155 (63-336) | |
| Concomitant infections | 7% | 8% | 8% | 0.6 |
| Karnofsky performance status ≤ 70% | 66% | 81% | 89% | 0.02 |
| Platelet count ≤100,000/mm3 | 37% | 16% | 19% | 0.02 |
| Eosinophil count ≤0.1 K/µL | 26% | 14% | 5% | 0.02 |
| NIH -CC lung involvement | ||||
| None-Mild | 75% | 95% | 92% | 0.01 |
| Moderate-Severe | 25% | 5% | 8% | |
| On steroids | 21% | 19% | 8% | 0.09 |
| History of grade II-IV acute GVHD | 39% | 24% | 32% | 0.2 |
| cGVHD Presentation | ||||
| Progressive | 24% | 27% | 27% | |
| Quiescent | 42% | 27% | 27% | 0.1 |
| de novo | 34% | 46% | 46% | |
| Organ Involvement according to NIH-CC | ||||
| Skin | ||||
| None or Mild | 82% | 57% | 78% | |
| Moderate | 5% | 24% | 11% | |
| Severe | 13% | 19% | 11% | |
| Liver | ||||
| None | 39% | 54% | 35% | |
| Mild | 21% | 24% | 30% | |
| Moderate | 18% | 14% | 11% | |
| Severe | 21% | 8% | 24% | |
| Gastrointestinal | ||||
| None | 74% | 76% | 86% | |
| Mild | 24% | 19% | 11% | |
| Moderate | 3% | 5% | 3% | |
| Number of Organs Involved | ||||
| 1 | 21% | 19% | 8% | |
| 2 | 26% | 16% | 47% | |
| 3 | 36% | 46% | 30% | |
| 4 | 10% | 16% | 8% | |
| 5 or 6 | 5% | 5% | 6% | |
| TGFβ Group | ||||
|---|---|---|---|---|
| Low | Intermediate | High | P | |
| Characteristics (assessed at cGVHD diagnosis, except age) | N=38 | N=37 | N=37 | Low vs. Other |
| TGFβ values, median (range) | 6K (800-11K) | 22K (12K-34K) | 46K (35K-105K) | |
| Age at transplant, yrs median (range) | 52 (19-67) | 52 (22-66) | 54 (18-68) | 0.1 |
| Days from HCT to cGVHD diagnosis, median (range) | 162 (37-485) | 176 (52-547) | 155 (63-336) | |
| Concomitant infections | 7% | 8% | 8% | 0.6 |
| Karnofsky performance status ≤ 70% | 66% | 81% | 89% | 0.02 |
| Platelet count ≤100,000/mm3 | 37% | 16% | 19% | 0.02 |
| Eosinophil count ≤0.1 K/µL | 26% | 14% | 5% | 0.02 |
| NIH -CC lung involvement | ||||
| None-Mild | 75% | 95% | 92% | 0.01 |
| Moderate-Severe | 25% | 5% | 8% | |
| On steroids | 21% | 19% | 8% | 0.09 |
| History of grade II-IV acute GVHD | 39% | 24% | 32% | 0.2 |
| cGVHD Presentation | ||||
| Progressive | 24% | 27% | 27% | |
| Quiescent | 42% | 27% | 27% | 0.1 |
| de novo | 34% | 46% | 46% | |
| Organ Involvement according to NIH-CC | ||||
| Skin | ||||
| None or Mild | 82% | 57% | 78% | |
| Moderate | 5% | 24% | 11% | |
| Severe | 13% | 19% | 11% | |
| Liver | ||||
| None | 39% | 54% | 35% | |
| Mild | 21% | 24% | 30% | |
| Moderate | 18% | 14% | 11% | |
| Severe | 21% | 8% | 24% | |
| Gastrointestinal | ||||
| None | 74% | 76% | 86% | |
| Mild | 24% | 19% | 11% | |
| Moderate | 3% | 5% | 3% | |
| Number of Organs Involved | ||||
| 1 | 21% | 19% | 8% | |
| 2 | 26% | 16% | 47% | |
| 3 | 36% | 46% | 30% | |
| 4 | 10% | 16% | 8% | |
| 5 or 6 | 5% | 5% | 6% | |
No relevant conflicts of interest to declare.
