ASH 2018 | Prediction of severe chronic graft-versus-host disease by host-derived CXCR3 ligand genes

At the 60^th American Society of Hematology Annual Meeting & Exposition, Hao Dai from German Cancer Research Centre, DKFZ, Heidelberg, Germany, presented a study evaluating the role of the CXCR3 axis in chronic graft-versus-host disease (cGvHD). Dai et al. assessed CXCR3 ligand serum levels in allograft recipients both in the pre-transplant period and on day 28 after transplantation. The serum levels were correlated to single nucleotide polymorphisms (SNPs) in the patients’ CXCR3/CXCR3L genes regarding the severity of cGvHD.

Patients and methods

No statin-based endothelial prophylaxis (SEP) training cohort:

• N = 287 patients who underwent transplantation at the Heidelberg University Hospital
• Overall survival > 6 months
• Patients did not receive SEP

SEP cohort:

• N = 401 patients who underwent transplantation at the Heidelberg University Hospital
• Overall survival > 6 months
• Patients received SEP

No-SEP validation cohort:

• N = 202 patients who underwent transplantation at Berlin Charité and survived more than 6 months

Methods:

• DNA samples were collected from n = 545 patients (no-SEP, n = 242; SEP, n = 303)
• CXCL9, CXCL10 and CXCL11 were assessed by ELISA at pre-transplant in n = 405 patients (no-SEP, n = 109; SEP, n = 296) and on day 28 in 494 patients (no-SEP, n = 152; SEP, n = 342)
• Eighteen SNPs (7 in CXCL9-11, 7 in CXCL4 and 4 in CXCR3 loci) were studied to assess the relationship with severe cGvHD

Key findings

• Severe cGvHD:
  • 50/287 patients (17.4%) in the no-SEP training cohort
  • 53/401 patients (13.2%) in the SEP cohort
  • 48/202 patients (23.8%) in the no-SEP validation cohort
• Higher serum CXCL9 levels at day 28 showed significant correlation with a higher risk of severe cGvHD in the no-SEP training cohort: HR = 1.38 (95% CI, 1.10–75), P = 0.01
• No significant correlation was observed in serum CXCL10 and CXCL11 levels
• SNP rs884304 in CXCL9-11 locus significantly correlated with severe cGvHD in patients with high-risk and low-risk genotypes: HR = 2.32 (95% CI, 1.21–46), P = 0.01
• To assess genetic risk score, rs3733236 and rs4282209 in CXCL9-11, rs655328 in CXCL4 loci SNPs were identified based on their effect on severe cGvHD, P < 0.10
• Patients with genotypes other than low-risk (rs884304GG, rs3733236AA/AG, rs4282209AA/AG and rs655328TT) were considered as high-risk
• High-risk patients: 21.4% (52/242) in the no-SEP training cohort, 22.4% (68/303) in the SEP cohort and 19.8% (40/202) in the no-SEP validation cohort
• Patients in the high-risk group showed higher serum CXCL9 levels at day 28
• High-risk patients had a significantly higher risk of severe cGvHD
• Patients in the SEP cohort did not have adverse effect of high risk genotypes: HR 1.30 (95% CI, 0.60–79), P = 0.50
• SEP reduced day 28 CXCL9 levels in high-risk patients but not in patients with low-risk genotype

In summary, severe cGvHD could be predicted both by a genetic risk group of four SNPs in recipients’ CXCR3 ligand genes and by serum CXCL9 levels 28 days after transplantation. The genetic variants from the recipients’ genome were correlated with day 28 serum CXCL9 levels. Furthermore, statin-based endothelial prophylaxis may reduce the risk of severe cGvHD by regulating serum CXCL9 levels.