Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group

Abstract

Numerous chronic graft-versus-host disease (cGVHD) biomarkers have been identified in limited, single-institution studies without validation. We hypothesized that plasma-derived biomarkers could diagnose, classify, and evaluate response in children with cGVHD. We performed a concomitant analysis of a number of known and predicted peripheral blood cGVHD biomarkers from a Children's Oncology Group (COG) phase 3 cGVHD therapeutic trial. A total of 52 newly diagnosed patients with extensive cGVHD were compared for time of onset after blood and marrow transplantation (BMT) (early, 3-8 months; late, > or = 9 months) with 28 time-matched controls with no cGVHD (early, 6 months after BMT; late, 12 months after BMT). Soluble B-cell activation factor (sBAFF), anti-dsDNA antibody, soluble IL-2 receptor alpha (sIL-2Ralpha), and soluble CD13 (sCD13) were elevated in patients with early-onset cGVHD compared with controls. sBAFF and anti-dsDNA were elevated in patients with late-onset cGVHD. Some of the biomarkers correlated with specific organ involvement and with therapeutic response. These 4 biomarkers had high specificity with higher sensitivity in combination. Changes in biomarker concentrations with immune reconstitution after transplantation significantly affected interpretation of results. The identified biomarkers have the potential for improved classification, early response evaluation, and direction of cGVHD treatment, but require validation in larger studies. This study is registered at www.cancer.gov/clinicaltrials as no. COG-ASCT0031.

Figure 1

Soluble biomarkers in cGVHD. Soluble factors were tested for (A) sBAFF, (B) sIL-2Rα, (C) IL-6, (D) TGF-β, (E) IFN-α, (F) MCP-1, (G) PDGF-AA, and (H) PDGF-BB by ELISA. Patients with early onset (3-8 months) cGVHD (▴) were compared with 6-month controls (■), patients with late onset (≥ 9 months) cGVHD (♦) were compared with 12-month controls (▾). (I) sCD13 activities were analyzed by the protocol described under “Methods.” (J) Absolute eosinophil counts were from center-derived complete peripheral blood counts. Bars indicate mean values for each group. ***P < .001; **P < .01; *P < .05. NS indicates not significant.

Figure 2

Autoantibodies in cGVHD. Autoimmune autoantibodies such as ANA (A), anti-dsDNA antibody (B), anticardiolipin antibody (C), and antimitochondrial antibody (D) were measured by ELISA, and patients with early onset (3-8 months) cGVHD (▴) were compared with 6-month controls (■); patients with late onset (≥ 9 months) cGVHD (♦) were compared with 12-month controls (▾). Bars indicate mean values for each group. ***P < .001. NS indicates not significant.

Figure 3

The levels of autoantibodies were lower in patients with acute GVHD history. A total of 5 markers (sIL-2Rα, sBAFF, sCD13, anti-dsDNA antibody, and ANA) in patients with de novo cGVHD (■) were compared with patients with a previous history of acute GVHD (▴) and non-GVHD control (▾).

Figure 4

The effect of steroid therapy on sBAFF. sBAFF levels at the onset were compared between those on steroids at diagnosis (■) and on no steroids (▴).

Figure 5

The ability of biomarker changes at 2 months to act as a surrogate endpoint. Soluble BAFF was measured as a ratio of the 2-month value compared with the initial value for each patient. Nonresponders (■) were compared with responders (▴) as determined by a clinical response at 9 months. The difference is significant (P = .05).