ST2 as a marker for risk of therapy-resistant graft-versus-host disease and death

Abstract

Background: No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation.

Methods: We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation.

Results: Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen.

Conclusions: ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation. (Funded by the National Institutes of Health.)

Figure 1. Outcomes According to Plasma Concentration of Suppression of Tumorigenicity 2 (ST2) and Grade of GVHD at Therapy Initiation

The 381 patients in the response-to-treatment set (Panel A) were divided into four groups on the basis of plasma ST2 concentration (with low defined as <740 pg per milliliter and high as ≥740 pg per milliliter) and GVHD grade at therapy initiation. The 6-month mortality without relapse after therapy was as follows: patients with low ST2 and grade I or II GVHD, 11% (95% confidence interval [CI], 7 to 17); patients with low ST2 and grade III or IV GVHD, 14% (95% CI, 6 to 34); patients with high ST2 and grade I or II GVHD, 31% (95% CI, 24 to 40); and patients with high ST2 and grade III or IV GVHD, 67% (95% CI, 55 to 79). The 1-year mortality with relapse was 28% (95% CI, 22 to 36), 18% (95% CI, 8 to 38), 21% (95% CI, 15 to 29), and 14% (95% CI, 7 to 26) in the respective groups. Overall survival at 6 months after therapy initiation was 73% (95% CI, 67 to 80), 75% (95% CI, 61 to 93), 56% (95% CI, 48 to 65), and 22% (95% CI, 14 to 36) in the respective groups. Among the 136 patients with lower gastrointestinal GVHD (Panel B), the 6-month mortality without relapse was as follows: patients with low ST2 and stage 1 gastrointestinal involvement, 10% (95% CI, 5 to 18); patients with low ST2 and stage 2 to 4 gastrointestinal involvement, 14% (95% CI, 7 to 27); patients with high ST2 and stage 1 gastrointestinal involvement, 46% (95% CI, 42 to 50); and patients with high ST2 and stage 2 to 4 gastrointestinal involvement, 71% (95% CI, 68 to 74). The 1-year mortality with relapse was 29% (95% CI, 24 to 35), 14% (95% CI, 7 to 27), 11% (95% CI, 7 to 17), and 16% (95% CI, 12 to 20) in the respective groups. Overall survival at 6 months after therapy initiation was 71% (95% CI, 57 to 89), 71% (95% CI, 54 to 94), 46% (95% CI, 32 to 65), and 18% (95% CI, 9 to 33) in the respective groups. Among the 203 patients with isolated skin GVHD (Panel C), the 6-month mortality without relapse was as follows: patients with low ST2 and stage 1 or 2 rash, 17% (95% CI, 7 to 27); patients with low ST2 and stage 3 or 4 rash, 15% (95% CI, 7 to 37); patients with high ST2 and stage 1 or 2 rash, 27% (95% CI, 6 to 48); and patients with high ST2 and stage 3 or 4 rash, 25% (95% CI, 9 to 41). The 1-year mortality with relapse was 26% (95% CI, 24 to 29), 14% (95% CI, 11 to 18), 19% (95% CI, 15 to 24), and 14% (95% CI, 9 to 20) in the respective groups. Overall survival at 6 months after therapy initiation was 68% (95% CI, 57 to 80), 78% (95% CI, 68 to 89), 57% (95% CI, 43 to 75), and 61% (95% CI, 47 to 79) in the respective groups. All outcomes were determined with the use of the Kaplan–Meier procedure. Mortality without relapse on the ordinate refers to death in the absence of relapse of the primary disease for which the transplantation was performed. Detailed hazard ratios for these outcomes are shown in Tables S13A through S13I in the Supplementary Appendix. GVHD was graded according to modified Glucksberg criteria (summarized in the Supplementary Appendix).

Figure 2. Plasma ST2 Concentrations within 21 Days after Transplantation According to Conditioning Intensity and Survival

Panel A shows the mean (±SE) plasma concentration of ST2 in patients in the pilot group receiving myeloablative conditioning who were alive at 180 days after transplantation and those who were dead at that time. Values at day 0 were as follows: alive at 180 days, 880±170 pg per milliliter; dead at 180 days, 1500±390 pg per milliliter (P = 0.09). Values at day 14 were 1400±240 pg per milliliter and 3200±570 pg per milliliter, respectively (P<0.001), and values at day 21 were 920±115 pg per milliliter and 3500±680 pg per milliliter, respectively (P<0.001). Panel B shows the mean (±SE) plasma concentration of ST2 in patients in the pilot group receiving reduced-intensity conditioning who were alive at 180 days after transplantation and those who were dead at that time. Values at day 0 were as follows: alive at 180 days, 430±170 pg per milliliter; dead at 180 days, 740±350 pg per milliliter (P = 0.40). Values at day 14 were 350±80 pg per milliliter and 2150±800 pg per milliliter, respectively (P<0.001), and values at day 21 were 630±225 pg per milliliter and 1430±525 pg per milliliter, respectively (P = 0.10).