Prognostic Biomarkers for Acute Graft-versus-Host Disease Risk after Cyclophosphamide–Fludarabine Nonmyeloablative Allotransplantation

Abstract

Five candidate plasma biomarkers (ST2, REG3α, elafin, TNFR1, sIL2Rα) were measured at specific time-points following cyclophosphamide/fludarabine-based nonmyeloablative allotransplantation (NMAT) in patients who did or did not develop acute graft-versus-host-disease (aGVHD). Plasma samples from 34 patients were analyzed at days +7, +14, +21 and +30. At a median follow-up of 358 days, 17 patients had experienced aGVHD with a median time to onset of day +36. Risk of aGVHD was associated with elevated plasma ST2 concentrations at day +7 (c-stat=0.72, p=0.03), day +14 (c-stat=0.74, p=0.04), and day +21 (c-stat=0.75, p=0.02); elevated plasma REG3α concentrations at day +14 (c-stat=0.73, p=0.03), day +21 (c-stat=0.76, p=0.01) and day +30 (c-stat=0.73, p=0.03); and elevated elafin at day +14 (c-stat=0.71, p=0.04). Plasma concentrations of TNFR1 and sIL2Rα were not associated with aGVHD risk at any of the time-points studied. This study identified ST2, REG3α and elafin as prognostic biomarkers to evaluate risk of aGVHD following Cy/Flu-based NMAT. These results need to be confirmed in an independent validation cohort.

Biomarkers for posttransplantation outcomes

“…c ST2 is the most validated biomarker for aGVHD and NRM measured alone 53,61,62 or with other markers. 54,63,64 ST2 was discovered by analyzing therapy-resistant aGVHD samples with a state-of-the-art proteomic technology that is gel-free and based on high-resolution MS. 53 ST2 was also tested and validated on several platforms such as with nonmyeloablative conditioning, 65 in cord blood transplantation, 61 and in HLA-haploidentical or HLA-matched transplantation with subsequent cyclophosphamide use. 62 ST2 as early as day 7 or 14 post-HSCT was also validated as a prognostic marker for aGVHD and NRM in large cohorts.…”

Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II

“…One example is the identification of three plasma biomarkers (suppression of tumorogenesis 2 (ST2), regenerating-islet-derived-3-alpha (REG3a), and elafin) associated with an increased risk of developing acute GVHD in alloHCT recipients of nonmyeloablative (fludarabine/cyclophosphamide) conditioning. 187 In addition to these ELISA-based approaches, there is substantial enthusiasm for the –omics technologies, specifically genomics, proteomics, and metabolomics, to identify patients at higher risk of adverse outcomes. One major challenge for the –omics tools is the interference from confounding factors.…”

Biomarkers for Allogeneic HCT Outcomes

“…We note that in this study the authors use the term predictive instead of the recommended prognostic term. Furthermore, the prognostic value of ST2 has been shown in patients cohorts receiving other HCT platforms such as HCT with non-myeloablative conditioning regimen (60), cord blood HCT (single or double) (61), HCT post cyclophosphamide as aGVHD prophylaxis (62). In a contemporary multicenter center cohort of 415 patients (170 children ≤10 and 245 subjects >10 years (both children and adults) recently published, landmark analyses showed for the first time that pre-HCT high ST2 was significantly associated with NRM particularly in children age ≤10 years [HR (CI): 4.82 (1.89-14.66), p = 0.0056 (63).…”