ST2 and REG3α as Predictive Biomarkers After Haploidentical Stem Cell Transplantation Using Post-transplantation High-Dose Cyclophosphamide

Abstract

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

Prognostic plasma biomarkers of early complications and graft‐versus‐host disease in patients undergoing allogeneic hematopoietic stem cell transplantation

“…The major limitation of this study is the significant overlap in biomarker levels between groups with and without HSCT related complications. Further, many groups have reported several cut-off values for ST2 (33.9 ng/mL [ 18 ]; 740pg/mL [ 29 ]; 3230 ng/mL [ 30 ]) and REG3 α (151 ng/mL [ 19 ]; 1989 pg/mL [ 30 ]) which makes establishing reproducible cut-off values for biomarkers a challenge. We also believe evaluating the biomarkers prospectively at this and earlier time points will better validate the association of these biomarkers with outcomes and could potentially explain their predictive values.…”

Biomarkers for Early Complications of Endothelial Origin After Allogeneic Hematopoietic Stem Cell Transplantation: Do They Have a Potential Clinical Role?

“…IL-2Rα, combined with measurement of regenerating islet-derived protein 3 alpha or REG3α [a GVHD target organ-specific damage biomarkers ( 122 )] and ST2 enabled the development of a validated predictive algorithm (Mount Sinai Acute GVHD International Consortium or MAGIC), based on ST2 and REG3α concentrations after one week of systemic glucocorticoid treatment, to predict life-threatening GVHD and NRM ( 98 ). Recent studies suggest that the measurement of REG3α and ST2 in haplo HCT may be associated with a higher incidence of GVHD and NRM ( 99 , 100 ). Moreover, MAGIC predictive algorithm not only is prognostic for NMR and overall survival, but it can be used as response biomarker for acute GVHD treatment ( 108 ).…”

Biomarkers of graft-vs-host disease: Understanding and applications for the future

“…Based on a similar concept, it will be necessary to stratify therapeutic strategies by considering both the severity of GVHD and responsiveness to treatment according to the proper combination of biomarkers to overcome refractory GVHD (Figure 2 ). There are several reports of biomarkers that predict responsiveness to GVHD therapy in a short observation period[ 47 , 48 ]. However, it must also be taken into consideration that the clinical outcomes of GVHD are affected by the progress of preventive and targeted therapy for GVHD.…”