Pentraxin 3 plasma levels at graft-versus-host disease onset predict disease severity and response to therapy in children given haematopoietic stem cell transplantation.

Erica Dander,Fabio Pasqualini,Giovanni Salvatori,Paola Vinci,Sonia Bonanomi,Francesca Masciocchi,Paola Quarello,Fabio Pagni,Attilio Rovelli,Claudia Cappuzzello,Giulia Prunotto,Franca Fagioli,Alberto Mantovani,Roberto Leone,Franco Locatelli,Adriana Balduzzi,Barbara Bottazzi,Maria Grazia Valsecchi,Andrea Biondi,Fabio Pavan,Matteo Parma,Elisabetta Terruzzi,Ivan Cuccovillo,Marina Sironi,Paola De Lorenzo,Cecília Garlanda ,Giovanna D’amico

doi:10.18632/oncotarget.13488

Abstract

Acute Graft-versus-Host Disease (GvHD) remains a major complication of allogeneic haematopoietic stem cell transplantation, with a significant proportion of patients failing to respond to first-line systemic corticosteroids. Reliable biomarkers predicting disease severity and response to treatment are warranted to improve its management. Thus, we sought to determine whether pentraxin 3 (PTX3), an acute-phase protein produced locally at the site of inflammation, could represent a novel acute GvHD biomarker. Using a murine model of the disease, we found increased PTX3 plasma levels after irradiation and at GvHD onset. Similarly, plasma PTX3 was enhanced in 115 pediatric patients on day of transplantation, likely due to conditioning, and at GvHD onset in patients experiencing clinical symptoms of the disease. PTX3 was also found increased in skin and colon biopsies from patients with active disease. Furthermore, PTX3 plasma levels at GvHD onset were predictive of disease outcome since they resulted significantly higher in both severe and therapy-unresponsive patients. Multiple injections of rhPTX3 in the murine model of GvHD did not influence the disease course. Taken together, our results indicate that PTX3 constitutes a biomarker of GvHD severity and therapy response useful to tailor treatment intensity according to early risk-stratification of GvHD patients.

Highlights

Acute Graft-versus-Host Disease (GvHD) still accounts for 15-30% of allogeneic stem cell transplant (HSCT)-related mortality [1]
pentraxin 3 (PTX3) plasma levels increase over baseline on day 0 and at disease onset in a mouse model of acute GvHD
Several ongoing clinical trials are evaluating the efficacy of other therapies relying on initial GvHD treatment in combination with other treatments originally used as second-line therapy, the results have so far proved inconclusive ( [24, 25] and NCT00609609)

Summary

Introduction

Acute Graft-versus-Host Disease (GvHD) still accounts for 15-30% of allogeneic stem cell transplant (HSCT)-related mortality [1]. The outcome of steroid-refractory patients is poor despite the introduction of several second- and third-line therapies [3] In this scenario, early identification of patients at high risk of developing severe/non responsive GvHD would potentially improve disease management through prompt adoption of risk-tailored therapies. The identification of new, highly sensitive, and measurable GvHD biomarkers, which could be validated in a homogeneous allo-HSCT setting, still remains an urgent clinical need. This is true for pediatric patients where the likelihood of developing GvHD, the response to therapy, and nonrelapse mortality rates are quite different from adult populations [13]

Methods

Results

Conclusion