Plasma Biomarker Predicts Lethal Acute Graft Versus Host Disease and Non-Relapse Mortality in Japanese Patients

Introduction Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment option for hematopoietic malignancies. In addition to relapse mortality, non-relapse mortality (NRM) such as severe graft-versus-host disease(GVHD) is a major cause of aHSCT. Pre-transplant clinical risk factors for acute GVHD include the degree of human leukocyte antigen (HLA) match between donor and recipient, recipient age, donor type, and conditioning regimen intensity. Although GVHD prophylaxis is usually decided by these risk factors, excessive immunosuppression induces opportunistic infection. Laboratory test cannot predict the risk of NRM or severe GVHD after aHSCT prior to the onset of GVHD symptoms; however, 2-biomarker (ST2 and REG3α) algorithm, namely MAGIC algorithm, may predict severe GVHD as has been shown recently (Hartwell et al. JCI Insight 2017). We retrospectively analyzed these 2 biomarkers in our patients to try whether the 2-biomarker algorithm is available to identify high risk of lethal GVHD and non-relapse mortality in Japanese patients.

Patients and Methods We retrospectively analyzed consecutive 47 patients who received aHSCT for hematologic malignancies at Kansai Medical University Hospital from January 1, 2010 until April 30, 2016.Overall survival (OS), non-relapse mortality, cause of death, and GVHD clinical staging were investigated. Non-relapse deaths were considered related to GVHD if the patient died from either GVHD itself or from an infection that developed while receiving systemic steroids (at least 10 mg prednisone daily or equivalent) for the treatment of GVHD. Bloodsamples were obtained 7 days after transplantation. ST2 and REG3α concentrations were analyzed by ELISA, and were used for the 2-biomarker algorithm (Hartwell et al. JCI Insight 2017).

Results Of the 47 patients (male 24, female 23), median age was 52 years (range, 22-69 years). Eleven patients received PBSCT, 27 patients received bone marrow transplantation, and 9 patients received cord blood transplantation. Of 27 patients who received bone marrow transplantation, 3 patients were transplanted allografts from HLA mismatched donor. Twenty-seven patients underwent reduced intensity conditioning regimen. The median survival time and 1-year OS rate were 375 days (range, 7-3236 days) and 53.2 %, respectively.The overall cumulative incidences of 6-month NRM was 23.4%. The incidence of grade II-IV and III-IV acute GVHD were 17.0%, and 13.2%, respectively. Twelve patients were identified as high risk (HR), and 35 patients were identified as low risk (LR) by the MAGIC algorithm. OS was 33.3% in HR and 71.4% in LR (p<0.05). Six-month cumulative incidence of NRM in HR patients was significantly higher than that of LR (58.3% vs. 11.4%, p<0.001) (Figure), whereas the relapse rate did not differ between risk groups. Four and three patients died from GVHD in HR and LR patients, respectively (33.3% vs. 8.6%, p<0.05). Severe gastrointestinal GVHD was greater in HR patients (18.7 % vs. 8.6%).

Conclusion The biomarker algorithm based on blood sample taken 7 day after aHSCT can identify HR patients of lethal GVHD and NRM in Japanese patients as well.

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