A Serum Biomarker Panel Composed of C-Reactive Protein and Albumin Could Predict the Transplant-Related Complications and the Outcomes of Allogeneic Hematopoietic Cell Transplantation
Authors: Ozeki Kazutaka , Ozawa Yukiyasu , Kawashima Naomi , Yamaga Yusuke , Adachi Yoshitaka , Umemura Koji , Okazaki Shoichiro , Kohno Akio , Miyamura Koichi , Morishita Yoshihisa 
Published: October 2019

Abstract
Background: Non-infectious transplant-related complications (TRCs) after allogeneic hematopoietic cell transplantation (allo-HCT) are associated with an unfavorable prognosis. Despite several proposed biomarkers, it remains difficult to predict survival outcomes before transplantation. Here we tested clinically available serum markers to identify patients at high risk of poor survival.
Patients and methods: Patients (median age, 45 years; range, 16-68 years) who received allo-HCT at 2 institutions between May 2000 and August 2014 were included in the analysis. A total of 383 patients [203 patients from Konan Kosei Hospital (KKH) and 180 patients from Japanese Red Cross Nagoya First Hospital (RCH)] were evaluated. TRCs within 100 days were categorized as complications with endothelial damage (TRC-ED), acute graft-versus-host disease (GVHD), and other complications. TRC-ED was defined as sinusoidal obstruction syndrome, transplant-associated microangiopathy, capillary leak syndrome, and idiopathic pulmonary syndrome. C-reactive protein (CRP), albumin (Alb), ferritin, cholinesterase (ChE), and uric acid (UA) were selected as candidate biomarkers based on the literature. The above biomarkers were evaluated for their associations with the TRC incidence and probabilities of overall survival (OS) and non-relapse mortality (NRM).
Results: Patient characteristics were comparable between the 2 hospital cohorts, except for a lower unrelated donor bone marrow transplant rate (38% vs. 58%) and a longer follow-up duration (5.6 years vs. 2.6 years) in the KKH cohort. Overall, 68% patients received allo-HCT for acute myeloid leukemia or myelodysplastic syndrome, and 37% patients had a high disease risk (non-remission). The graft source was cord blood in 24% patients, and 73% patients received a myeloablative conditioning regimen. The cumulative TRC-ED incidence was 21.7% at day 100. Acute GVHD occurred in 38.1% patients (n = 147) with grade III/IV seen in 41 patients.
Low serum Alb (<3.5 g/dL) and ChE (<200 IU/L) with high CRP (>0.5 mg/dL) and ferritin (>2000 ng/mL) levels before pre-conditioning were significantly associated with inferior OS in a univariate analysis (log-rank test). All markers except ferritin and UA were statistically significant prognostic factors for NRM (Gray test). Low Alb and high CRP, which had the lowest p-values, were chosen as risk markers for a combined panel. The 5-year OS was 60% for patients with neither risk marker, 48% for those with either marker, and 20% for those with both markers. When patients were divided into low-risk (high Alb and low CRP) and high-risk combinations (low Alb and/or high CRP), the high-risk combination was identified as a strong prognostic factor for NRM [hazard ratio (HR): 2.27; 95% confidence interval (CI), 1.48-3.47; p = 0.00016; Fine-Gray test] and OS (HR: 1.60; 95% CI, 1.16-2.22; p = 0.0045; Cox regression hazard model) in a multivariate analysis with clinical confounders. Disease risk was another risk factor for OS, but not NRM.
The high-risk combination also predicted TRC-ED occurrence. The cumulative TRC-ED incidence at day 100 was 31% and 17% in patients with high-risk and low-risk combinations, respectively (p = 0.00165). Substituting low ChE for low Alb as a marker yielded a combination of high CRP and low ChE, which was a better predictor for TRC-ED. Both combined markers were independently associated with a higher TRC-ED incidence in a multivariate analysis. No significant differences were observed in the cumulative incidence of grade III/IV acute GVHD at day 100 between the high-risk and low-risk groups for any biomarker.
Conclusions: A combined panel comprising Alb and CRP provided significant power for pre-transplant TRC-ED occurrence and survival predictions. Independent cohort confirmations and further investigations of underlying mechanisms are warranted in future studies.

Disclosures
No relevant conflicts of interest to declare.