C-Reactive Protein Levels at Diagnosis of Acute Graft-versus-Host Disease Predict Steroid-Refractory Disease, Treatment-Related Mortality, and Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Acute graft-versus-host disease (aGVHD) remains a cause of excessive morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Primary treatment consists of high-dose corticosteroids, but a small group of patients develop steroid-refractory disease, and their prognosis is especially poor. There is experimental evidence that coexisting inflammation aggravates aGVHD. Because C-reactive protein (CRP) is a systemic inflammatory marker, we aimed to investigate whether plasma CRP concentrations at the diagnosis of aGVHD can predict the risk of failing first-line therapy and developing steroid-refractory disease. We retrospectively studied 461 patients who underwent HSCT between 2010 and 2015. aGVHD grade II-IV was diagnosed in 148 patients (32%). CRP level and total white blood cell, lymphocyte, and neutrophil counts were available for all patients at the time of aGVHD diagnosis. According to local protocol, patients with failed response to high-dose steroid therapy (2 mg/kg) were treated with the TNF-α inhibitor infliximab and categorized as having steroid-refractory disease. Of 148 patients with grade II-IV aGVHD, 28 (19%) developed steroid-refractory disease. In these patients, plasma CRP concentration at diagnosis ranged between <1 and 253 mg/L. CRP levels were significantly higher in patients who developed steroid-refractory disease compared with those who responded to high-dose corticosteroid therapy (odds ratio, 1.50; 95% confidence interval, 1.18-1.93; P = .001). This translated into significantly increased transplantation-related mortality and decreased overall survival in the patients with high CRP levels. Total white blood cell, lymphocyte, and neutrophil counts were not associated with steroid resistance in the patients with aGVHD. These results suggest that CRP level at diagnosis is a valid predictor of the development of steroid-refractory disease in patients who develop grade II-IV aGVHD after HSCT.

Exploration of the association between the single-nucleotide polymorphism of co-stimulatory system and rheumatoid arthritis

“…Our previous study showed that rs3181098 had association with graftversus-host disease (GVHD) of post-hematopoietic stem cell transplantation (HSCT) in acute leukemia patients (25). Minculescu et al (26) showed that CRP level could be a valid predictor of the development of steroid-refractory disease in patients who develop severe GVHD after HSCT. Thus, rs3181098 may influence the production of CRP, thereby developing GVHD.…”

A phase 2 trial of the somatostatin analog pasireotide to prevent GI toxicity and acute GVHD in allogeneic hematopoietic stem cell transplant

“…When comparing pre-HCT to post-HCT (D14) samples, changes in MIP-1a, MIP-1b, TNF-a, IL-8.Pro, and IL-6, were associated with increased risk of death in our sample (HR 1.16, 8.71, 2.64, 6, and 1.38 respectively, with p<0.05). Furthermore in the pasireotide group, pre-to-post-HCT changes were noted in markers previously associated with transplant outcomes including GVHD (with increases in CRP [ 46 , 47 ], SAA [ 48 ], IL7 [ 49 ], TSLP [ 50 ], PlGF [ 51 ], IL6 [ 42 ], IL27 [ 52 ], TNFR1 [ 53 ], IL1RL/ST2 [ 54 ], MMP3 [ 55 ], TNFRII [ 56 ] and decreases in bFGF [ 57 ], IL12/p70 [ 41 ], IL6Ra [ 58 ], and Paraoxonase [ 48 ]), non-relapse mortality (D-Dimer [ 59 ]) and OS (Il1RL/ST2) [ 60 ]. Differences in sample size and collection media restricted our ability to compare inflammatory and metabolomics profiling between pasireotide and controls, however the associations and references listed above in the pasireotide group are consistent with prior reports of the prognostic relevance of inflammatory and metabolic markers in HCT.…”

An Intelligent Clinical Decision Support System for Predicting Acute Graft-versus-host Disease (aGvHD) following Allogeneic Hematopoietic Stem Cell Transplantation

“…The third predictor for predicting aGvHD is CRP with the importance of 14.8%. High levels of this predictor in patients increase the risk of aGvHD, especially grade II to IV, asymptomatic death, and decreased overall survival [44][45][46][47][48].…”