Association Between Low Plasma Level of Citrulline Before Allogeneic Hematopoietic Cell Transplantation and Severe Gastrointestinal Graft vs Host Disease

Background & aims: The gastrointestinal form of acute graft vs host disease increases morbidity and mortality following allogeneic hematopoietic cell transplantation. Plasma levels of citrulline, a non-proteinogenic amino acid, indicate functional enterocyte mass. We measured citrulline in patients before allogeneic hematopoietic cell transplantation and investigated its association with incidence and severity of gastrointestinal graft vs host disease.

Methods: We performed a retrospective study with 191 patients (69 women, 122 men; median age of 52 years) who underwent allogeneic hematopoietic cell transplantation for hematological malignancies at a tertiary center of France from January 2013 through April 2015. Levels of citrulline in plasma samples collected 30 days before graft infusion were measured by high performance liquid chromatography with tandem mass spectrometry. We assigned patients to groups with a high level of citrulline (>26 μmol/L) or low level of citrulline (≤26 μmol/L). The primary outcomes were difference between groups in incidence of stage 2-4 gastrointestinal graft vs host disease, death without hematological disease relapse (non-relapse mortality), relapse of the hematological disease, and overall survival through 2 years after transplantation.

Results: Ninety-six patients (50%) developed acute graft vs host disease and 37 (19%) developed a gastrointestinal form. Among patients with gastrointestinal involvement, 33 patients (89%) had stage 2-4 gastrointestinal graft vs host disease. In univariable analysis, low level of citrulline associated with higher cumulative incidence of stage 2-4 gastrointestinal graft vs host disease, non-relapse mortality, and shorter overall survival. In multivariable analysis, low level of citrulline was the only risk factor independently associated with stage 2-4 gastrointestinal graft vs host disease (hazard ratio, 3.06; 95% CI, 1.37-6.85; P = .007); it also associated with increased non-relapse mortality (hazard ratio, 2.29; 95% CI, 1.24-4.22; P = .008).

Conclusions: In a retrospective study with 191 patients, we associated a low plasma level of citrulline before allogeneic hematopoietic cell transplantation with a higher risk for stage 2-4 gastrointestinal graft vs host disease and non-relapse mortality. This marker might be used to manage patients before allogeneic hematopoietic cell transplantation.