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

doi:10.1016/j.cgh.2017.12.024

Clinical Gastroenterology and Hepatology

Volume 16, Issue 6, June 2018, Pages 908-917.e2

https://doi.org/10.1016/j.cgh.2017.12.024 Get rights and content

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.

Section snippets

Patients and Methods

The study was performed according to institutional guidelines and in accordance with the Declaration of Helsinki. The analyses in the present study were performed on data entered into a prospective database of patients undergoing allo-HCT between 2013 and 2015 at the Lille University Hospital. All enrolled patients provided their written and informed consent before undergoing allo-HCT. All data were anonymized for use for research purposes.

Patient Outcome

Ninety-six patients (50%) developed aGvHD: 36 (19%) grade I GvHD, 25 (13%) grade II GvHD, and 35 (18%) grade III-IV GvHD. Ninety-five patients (50%) did not develop GvHD (grade 0 GvHD). Among patients who developed aGvHD, 78 (81%) had skin involvement, 11 (11%) had liver, and 37 (39%) had GI involvement. Among patients with GI involvement, 33 (89%) had stage 2–4 GI-GvHD. The median follow-up was 944 days (range, 891–997) and the OS estimated for the whole cohort was 57% at 2 years. The OS at 2

Discussion

The benefits of allo-HCT remain hampered by severe aGvHD and particularly GI-GvHD. The aim of this study was to assess plasma citrulline level before conditioning treatment as a predictive factor of GI-GvHD in a large cohort of patients undergoing allo-HCT. We observed that low plasma citrulline level (≤26 μmol/L) before conditioning was strongly associated with higher cumulative incidence of stage 2–4 GI-GvHD, grade III-IV GvHD, resulting in significant higher NRM. Pretransplant low citrulline

Acknowledgments

The authors thank the staff of the hematology department of the University Hospital of Lille, France, for patients’ recruitment and blood sample collection. The authors acknowledge Marie-Adelaide Bout and the laboratory of metabolism of the University Hospital of Lille, France, for the amino acid analyses for material support. The authors thank the Lille Inflammation Research International Center of UMR 995 Inserm and the DigestScience foundation for its support.

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Citation Excerpt :
When intestinal mucosal damage occurs, i-FABP is released into the circulation. [16,38,39] Citrulline is an amino acid produced by small bowel enterocytes from glutamine and derived amino acids Decreased plasma citrulline reflects reduced enterocyte mass and function. [17,40] Ex-vivo assessment of physical gut barrier integrity and permeability is possible through immunohistochemical staining of tight junctions and zonula adherens components. [18]
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La maladie du greffon contre l’hôte (GVH) est la complication la plus fréquente après allogreffe de cellules souches hématopoïétiques dont la fréquence varie entre 30 % et 50 %. La GVH est la principale cause de décès non liés à la rechute et une cause de mortalité précoce. La GVH digestive se traduit par des manifestations digestives qui impliquent l’intestin grêle et le colon. Le patient peut alors présenter des diarrhées, des hémorragies intestinales, des douleurs intestinales mais aussi des signes cliniques comme des nausées et des vomissements pouvant conduire à une anorexie. La GVH digestive favorise la dénutrition ainsi que des pertes importantes en vitamines et oligo-éléments. En cas de diarrhée isolée, le diagnostic différentiel n’est pas aisé entre une GVH digestive, infection ou intolérance médicamenteuse. Les corticostéroïdes avec ou sans inhibiteurs de la calcineurine représentent le traitement de choix en première ligne. Toutefois, il n’existe pas de consensus sur le traitement de rattrapage de deuxième ligne en cas de GVH digestive corticorésistante. L’évaluation de l’état nutritionnel précoce permettrait également de lutter contre la dénutrition, qui est un facteur de risque indépendant de mortalité. Dans cet atelier, nous nous sommes focalisés sur la prise en charge des patients allogreffés présentant une GVH digestive, en particulier, corticorésistante.
Graft-versus-host disease (GVHD) is the most common complication after allogeneic hematopoietic cell transplantation (allo-HCT) with a frequency range of 30% to 50%. GVH is the leading cause of non-relapse-related deaths and a cause early mortality. Gastro-intestinal (GI) GVH results in digestive manifestations that involve the small intestine and the colon. The patient may then have diarrhea, intestinal bleeding, abdominal pain but also clinical signs such as nausea and vomiting may lead to anorexia. GI-GVHD promotes undernutrition as well as significant losses of vitamins and trace elements. In the case of post-transplant diarrhea, differential diagnosis can include GI-GVHD, infection and drug toxicity. Although, corticosteroids w/wo calcineurin inhibitors represent the standard of care in first line treatment, there is no consensus regarding salvage therapy in case of corticoresistant GI-GVH. In addition, assessment of early nutritional status would help combating undernutrition, which is an independent risk factor for mortality in patients with GI-GVHD. In this workshop of the Fancophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) we focused on the management of patients developing GI-GVHD following allo-HCT.
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: Conflicts of interest The authors disclose no conflicts.

: Funding This study was supported by a grant from Nutricia Nutrition Clinique on behalf of the Société Francophone Nutrition Clinique et Métabolique awarded to Thomas Hueso.

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

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients and Methods

Patient Outcome

Discussion

Acknowledgments

Blood

Blood

Leuk Res

Biol Blood Marrow Transplant

Blood

Blood

Blood

Blood

Blood

J Crit Care

Biol Blood Marrow Transplant

Surgery

Blood

Blood

Gut toxicity during hemopoietic stem cell transplantation may predict acute graft-versus-host disease severity in patients

Dig Dis Sci

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