Prophylactic Intervention with N-Acetyl-L-Cysteine before Allotransplant Could Reduce the Occurrence of Poor Hematopoietic Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

▪BackgroundPoor hematopoietic reconstitution including poor graft function (PGF), characterized by pancytopenia, and prolonged isolated thrombocytopenia (PT), defined as the engraftment of all peripheral blood cells other than platelets, remains a life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the clinical management is challenging. Endothelial cells (ECs) play a crucial role in regulating hematopoiesis in bone marrow (BM) microenvironment. N-acetyl-L-cysteine (NAC), a reactive oxygen species (ROS) scavenger, is clinical used as a mucolytic drug. In this regard, we reported that PGF and PT patients had impaired BM ECs post-HSCT (BBMT 2013; BMT 2016; Blood 2016; AJH 2018). Recently, we reported in vitro treatment with NAC could improve the defective HSCs through repairing the impaired BM ECs of PGF and PT patients ( Blood 2016; AJH 2018). However, our previous studies evaluated BM ECs in PGF and PT patients at +3 month(M) post-HSCT. Therefore, whether BM ECs dysfunction in PGF and PT patients is responsible for the defective hematopoiesis, or vice versa, requires to be further clarified. Moreover, prophylactic intervention to improve the impaired BM ECs and HSCs remains unidentified.AimsIn order to investigate whether the defective BM ECs pre-HSCT is the risk factor for the occurrence of PGF and PT post-HSCT. Moreover, to evaluate whether prophylactic NAC intervention could repair the impaired BM ECs and reduce the incidence of PGF and PT.MethodsTwo registered prospective clinical trials were included. The first trial compared the dynamic reconstitution of the BM ECs pre- and post-HSCT among PGF, PT, and good graft function (GGF) patients at Peking University People's Hospital. Multivariate analyses were performed to identify the risk factors for the occurrence of PGF and PT. Receiver operating characteristic (ROC) curves were used to identify the cut-off percentage of BM ECs pre-HSCT to predict high risk patients for PGF and PT. Subsequently, the second trial was performed to investigate whether prophylactic NAC intervention could reduce the incidence of PGF and PT and its underlying mechanism. The quantity and function of BM ECs were evaluated at -14 day (D), 0D pre-HSCT, and +1M, +2M post-HSCT in the patients who were willing to provide BM samples after the written consent.ResultsIn the first trial, 15 patients of the enrolled 68 patients developed PGF or PT, whereas the remaining 53 patients were GGF at +2M post-HSCT. PGF and PT patients demonstrated impaired BM ECs at -14D pre-HSCT and defective dynamic reconstitution at +1M, +2M post-HSCT. Moreover, the BM ECs impairment positively correlated with their ROS levels. Multivariate analysis identified BM EC<0.1% at -14D pre-HSCT was the independent risk factor for the higher incidence of PGF and PT post-HSCT. Based on the ROC cut-off percentage of BM ECs pre-HSCT, the enrolled patients were designated into EC≥0.1% group (N=38) and EC <0.1% group (N=30). Significant higher incidence of PGF and PT was found in EC<0.1% group compared to those in EC ≥0.1% group.The second trial enrolled EC<0.1% patients (N=35) to accept oral NAC (400 mg three times per day) from -14D pre-HSCT to +2M post-HSCT continuously. The remaining EC ≥0.1% patients (N=39) received allo-HSCT only. Prophylactic NAC intervention promoted the dynamic reconstitution of BM ECs and CD34+ cells, whereas reducing their ROS levels, in EC<0.1% group to the similar levels in EC≥0.1% group post-HSCT, which was further confirmed by in situ BM trephine biopsies analyses. No significant difference was observed in the incidence of PGF and PT between the two groups. Importantly, prophylactic NAC intervention significantly reduced the incidence of PGF and PT in EC<0.1% group of the second trial compared with those in EC<0.1% without prophylactic NAC group of the first trial.Summary / Conclusion: BM EC<0.1% at -14D pre-HSCT helps to identify high risk patients for the occurrence of PGF and PT post-HSCT. Prophylactic NAC intervention was safe and effective to prevent the occurrence of PGF and PT in EC<0.1% patients through repairing the impaired BM ECs. Although requiring validation, our data indicate that the impaired BM ECs pre-HSCT is responsible for the occurrence of PGF and PT. Therefore, improvement of BM ECs through prophylactic NAC intervention may represent a promising therapeutic approach to promote hematopoietic recovery post-HSCT. DisclosuresNo relevant conflicts of interest to declare.