Dataset Information

NRF2 -617 C/A Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens.

ABSTRACT: Busulfan (BU) is widely used in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). The exposure-escalated BU directed by therapeutic drug monitoring (TDM) is extremely necessary for the patients with high-risk hematologic malignancies in order to diminish relapse, but it increases the risk of drug-induced toxicity. BU exposure, involved in the glutathione- (GSH-) glutathione S-transferases (GSTs) pathway and proinflammatory response, is associated with clinical outcomes after HSCT. However, the expression of genes in the GSH-GSTs pathway is regulated by NF-E2-related factor 2 (Nrf2) that can also alleviate inflammation. In this study, we evaluated the influence of NRF2 polymorphisms on BU exposure, proinflammatory cytokine levels, and clinical outcomes in HSCT patients. A total of 87 Chinese adult patients receiving twice-daily intravenous BU were enrolled. Compared with the patients carrying wild genotypes, those with NRF2 -617 CA/AA genotypes showed higher plasma interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF)-? levels, poorer overall survival (OS; RR = 3.91), and increased transplant-related mortality (TRM; HR = 4.17). High BU exposure [area under the concentration-time curve (AUC) > 9.27 mg/L × h)] was related to BU toxicities. Furthermore, NRF2 -617 CA/AA genotypes could significantly impact TRM (HR = 4.04; p = 0.0142) and OS (HR = 3.69; p = 0.0272) in the patients with high BU AUC. In vitro, we found that high exposure of endothelial cell (EC) to BU, in the absence of Nrf2, elicited the hyperstimulation of NF-?B-p65, accompanied with the elevated secretion of proinflammatory cytokines, and led to EC death. These results showed that NRF2 -617 CA/AA genotypes, correlated with high proinflammatory cytokine levels, could predict inferior outcomes in HSCT patients with high BU AUC. Thus, NRF2 -617 CA/AA genotyping combined with TDM would further optimize personalized BU dosing for sufficient efficacy and safety endpoint.

SUBMITTER: Huang J

PROVIDER: S-EPMC7770105 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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<i>NRF2 -617 C/A</i> Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens.

Huang Jingjing J Hao Chenxia C Li Ziwei Z Wang Ling L Jiang Jieling J Tang Wei W Wang Lining L Zhang Weixia W Hu Jiong J Yang Wanhua W

Frontiers in pharmacology 20201215

Busulfan (BU) is widely used in conditioning regimens prior to hematopoietic stem cell transplantation (HSCT). The exposure-escalated BU directed by therapeutic drug monitoring (TDM) is extremely necessary for the patients with high-risk hematologic malignancies in order to diminish relapse, but it increases the risk of drug-induced toxicity. BU exposure, involved in the glutathione- (GSH-) glutathione S-transferases (GSTs) pathway and proinflammatory response, is associated with clinical outcom ...[more]

PMID: 33384597

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Project description:AimsBusulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric haematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post-HSCT period. The main objectives were: (i) to establish a mechanistic pharmacokinetic-pharmacodynamic (PKPD) model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan-based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT.MethodsData on 126 patients, 72 receiving busulfan (7 months-18 years, 5.1-47.0 kg) and 54 treosulfan (4 months-17 years, 3.8-35.8 kg), were collected. In total, 8935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. Absolute neutrophil count profiles were modelled semimechanistically, accounting for transplant effects and differing set points pre- and post-transplant.ResultsPK were best described by 2-compartment models for both drugs. The Friberg semimechanistic neutropenia model was applied with a linear model for busulfan and a maximum efficacy model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the absolute neutrophil count begin to grow after HSCT.ConclusionA semimechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab coadministration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion.

Project description:BackgroundAllogeneic stem cell transplantation (allo-HSCT) is the ultimate cure for acute lymphoblastic leukemia (ALL).AimThis study was performed to compare the outcomes of ALL patients receiving busulfan (Bu) with cyclophosphamide (Cy)-based or total body irradiation (TBI)-based regimen in a Chinese population.MethodsWe enrolled 224 adult patients with ALL who received allo-HSCT at National Taiwan University Hospital between 1997 and 2016.ResultsThe median age at transplantation was 33 years. Before allo-HSCT, 75.9% of patients attained first or late complete remission. A total of 141 patients (62.9%) received Bu/Cy-based conditioning, either myeloablative (MA) or reduced-intensity stem cell transplantation (RIST), and 83 patients received a TBI-based regimen (MA-TBI). Patients receiving the MA-Bu regimen had longer relapse-free survival (RFS) than those receiving the MA-TBI regimen (median, 24.1 vs. 6.7 months, p = .044). There was no difference in overall survival (OS, MA-Bu vs. MA-TBI vs. RIST-Bu: 39.4 vs. 28.2 vs. 13.1 months, p = .276), treatment-related mortality (TRM), or incidences of grade 3-4 acute graft-versus-host disease (GvHD). Among patients receiving identical GvHD prophylactic regimens, there was no difference between MA-Bu and MA-TBI groups regarding the incidence of grade 3-4 acute GvHD, grade 2-4, and all-grade chronic GvHD. In subgroup analysis, patients receiving oral busulfan had comparable RFS and OS to the intravenous busulfan group (p = .436 and p = .236, respectively), but a higher TRM (25% vs. 9.8%, p = .016). In the multivariable analysis, disease status before allo-HSCT was the only risk factor impacting RFS and OS.ConclusionIn summary, patients receiving Bu/Cy-based or TBI-based regimens as conditioning had similar results in terms of OS, TRM, and acute GvHD, whereas the use of myeloablative Bu/Cy resulted in a better RFS. A Bu-based regimen could be an alternative conditioning choice for patients who are ineligible to receive TBI. Prospective and randomized controlled trials are warranted to validate the long-term outcomes.

Dataset Information

NRF2 -617 C/A Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens.

Publications

<i>NRF2 -617 C/A</i> Polymorphism Impacts Proinflammatory Cytokine Levels, Survival, and Transplant-Related Mortality After Hematopoietic Stem Cell Transplantation in Adult Patients Receiving Busulfan-Based Conditioning Regimens.

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