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Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with ?-thalassemia major.

ABSTRACT: ?-thalassemia is a group of inherited blood disorders that result in defects in ?-globin chain production. Cooley anemia (CA), or ?-thalassemia major, is the most severe form of the disease and occurs when an individual has mutations in both copies of the adult ?-globin gene. Patients with CA fail to make adult hemoglobin, exhibit ineffective erythropoiesis, experience severe anemia, and are transfusion dependent for life. Currently, allogeneic bone marrow transplantation (BMT) is the only cure; however, few patients have suitable donors for this procedure, which has significant morbidity and mortality. In this study, a novel humanized murine model of CA is rescued from lethal anemia by allogeneic BMT in the absence of cytoreductive conditioning. A single intravenous postnatal injection of allogeneic bone marrow results in stable, mixed hematopoietic chimerism. Five months after transplantation, donor cells accounted for approximately 90% of circulating erythrocytes and up to 15% of hematopoietic stem and progenitor cells. Transplanted mice are transfusion independent, have marked improvement of hematological indices, exhibit no growth retardation or signs of graft-versus-host disease, and are fertile. This study describes a method for the consistent engraftment of allogeneic donor hematopoietic cells that rescues a humanized mouse model of CA from lethal anemia, all in the absence of toxic cytoreductive conditioning.

SUBMITTER: Huo Y

PROVIDER: S-EPMC5729620 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with β-thalassemia major.

Huo Yongliang Y Lockhart Jonathan R JR Liu Shanrun S Fontenard Suean S Berlett Mike M Ryan Thomas M TM

Blood advances 20171128 25

β-thalassemia is a group of inherited blood disorders that result in defects in β-globin chain production. Cooley anemia (CA), or β-thalassemia major, is the most severe form of the disease and occurs when an individual has mutations in both copies of the adult β-globin gene. Patients with CA fail to make adult hemoglobin, exhibit ineffective erythropoiesis, experience severe anemia, and are transfusion dependent for life. Currently, allogeneic bone marrow transplantation (BMT) is the only cure; ...[more]

PMID: 29296892

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Project description:A toxicity-reduced conditioning regimen with treosulfan, fludarabine, and thiotepa in patients with high-risk β-thalassemia major has significantly improved hematopoietic stem cell transplantation (HCT) outcomes. However, complications resulting from regimen-related toxicities (RRTs), mixed chimerism, and graft rejection remain a challenge. We evaluated the dose-exposure-response relationship of treosulfan and its active metabolite S, S-EBDM, in a uniform cohort of patients with β-thalassemia major to identify whether therapeutic drug monitoring (TDM) and dose adjustment of treosulfan is feasible. Plasma treosulfan/S, S-EBDM levels were measured in 77 patients using a validated liquid chromatography with tandem mass spectrometry method, and the pharmacokinetic parameters were estimated using nlmixr2. The influence of treosulfan and S, S-EBDM exposure, and GSTA1/NQO1 polymorphisms on graft rejection, RRTs, chimerism status, and 1-year overall survival (OS), and thalassemia-free survival (TFS) were assessed. We observed that treosulfan exposure was lower in patients with graft rejection than those without (1,655 vs. 2,037 mg•h/L, P = 0.07). Pharmacodynamic modeling analysis to identify therapeutic cutoff revealed that treosulfan exposure ≥1,660 mg•hour/L was significantly associated with better 1-year TFS (97% vs. 81%, P = 0.02) and a trend to better 1-year OS (90% vs. 69%, P = 0.07). Further, multivariate analysis adjusting for known pre-HCT risk factors also revealed treosulfan exposure <1,660 mg•h/L (hazard ratio (HR) = 3.23; 95% confidence interval (CI) = 1.12-9.34; P = 0.03) and GSTA1*B variant genotype (HR = 3.75; 95% CI = 1.04-13.47; P = 0.04) to be independent predictors for inferior 1-year TFS. We conclude that lower treosulfan exposure increases the risk of graft rejection and early transplant-related mortality affecting TFS. As no RRTs were observed with increasing treosulfan exposure, TDM-based dose adjustment could be feasible and beneficial.

Dataset Information

Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with ?-thalassemia major.

Publications

Allogeneic bone marrow transplant in the absence of cytoreductive conditioning rescues mice with β-thalassemia major.

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