scholarly journals Anti-Thymocyte Globulin Treatment Augments 1,25-Dihydroxyvitamin D3 Serum Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation

2022 ◽  
Vol 12 ◽  
Author(s):  
Carina Matos ◽  
Katrin Peter ◽  
Laura Weich ◽  
Alice Peuker ◽  
Gabriele Schoenhammer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Vitamin D3 ◽  
Serum Levels ◽  
Dihydroxyvitamin D3 ◽  
Hematopoietic Stem ◽  
1,25 Dihydroxyvitamin D3 ◽  
Vitamin D3 Supplementation ◽  
Related Mortality

Application of anti-thymocyte globulin (ATG) is a widely used strategy for the prevention of graft-versus-host disease (GvHD). As vitamin D3 serum levels are also discussed to affect hematopoietic stem cell transplantation (HSCT) outcome and GvHD development, we analysed a possible interplay between ATG treatment and serum levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in 4 HSCT cohorts with different vitamin D3 supplementation. ATG is significantly associated with higher serum level of 1,25-dihydroxyvitamin D3 around HSCT (day -2 to 7, peri-transplant), however only in patients with adequate levels of its precursor 25-hydroxyvitamin D3. ATG exposure had no impact on overall survival in patients supplemented with high dose vitamin D3, but was associated with higher risk of one-year treatment-related mortality (log rank test p=0.041) in patients with no/low vitamin D3 supplementation. However, the difference failed to reach significance applying a Cox-model regression without and with adjustment for baseline risk factors (unadjusted P=0,058, adjusted p=0,139). To shed some light on underlying mechanisms, we investigated the impact of ATG on 1,25-Dihydroxyvitamin D3 production by human dendritic cells (DCs) in vitro. ATG increased gene expression of CYP27B1, the enzyme responsible for the conversion of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3, which was accompanied by higher 1,25-dihydroxyvitamin D3 levels in ATG-treated DC culture supernatants. Our data demonstrate a cooperative effect of 25-hydroxyvitamin D3 and ATG in the regulation of 1,25-dihydroxyvitamin D3 production. This finding may be of importance in the context of HSCT, where early high levels of 1,25-dihydroxyvitamin D3 levels have been shown to be predictive for lower transplant related mortality and suggest that vitamin D3 supplementation may especially be important in patients receiving ATG for GvHD prophylaxis.

scholarly journals 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

2020 ◽  
Vol 11 ◽  
Author(s):  
Jingjing Huang ◽  
Chenxia Hao ◽  
Ziwei Li ◽  
Ling Wang ◽  
Jieling Jiang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Proinflammatory Cytokine ◽  
Hematopoietic Stem ◽  
Cytokine Levels ◽  
Conditioning Regimens ◽  
Related Mortality

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)-α 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-κB-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.

Population Pharmacokinetic of Oral Busulfan in Japanese Undergoing Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5317-5317
Author(s):  
Noriaki Sasaki ◽  
Kentaro Ogata ◽  
Keita Yamauchi ◽  
Yasushi Takamatsu ◽  
Junji Suzumiya ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Total Bilirubin ◽  
Total Body Weight ◽  
Serum Levels ◽  
Japanese Adult ◽  
Hematopoietic Stem ◽  
Total Body

Abstract We previous evaluated busulfan (BU) pharmacokinetics (PK) in seven Japanese adult patients who underwent allogenic hematopoietic stem cell transplantation (HSCT) at Fukuoka University Hospital. We showed that the average plasma BU concentrations at steady state (Css) ranged from 745 to 2422 ng/mL. BU population PK (PPK) parameters for Caucasian have already been reported. However, few data are available for Asian people. We therefore investigated the PPK parameters of BU in 82 Japanese adult patients (51 males and 31 females) who underwent HSCT following a BU-containing conditioning regimen. Their average age was 43.4 years, ranging from 16 to 68 years. Blood samples were collected in heparinized tubes at 0.5,1,2,4 and 6 hours after the oral administration of BU, and the plasma BU concentrations were measured by high performance liquid chromatography (HPLC). A one compartment open model with first-order absorption was used. We estimated individual BU doses by using Bayesian, and PK parameters by using nonlinear mixed effects modeling (NONMEM) computer program. Since Oral clearance (L/h/kg) (CL/F) and distribution volumes (L/kg) (Vd/F) were proportional to total body weight, so we set the following formulas. The final PPK parameters were CL/F = 0.139•TBW•1.14GEN •1.09VPA •1.52TBIL≥1.2, Vd/F = 0.76•TBW•0.902GEN, absorption rate constant (h−1) (ka) = 2.58. TBW is total body weight (kg), VPA = 1 for concomitant administration of valproic acid and 0 for another anticonvulsant, GEN = 1 for patients gender female and 0 for male, TBIL≥1.2 = 1 for total bilirubin above 1.2 mg/dL and 0 for below. CL/F in Japanese and Caucasian were 0.139 and 0.149, respectively, Vd/F were 0.76 and 0.64, respectively, and ka were 2.58 and 1.68, respectively. These data showed that CL/F and Vd/F were almost same between Japanese and Caucasian, but ka was larger. We also found that high serum levels of total bilirubin and administration of VPA induced the increase of CL/F at 52 % and 9 %, respectively. The interindividual variabilities in CL/F, Vd/F and ka were 21.9%, 20.9% and 82.3%, respectively, and the residual variability was 18.4% as coefficient of variation. This study represented that oral BU PPK parameters in Japanese were different from that in Caucasian. BU PPK parameters were influenced by gender, serum levels of total bilirubin and administration of VPA. Our study showed that BU PPK differed between Japanese and Caucasian.

Decreased Serum Levels of Surfactant Protein D (SP-D) Prior Transplant Is Associated with the Development of Bronchiolitis Obliterans (BO) and Idiopathic Pneumonia Syndrome (IPS) Following Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2915-2915
Author(s):  
Takahiko Nakane ◽  
Hirohisa Nakamae ◽  
Hiroshi Kamoi ◽  
Hideo Koh ◽  
Yasunobu Takeoka ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Bronchiolitis Obliterans ◽  
Serum Levels ◽  
Surfactant Protein ◽  
Surfactant Protein D ◽  
Hematopoietic Stem ◽  
Idiopathic Pneumonia Syndrome

Abstract Non-infectious pulmonary complications which occur beyond 3 months of allogeneic hematopoietic stem cell transplantation (allo-HSCT) have become recognized as a critical problem. Above all, bronchiolitis obliterans (BO) and idiopathic pneumonia syndrome (IPS) are difficult to be cured and cause high mortality. Therefore, early identification of patients with higher risk for BO/IPS may lead to improving outcome of allo-HSCT. Surfactant protein D (SP-D) is one of collectins mainly synthesized by alveolar type II cells. The best known function is to prevent the collapse of alveoli by decreasing surface tension at alveolar air-lipid interface, and SP-D plays an important roles as a mediator in innate immunity in the lung. In clinical practice, high serum SP-D level is used as a marker lung diseases. Recently, low production of SP-D in the alveoli has been considered as an important pathgenesis of adult respiratory distress. We analyzed serum SP-D levels before allo-HSCT of 42 patients who received allo-HSCT in our institution between November 2001 and February 2006 and survived more than 90 days after transplant. In all patients, 5 patients had BO and 3 had IPS at a median interval of 303 and 117 days of transplantation (range; 100–452 and 95–153 days). As a result of univariate analysis, BO/IPS patients had lower serum SP-D levels prior allo-HSCT and extensive type of cGVHD except lung compared with no BO/IPS patients (p=0.06 and 0.07). KL-6 had also mildly associated with BO/IPS. On the other hand, we couldn’t find the association in sex, age, donor source, conditioning regimen, disease status, aGVHD, and FEV1.0/FVC and SP-A prior HSCT. We could not clarify the precise mechanism of the association between Decreased serum levels of SP-D and the development of BO and IPS following allo-HSCT. However, we speculate that low production of SP-D in the alveoli, which causes innate immune compromise, might contribute to extreme pulmonary alloreaction.

Human Leukocyte Antigens of A33, B58 or DR7 Decrease the Treatment-Related Mortality in HLA-Matched Sibling Hematopoietic Stem Cell Transplantation in Association with Heat Shock Protein 70-Hom Polymorphisms.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1103-1103
Author(s):  
Jin Won Kim ◽  
So Yeon Oh ◽  
Hye Jin Kim ◽  
Hyeon Gyu Yi ◽  
Kyung-Hun Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Human Leukocyte ◽  
Hematopoietic Stem ◽  
Matched Sibling ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Human leukocyte antigens(HLA) are expected to influence outcomes or adverse effects in allogeneic hematopoietic stem cell transplantation through its immunologic function. However, the types of HLA and its mechanism to affect clinical outcomes are not well defined. In the other hand, heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses and was reported to influence the incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. And it was also reported that HLA types were associated with polymorphisms of HSP70-hom in several diseases. So, we evaluated the association between HLA types and HSP70-hom polymorphisms and identified the specific HLA types to affect clinical outcomes in allogeneic hematopoietic stem cell transplantation. We analyzed the DNA of patients and donors who underwent allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donors at single institute between 1998 and 2005 for malignancy or aplastic anemia. The HSP70-hom polymorphisms, rs2227956 and rs2075800, were genotyped and HLA typing was conducted in 141 patients and their donors. Individual haplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. The HSP70-hom polymorphisms of patients were completely identical to those of their donors. Patients(101) with TG haplotype (TG/TA, TG/TG or TG/CG) did not only show less treatment-related mortality but also had longer overall survival compared with those(40) with non-TG haplotype (TA/TA or TA/CG). (P=0.011, P=0.013,respectively) TG haplotype was associated with HLA types of A33, B58 and DR7.(P<0.001, P=0.002, P=0.039, respectively) Patients with HLA types of A33, B58 or DR7 showed less treatment-related mortality compared with patients without the these HLA types in multivariate analyses with age, sex, transplant method, stem cell source and risk group.(P=0.034, HR=0.397, 95% CI: 0.169–0.931) In conclusion, HLA types of A33, B58 or DR7 in HLA-matched sibling hematopoietic stem cell transplantation were protective for treatment-related mortality in association with HSP70-hom polymorphisms. Figure Figure

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