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1.
Population pharmacokinetics of cyclosporine A in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation
Cai, R., Zhang, L., Wu, T., Huang, Y., Lu, J., Huang, T., Wu, Y., Wu, D., Qi, J., Niu, L., et al
European journal of clinical pharmacology. 2024
Abstract
PURPOSE To establish the population pharmacokinetics (PPK) model of cyclosporine A(CsA) in pediatric patients with thalassemia undergoing allogeneic hematopoietic stem cell transplantation (HSCT), aiming at providing a reference for clinical dose individualization of CsA. METHODS Children with thalassemia who underwent allogeneic HSCT were enrolled retrospectively. The PPK structural model and the random variable model of CsA were established on NONMEN. And goodness of fit plots (GOFs), visual predictive check (VPC), and bootstrap and normalized prediction distribution errors (NPDE) were used to evaluate the final model. RESULTS A one-compartment model with first-order absorption was employed to fit the base model. A total of 74 pediatric patients and 600 observations of whole blood concentration were included. The final model included weight (WT) in clearance (CL), alongside post-operative day (POD), fluconazole (FLUC), voriconazole (VORI), posaconazole (POSA), and red blood cell count (RBC) significantly. All the model evaluations were passed. CONCLUSION In the PPK model based on the pediatric cohort on CsA with thalassemia undergoing allogeneic HSCT, WT, POD, FLUC, VORI, POSA, and RBC were found to be the significant factors influencing CL of CsA. The reliability and robustness of the final model were excellent. It is expected that the PPK model can assist in individualizing dosing strategy clinically.
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2.
Comparison of tacrolimus vs. cyclosporine in pediatric hematopoietic stem cell transplantation for thalassemia
Zhumatayev, S., Yalcin, K., Celen, S. S., Karaman, I., Daloglu, H., Ozturkmen, S., Uygun, V., Karasu, G., Yesilipek, A.
Pediatric transplantation. 2024;28(1):e14688
Abstract
OBJECTIVES Graft-versus-host disease (GvHD) is one of the leading causes of morbidity and mortality in patients undergoing allogeneic HSCT, and effective prevention of GvHD is critical for the success of the HSCT procedure. Calcineurin inhibitors (CNI) have been used for decades as the backbone of GvHD prophylaxis. In this study, the efficacy and safety of Cyclosporine A (CsA) and tacrolimus (TCR) were compared in pediatric HSCT for thalassemia. MATERIALS AND METHODS This is a retrospective analysis of 129 pediatric patients who underwent HSCT with the diagnosis of thalassemia at Medicalpark Göztepe and Antalya Hospitals between January 2017 and December 2020. RESULTS Despite the GvHD prophylaxis, grade II-IV acute GvHD developed in 29 patients. Of these patients, 12 had only gut, 10 had only skin, 6 had combined gut and skin, and one had only liver GvHD. Fifteen of these 29 patients were in the CsA group, and 14 of them were in the TCR group. There was no significant difference between the groups in terms of acute GvHD occurrence, GvHD stage, or involvement sites. In terms of CNI-related toxicity, neurotoxicity in 15 (CsA n = 9, TCR n = 6) and nephrotoxicity in 18 (CsA n = 4, TCR n = 14) patients were observed. While there was no difference between the two groups in terms of neurotoxicity, more nephrotoxicity developed in patients using TCR (p = .013). There was no significant difference between the groups in terms of engraftment syndrome, veno-occlusive disease, CMV reactivation, PRES, or graft rejection. CONCLUSION Regarding GvHD, there was no difference in efficacy between TCR and CsA usage. Patients taking TCR experienced noticeably higher nephrotoxicity in terms of adverse effects. This difference should be considered according to the patient's clinical situation while choosing a CNI.
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Addition of ruxolitinib in Graft-versus-Host disease prophylaxis for pediatric β-Thalassemia major patients after allogeneic stem cell transplantation: A retrospective cohort study
Hong, X., Chen, Y., Lu, J., Lu, Q.
Pediatric transplantation. 2023;:e14466
Abstract
BACKGROUND To evaluate the effect of addition of ruxolitinib in Graft-versus-Host Disease (GVHD) prophylaxis on pediatric patients with β-thalassemia major after allogeneic hematopoietic stem cell transplantation(HSCT). METHODS This retrospective study reviewed 49 consecutive β-thalassemia major pediatric patients who underwent HSCT from unrelated or haploidentical donors from February 2018 to October 2022. All transplantation recipients received cyclosporine A (CsA), mycophenolate mofetil (MMF), and short-term methotrexate (MTX) as GVHD prophylaxis; while 27 of them in the ruxolitinib group had added ruxolitinib oral to GVHD prophylaxis regimen at 2.5 mg twice daily once successful engraftment after January 2020. RESULTS The outcome showed that the ruxolitinib group had a lower cumulative incidence than the control group regardless of acute GVHD (22.2% vs.40.9%; p = .153) or chronic GVHD (18.5% vs.40.9%; p = .072); especially, the incidence of grade III-IV acute GVHD was reported significantly less frequently in ruxolitinib group than that of the control group (0 vs. 27.3%, p = .005). No significant difference was detected between the two groups in EBV (Epstein-Barr virus)/CMV (cytomegalovirus) reactivation and BKV (BK virus) infection (p = .703, 1.000, and .436, respectively). Twenty-six patients (96.3%) in the ruxolitinib group were alive, while two patients (9.1%) in the control group died of intestinal acute GVHD. The 2-year overall survival (OS) and thalassemia-free survival (TFS) were both 96.296% in the ruxolitinib group, while both 90.909% in the control group. CONCLUSION This study reveals that ruxolitinib prophylaxis is a promising option to decrease the incidence of grade III-IV acute GVHD in pediatric patients with β-thalassemia major.
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Influential Factors and Efficacy Analysis of Tacrolimus Concentration After Allogeneic Hematopoietic Stem Cell Transplantation in Children with ß-Thalassemia Major
Li, C., Lu, J., Zhou, S., Wei, Y., Lv, C., Liu, T., Wu, Y., Wu, D., Qi, J., Cai, R.
Pharmacogenomics and personalized medicine. 2021;14:1221-1237
Abstract
PURPOSE To analyze factors influencing tacrolimus (TAC) trough concentration (C(0)) in ß-thalassemia major (ß-TM) pediatric patients after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) and to investigate the effects of genotype polymorphism and drug-drug interactions on TAC trough concentration in children with ß-TM. Furthermore, to analyze the correlation between TAC C(0) and efficacy and adverse reactions. PATIENTS AND METHODS Prospectively collection of demographic information and details of combined treatment of patients with ß-TM receiving HSCT, and genotypes of CYP3A4, CYP3A5, and ABCB1 (rs1045642, rs1128503, rs2032582) were obtained for each patient. Univariate analysis and multiple linear regression analysis were used to investigate influencing factors on TAC C(0). The impact of different genotypes and the co-administration of azole antifungal drugs on ß-TM patients receiving TAC were evaluated, together with the correlation between acute graft-versus-host disease (aGVHD), infection, and liver injury of TAC C(0). RESULTS A total of 46 patients with 587 concentration data were included. The multiple linear regression results showed that the patient's sex, weight, postoperative time, hemoglobin, platelet count, serum cystatin C, and combined voriconazole were independent influencing factors of the infusion trough concentration/daily dose, C(0)/D(iv). Age, body surface area, postoperative time, co-administration of voriconazole, and CYP3A4*18B are independent influencing factors of C(0)/D(po). Group comparisons showed that voriconazole can affect TAC C(0) administered intravenously (IV) and orally in ß-TM pediatric patients, while patient genotype can affect TAC C(0) during oral administration. TAC C(0) does not correlate with aGVHD or liver injury, but infection may be associated with TAC C(0). CONCLUSION The concentration of TAC should be closely monitored when co-administered with voriconazole. It is worth considering that the influence of genotype on the trough concentration of oral TAC and individualized drug administration warrant investigation. Finally, this study indicated that C(0) is not suitable as an indicator of the efficacy of TAC.
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Successful mismatched hematopoietic stem cell transplantation for pediatric hemoglobinopathy by using ATG and post-transplant cyclophosphamide
Oostenbrink, L. V. E., Pool, E. S., Jol-van der Zijde, C. M., Jansen-Hoogendijk, A. M., Vervat, C., van Halteren, A. G. S., Bredius, R. G. M., Smiers, F. J. W., van Tol, M. J. D., Schilham, M. W., et al
Bone marrow transplantation. 2021
Abstract
The use of HLA-mismatched (un)related donors is historically associated with a higher incidence of transplant-related complications and mortality. However, the use of such donors may overcome the limited availability of HLA-matched donors for patients with ß-thalassemia major (TM) and sickle cell disease (SCD). We investigated hematopoietic stem cell transplantation (HSCT) outcomes of pediatric TM and SCD patients treated with a mismatched donor using a treosulfan-based conditioning in combination with ATG and post-transplant cyclophosphamide (PT-CY) and compared these results to the clinical outcome of patients treated by matched donor HSCT without PT-CY. Thirty-eight children (n?=?24 HLA-identical or 10/10-matched donors; n?=?14 HLA-mismatched donors), who received a non-depleted bone marrow graft were included. Event-free survival (EFS) and GvHD were not higher in the mismatched PT-Cy group as compared to the matched group. Moreover, despite delayed neutrophil engraftment (day +22 vs. +26, p?=?0.002) and immune recovery in the mismatched PT-Cy group, this did not result in more infectious complications. Therefore, we conclude that in the absence of an HLA-identical or a matched unrelated donor, HSCT with a mismatched unrelated or haploidentical donor in combination with ATG plus PT-CY can be considered a safe and effective treatment option for pediatric hemoglobinopathy patients.
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6.
Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics
Zhou, S., Zhang, R., Lv, C., Lu, J., Wei, Y., Li, C., Chen, M., Li, Q., Liu, T.
The Annals of pharmacotherapy. 2020;:1060028020959039
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with ß-thalassemia major (ß-TM) undergoing HSCT are insufficient. OBJECTIVE To establish a PPK model of tacrolimus in children with ß-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. METHODS Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. RESULTS A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. CONCLUSION AND RELEVANCE A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.
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Co-transplantation of bone marrow-derived mesenchymal stem cells with hematopoietic stem cells does not improve transplantation outcome in class III beta-thalassemia major: A prospective cohort study with long-term follow-up
Rostami, T., Maleki, N., Kasaeian, A., Nikbakht, M., Kiumarsi, A., Asadollah Mousavi, S., Ghavamzadeh, A.
Pediatric transplantation. 2020;:e13905
Abstract
Bone marrow transplantation is the only curative treatment for beta-thalassemia major. Data on the co-transplantation of MSCs with HSCs in beta-thalassemia major patients are scarce. We aimed to investigate the outcomes of thalassemia major patients who underwent bone marrow-derived MSC co-transplantation with HSCs compared with those who only received HSCs. This prospective randomized study included patients with class III thalassemia major undergoing HSCT divided randomly into two groups: Thirty-three patients underwent co-transplantation of bone marrow-derived MSCs with HSCs, and 26 patients only received HSCs. Five-year OS, TFS, TRM, graft rejection rate, and GVHD were estimated. The 5-year OS was 66.54% (95% CI, 47.8% to 79.9%) in patients who underwent co-transplantation of MSCs with HSCs vs 76.92% (95% CI, 55.7% to 88.9%) in patients who only received HSCs (P = .54). No significant difference was observed in the 5-year TFS between the two groups (59.1% vs 69.2%; P = .49). The 5-year cumulative incidence of TRM was not statistically significant among patients who underwent co-transplantation of MSCs with HSCs (27.27%) vs those who only received HSCs (19.23%; P = .61). There was no statistically significant difference in graft rejection, acute GvHD, and chronic GvHD between the two groups. Based on our findings, the co-transplantation of MSCs and HSCs to class III thalassemia major patients does not alter their transplantation outcomes including OS, TFS, rejection rate, transplant-related mortality, and GvHD.
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Graft Versus Host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft Versus Host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta Thalassemia Major with Busulfan, Fludarabine, and Thiotepa
Khandelwal, P., Yeh, R. F., Yu, L., Lane, A., Dandoy, C. E., El-Bietar, J., Davies, S. M., Grimley, M. S.
Transplantation. 2020
Abstract
INTRODUCTION We hypothesized that the addition of 4 doses of abatacept to our standard acute graft versus host disease (GVHD) prophylaxis would reduce the incidence of day+100 severe acute GVHD in children with transfusion dependent beta- thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment. METHODS Twenty-four children with beta-thalassemia major received abatacept at a dose of 10 mg/kg intravenously on days -1, +5, +14 and +28 after HSCT in addition to calcineurin inhibitors and methylprednisolone. Outcomes were compared to 8 beta thalassemia patients who received standard acute GVHD prophylaxis. RESULTS There was no difference in engraftment between the 2 groups. No patient had grades III- IV acute GVHD by day+100 in the abatacept cohort compared to 50% in the standard acute GVHD prophylaxis group (p=0.001). Viral reactivation occurred in 5 children in the standard acute GVHD cohort and in 20 children in the abatacept cohort (p=0.2). Thalassemia-free survival after HSCT was 100% in the abatacept cohort compared to 62.5% in the standard cohort at last follow up (p=0.007). CONCLUSIONS Adding abatacept to our routine GVHD prophylaxis reduced the incidence of day+100 severe acute GVHD without impacting engraftment or survival.
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Abatacept is effective as GVHD prophylaxis in unrelated donor stem cell transplantation for children with severe sickle cell disease
Ngwube, A., Shah, N., Godder, K., Jacobsohn, D., Hulbert, M. L., Shenoy, S.
Blood advances. 2020;4(16):3894-3899
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Abstract
We report results of a phase 1 multicenter stem cell transplantation (SCT) trial from HLA-matched (n = 7) or one-antigen-mismatched (n = 7) unrelated donors (URD) using bone marrow or cord blood as stem cell source, following reduced-intensity conditioning (RIC) in severe sickle cell disease (SCD). Conditioning included distal alemtuzumab, fludarabine, and melphalan (matched donors), with thiotepa (mismatched donors). Abatacept, a selective inhibitor of T cell costimulation, was added to tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis to offset GVHD risks, and was administered for longer duration in bone marrow recipients than in cord blood recipients because of increased incidence of chronic GVHD with bone marrow. Median age at transplant was 13 years (range, 7-21 years). The incidence of grades II to IV and grades III to IV acute GVHD at day +100 was 28.6% and 7%, respectively. One-year incidence of chronic GVHD was 57% and mild/limited in all but 1 patient who received abatacept for a longer duration. Only 1 patient developed reversible posterior encephalopathy syndrome and recovered. With a median follow-up of 1.6 years (range, 1-5.5 years), the 2-year overall and disease-free survival was 100% and 92.9%, respectively. The encouraging results from the phase 1 portion of this RIC SCT trial, despite risk factors such as older age, URD, and HLA-mismatch, support further evaluation of URD SCT in clinical trial settings. The phase 2 portion of the trial is in progress. This trial was registered at www.clinicaltrials.gov as NCT03128996.
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Posterior Reversible Encephalopathy Syndrome after Hematopoietic Cell Transplantation in Children with Hemoglobinopathies
Gaziev, J., Marziali, S., Paciaroni, K., Isgro, A., Di Giuliano, F., Rossi, G., Marziali, M., De Angelis, G., Alfieri, C., Ribersani, M., et al
Biology of Blood & Marrow Transplantation. 2017;23(9):1531-1540
Abstract
Posterior reversible encephalopathy syndrome (PRES) is a serious adverse event associated with calcineurin inhibitors used for graft-versus-host disease (GVHD) prophylaxis. We compared the incidence of PRES in children with thalassemia (n=222, 1.4 to 17.8 years old) versus sickle cell disease (SCD; n=59, 2 to 17 years old) who underwent hematopoietic cell transplantation from HLA-matched siblings or alternative donors and analyzed the risk factors for PRES. Overall, 31 children developed calcineurin inhibitor-related PRES (11%), including 30 patients with seizures and 1 patient without seizures. PRES incidence was significantly higher in SCD patients (22%; 95% confidence interval [CI], 10% to 32%) than in thalassemia patients (8%; 95% CI, 5% to 12%;P=.002). In multivariate analysis, factors associated with PRES were hypertension (hazard ratio [HR], 5.87; 95% CI, 2.57 to 13.43; P=.0001), SCD (HR, 2.49; 95% CI, 1.25 to 4.99; P=.009), and acute GVHD (HR 2.27; 95% CI, 1.06 to 4.85; P=.031). In the entire cohort overall survival (OS) was significantly higher in patients without versus with PRES (90% versus 77%; P=.02). In a subgroup analysis that including matched sibling transplants, OS and disease-free survival (DFS) were similar in thalassemia patients without PRES (92% and 88%, respectively) and with PRES (82% and 73%, respectively), whereas SCD patients with PRES had significantly lower OS (67%) and DFS (67%) than patients without PRES (94% and 94%, respectively; P=.008). Thus, SCD patients had a significantly higher incidence of PRES than thalassemia patients, and hypertension and GVHD were the 2 main risk factors for PRES in patients with hemoglobinopathies. Although PRES did not significantly influence survival in patients with thalassemia, patients with SCD had significantly lower survival after PRES.