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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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3.
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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4.
Exposure-response analysis of alemtuzumab in pediatric allogeneic HSCT for nonmalignant diseases: the ARTIC study
Achini-Gutzwiller, F., Schilham, M. W., von Asmuth, E. G. J., Jansen-Hoogendijk, A., Jol-van der Zijde, C. M., van Tol, M. J. D., Bredius, R. G., Güngör, T., Lankester, A. C., Moes, D. J.
Blood advances. 2023
Abstract
Alemtuzumab (anti-CD52 antibody) is frequently prescribed to children with non-malignant diseases undergoing allogeneic hematopoietic stem cell transplantation (HSCT) to prevent graft failure (GF) and acute graft-versus-host disease (aGvHD). This multicenter study aimed at the characterization of alemtuzumab population pharmacokinetics to perform a novel model-based exposure-response analysis in 53 children with non-malignant immunological or hematological disease and a median age of 4.4 years (IQR 0.8, 8.7). Median cumulative alemtuzumab dose was 0.6 mg/kg (IQR 0.6-1) administered over 2-7 days. A 2-compartment population pharmacokinetic model with parallel linear and non-linear elimination including allometrically scaled bodyweight [median 17.50 kg (IQR 8.76, 33.00)] and lymphocyte count at baseline [mean 2.24 10*9/L (SD 1.87)] as significant pharmacokinetic predictors was developed using non-linear mixed effects modelling (NONMEM). According to the model estimated median concentration at day of HSCT (0.77 µg/mL, IQR 0.33-1.82), patients were grouped into a low (0.77 µg/mL) exposure group. High alemtuzumab exposure at day of HSCT correlated with delayed CD4+ and CD8+ T-cell reconstitution (p-value <0.0001) and increased risk of graft failure (p-value=0.043). In contrast, alemtuzumab exposure did not significantly influence the incidence of aGvHD ≥ grade II, mortality, chimerism at 1-year, viral reactivations and autoimmunity at a median follow-up of 3.3 years (IQR 2.5-8.0). In conclusion, this novel population PK model is suitable for individualized intravenous precision dosing to predict alemtuzumab exposure in pediatric allogeneic HSCT for non-malignant diseases, aiming at the achievement of early T-cell reconstitution and prevention of graft failure in future prospective studies.
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5.
Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia
Alsultan, A., Abujoub, R., Alsudairy, R., Memon, S., Jarrar, M. S., Alafghani, S., Aldaama, S., Ballourah, W., Almanjomi, F., Essa, M. F.
British journal of haematology. 2023
Abstract
When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.
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6.
Impact of Conditioning Regimen and Graft-versus-Host Disease Prophylaxis on The Outcome of Haploidentical Peripheral Blood Stem Cell Transplantation for High-Risk Severe Aplastic Anaemia in Children and Young Adults: A Report from the Pediatric
Kharya, G., Jaiswal, S. R., Bhat, S., Raj, R., Yadav, S. P., Dua, V., Sen, S., Bakane, A., Badiger, S., Uppuluri, R., et al
Transplantation and cellular therapy. 2022
Abstract
Allogenic hematopoietic cell transplant (HCT) is the best curative approach patients with severe aplastic anemia (SAA). Outcome of HCT from haploidentical family donor (HFD) has improved, making it a feasible option for patients lacking HLA-identical donor. However, data on HFD-HCT for younger patients with SAA is sparse. In multicentre retrospective study, we report outcome of 79 patients undergoing HFD-HCT for SAA. All were heavily pre-transfused, median time to HCT >12 months and 67% had failed previous therapies. Conditioning was based on Flu-Cy-ATG/TBI with or without thiotepa/melphalan (TT/Mel). Post-transplantation cyclophosphamide (PTCy) and CNI/Sirolimus were employed as GvHD prophylaxis with or without abatacept. Primary graft failure (PGF) was 16.43%, less in those conditioned with TT/Mel. Incidence of acute and chronic GVHD were 26.4% and 18.9%. At a median follow-up of 48 months, the overall survival (OS) and event free survival (EFS) were 61.6% and 58.1% respectively. Both OS/EFS were better in TT/Mel group and with abatacept as GVHD prophylaxis. On multivariate analysis, use of Abatacept was found to favourably impact the outcome variables including GVHD and EFS. Our study suggests that PTCy-based HFD-HCT is a reasonable option for young patients with high-risk SAA, where optimisation of conditioning and GVHD prophylaxis might improve outcomes further.
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7.
Assessing the Efficacy of Alkylating Agent Regimens in the Treatment of Infantile Malignant Osteopetrosis: Cyclophosphamide, Busulfan, or Thiotepa
Wagh, H., Arif, A., Reddy, A. J., Tabaie, E., Shekhar, A., Min, M., Nawathey, N., Bachir, M., Brahmbhatt, H.
Cureus. 2022;14(7):e26600
Abstract
Infantile malignant osteopetrosis is a debilitating disease that requires total bone marrow irradiation and transplant procedures for patients to survive. The major complication of this procedure is graft vs host disease (GVHD), followed by infections and end organ toxicity. Therefore, current research efforts into treatment mainly aim to reduce GVHD while limiting infections and organ toxicity. Different regimens of alkylating agents have been used to try to reduce GVHD. The most common regimen is cyclophosphamide (Cy) with busulfan (Bu), followed by Cy with Bu and thiotepa (Thio). This meta-analysis aimed to evaluate the efficacy of different treatments by comparing mortality and morbidity causes and rates across groups. The mean one-year survival rate for the Cy, Bu, Thio regimen studies in the human leukocyte antigen (HLA) unmatched group (45.01%) was statistically lower than the one-year survival rate for the studies using just a Cy, Bu regimen (70.8%) in the HLA unmatched studies (p<0.00142). The one-year survival in the studies which had HLA-matched donors was 80.56%, which is statistically higher (p<0.001) than the one-year survival in the HLA-unmatched studies (53.96%), indicating a benefit of finding HLA-matched donors. It seems that price and availability could be a factor in the widespread use of Cy.
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8.
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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9.
Clinical study of graft-versus-host disease prophylaxis in unrelated hematopoietic stem cell transplantation for pediatric nonmalignant diseases with different doses anti-human T-lymphocyte immunoglobulin
Atay, D., Akcay, A., Yenigurbuz, F. D., Akinci, B., Bagirova, K., Hasanova, S., Ozturk, G.
Pediatric transplantation. 2021;:e14098
Abstract
BACKGROUND Anti-human T-lymphocyte immunoglobulin is commonly used as prophylaxis for graft-versus-host disease after allogeneic hematopoietic stem cell transplantation from unrelated donors. The studies according to optimum dose of ATLG especially in pediatric patients are limited. PATIENTS AND METHODS Outcomes of 99 pediatric patients diagnosed with nonmalignant diseases, who received ATLG as GVHD prophylaxis for matched unrelated donor HSCT at a dose of 10 mg/kg (group 1), 20 mg/kg (group 2), and 30 mg/kg (group 3), were analyzed retrospectively. RESULTS The incidences of acute and chronic GVHD were statistically not different between three groups (p = .20 and p = .13), but we did not observe chronic GVHD in group 3 patients. Cox regression analysis showed that ATLG dose of 10 mg/kg (p = .007) and severe acute GVHD (p = .001) were significant prognostic factors for inferior overall survival. Although ATLG dose of 10 mg/kg is effective in pediatric patients on acute and chronic GVHD prevention, TRM and overall survival were superior in ATLG doses =20 mg/kg (p = .04 and p = .037) with no difference between 20 and 30 mg/kg. CONCLUSION Although ATLG dose of 10 mg/kg is effective in pediatric patients on acute and chronic GVHD prevention and safe from the point of infection, TRM and OS were superior in ATLG doses =20 mg/kg with no difference between 20 and 30 mg/kg. These observations should be supported with other multicenter prospective studies including larger patient population.
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10.
Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate
Yang, K., Gong, S., Jiang, T., Liang, X., Hu, J., Zhu, P., Nie, L., Xu, Y., Fu, B.
Transplantation and cellular therapy. 2021;27(5):429.e1-429.e7
Abstract
Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.