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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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Outcomes following intolerance to calcineurin inhibitor-based graft-versus-host disease prophylaxis in children after allogeneic hematopoietic cell transplantation
Wu, D., Li, Y., Bi, Y., Lannom, T. M., Ward, D. A., Qudeimat, A., Madden, R. M., Sharma, A., Epperly, R., Mamcarz, E., et al
Pediatric blood & cancer. 2023;:e30517
Abstract
Calcineurin inhibitors (CNI), cyclosporine and tacrolimus, are commonly used for pharmacologic prophylaxis of graft-versus-host disease after allogeneic hematopoietic cell transplantation (HCT). Unfortunately, their use is associated with significant toxicities. While intolerance to CNI is well defined, there is very little information on how they impact outcomes after HCT in children. Our retrospective study in a cohort of 82 children shows a high intolerance rate of 39% in this population associated with lower event-free survival and a higher transplant-related mortality.
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Graft-Versus-Host Disease Prophylaxis with Post-Transplantation Cyclophosphamide versus Cyclosporine A and Methotrexate in Matched Sibling Donor Transplantation
Nagler, A., Labopin, M., Dholaria, B., Wu, D., Choi, G., Aljurf, M., Ciceri, F., Gedde-Dahl, T., Meijer, E., Niittyvuopio, R., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Cyclosporine A and methotrexate (CSA/MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplant cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myeloid leukemia (AML). In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%, p=0.039) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%, p=0.90) and 2-year chronic GVHD (42.6% versus 42.6%, p=0.84) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%, p=0.052), overall survival (OS, 70.6% versus 79.7%, p=0.15) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%, p=0.49) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
PICO Summary
Population
Patients who underwent matched sibling donor (MSD) allogeneic transplant for acute myeloid leukemia, (AML) reported to the EBMT registry (n=1320)
Intervention
Post-transplant cyclophosphamide (PTCy, n=118)
Comparison
Cyclosporine A and methotrexate (CSA/MTX, n=1202)
Outcome
In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2-year (41.1% versus 21.3%) compared to CSA/MTX. The incidence of day 180 grade II-IV acute GVHD (25.2% versus 25.4%) and 2-year chronic GVHD (42.6% versus 42.6%) were comparable between PTCy and CSA/MTX, respectively. Similarly, 2-year leukemia-free survival (LFS, 54.4% versus 74.32%), overall survival (OS, 70.6% versus 79.7%) and GVHD-free-relapse-free survival (GRFS, 38.1% versus 52.5%) were not statistically different between PTCy versus CSA/MTX. In conclusion, GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS compared to conventional CSA/MTX in patients undergoing allo-HCT from MSD. The higher relapse observed with PTCy needs further evaluation in a prospective study.
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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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A comparative study of porcine antihuman lymphocyte globulin versus antithymocyte globulin-fresenius in an allogeneic hematopoietic cell transplantation conditioning regimen for severe aplastic anemia
Zhang, Y., Liu, L., Si, Y., Miao, M., Qiu, H., Tang, X., Han, Y., Fu, C., Jin, Z., Chen, S., et al
Hematology (Amsterdam, Netherlands). 2021;26(1):741-750
Abstract
OBJECTIVES To compare the outcomes of antihuman T lymphocyte globulin (ATG-F) and porcine antihuman lymphocyte globulin (p-ALG) as part of a conditioning regimen in hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia (SAA). METHODS we performed a retrospective analysis, evaluating the outcome of patients with SAA who received ATG-F based conditioning (n?=?26) with those receiving p-ALG conditioning (n?=?34). RESULTS The median time to neutrophil engraftment was 11 days (range, 8?-?38) and 11 days (range, 9?-?24) in the p-ALG and ATG-F groups (P?=?0.857); the median platelet engraftment time was 15 (range, 9?-?330) days and 13 (range, 10?-?56) days (P?=?0.155). There were no significant differences in grades II?-?IV acute graft-versus-host disease (aGVHD), grades III?-?IV aGVHD, chronic GVHD (cGVHD), and the moderate-severe cGVHD between the ATG-F and p-ALG groups (P>0.05). DISCUSSION Patients in the ATG-F group functioned significantly better on role-physical (P?=?0.006), general health (P?=?0.029), and physical component summary (P?=?0.009). The estimated overall survival and failure free survival rates at 5 years were 88.5%?±?6.3% vs. 82.4%?±?6.5% (P?=?0.515), 84.6%?±?7.1% vs. 79.4%?±?6.9%, respectively (P?=?0.579). The infection rates were 61.53% and 47.05%, respectively (P?=?0.265). CONCLUSION As part of the conditioning regimen, p-ALG achieved a similar efficacy as ATG-F without increasing the incidence of transplantation complications in SAA patients.
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Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia
Nagler, A., Kanate, A. S., Labopin, M., Ciceri, F., Angelucci, E., Koc, Y., Gulbas, Z., Arcese, W., Tischer, J., Pioltelli, P., et al
Haematologica. 2020
Abstract
Graft-versus-host disease (GVHD) prophylaxis for unmanipulated haploidentical hematopoietic cell transplantation (haplo-HCT) include post-transplant cyclophosphamide (PTCy) and anti-thymocyte globulin (ATG). Utilizing EBMT registry, we compared ATG versus PTCy based GVHD prophylaxis in adult acute lymphoblastic leukemia (ALL) patients undergoing haplo-HCT. Included were 434 patients; ATG (n=98) and PTCy (n=336). Median follow-up was ~2 years. Baseline characteristics were similar between the groups except that the ATG-group was more likely to have relapsed/refractory ALL (P=0.008), non-TBI conditioning (P<0.001), peripheral blood graft source (P=<0.001) and transplanted at an earlier time-period (median year of HCT 2011 vs. 2015). The 100-day grade II-IV and III-IV acute-GVHD was similar between ATG and PTCy, as was 2-year chronic-GVHD. On multivariate analysis (MVA), leukemia-free survival (LFS) and overall survival (OS) was better with PTCy compared to ATG prophylaxis. Relapse incidence (RI) was lower in the PTCy group (P=0.03), while non-relapse mortality (NRM) was not different. Advanced disease and lower performance score were associated with poorer LFS and OS and advanced disease with inferior GVHD-free/relapse-free survival (GRFS). Peripheral grafts were associated with higher GVHD compared to bone marrow grafts. In ALL patients undergoing unmanipulated haplo-HCT, PTCy for GVHD prevention resulted in lower RI and improved LFS and OS compared to ATG.
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Comparison of two different rabbit antithymocyte globulin (r-ATG) preparations:Thymocyte r-ATG versus T lymphoblast cell line r-ATG in allogeneic hematopoietic stem cell transplantation for acquired severe aplastic anemia: propensity score-matched analysis
Liu, L., Xu, G., Zhang, Y., Jiao, W., Lei, M., Zhou, H., Wang, Q., Qiu, H., Tang, X., Han, Y., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
We retrospectively analyzed the outcomes of 214 severe aplastic anemia (SAA) patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with rabbit antithymocyte globulin (r-ATG) or ATG-Fresenius (ATG-F). Using propensity score matching, we performed a case-control study comparing 44 and 23 patients in the r-ATG and ATG-F groups, respectively. The median time for myeloid engraftment was 11 vs. 11 days (P?=?0.368) and for platelet engraftment was 11 vs. 13 days (P?=?0.030) in the r-ATG and ATG-F groups, respectively. The r-ATG group showed a lower incidence of grades III-IV acute graft-versus-host disease (aGVHD) than the ATG-F group (2.27% vs. 17.39%, P?=?0.026). Similar outcomes were observed between the r-ATG and ATG-F groups for infection rate (59.09% vs. 56.52%, P?=?0.840), grades II-IV aGVHD (20.45% vs. 21.74%, P?=?0.948), overall incidence of chronic GVHD (26.83% vs. 22.73%, P?=?0.704), moderate-severe chronic GVHD (9.76% vs. 13.64%, P?=?0.648), and transplantation-related mortality (11.36% vs. 4.35%, P?=?0.614). There was no statistical difference in 5-year overall survival (86.40% vs. 95.7%, P?=?0.245), GVHD-free, failure-free survival (77.30% vs. 78.30%, P?=?0.986), or health-related quality of life (P ? 0.05) between the r-ATG and ATG-F.
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Allogeneic peripheral blood stem cell transplantation with anti-thymocyte globulin versus allogeneic bone marrow transplantation without anti-thymocyte globulin
Baron, F., Galimard, J. E., Labopin, M., Yakoub-Agha, I., Niittyvuopio, R., Kroger, N., Griskevicius, L., Wu, D., Forcade, E., Richard, C., et al
Haematologica. 2019
Abstract
We compared severe graft-versus-host-disease free and relapse-free survival and other transplantation outcomes of acute myeloid leukemia patients given bone marrow without anti-thymocyte globulin, versus peripheral blood stem cells with anti-thymocyte globulin after myeloablative conditioning. In the cohort of patients receiving grafts from a human-leukocyte-antigen matched sibling donor, patients given peripheral blood stem cells with anti-thymocyte globulin (n=1,021) and those given bone marrow without anti-thymocyte globulin (n=1,633) presented comparable severe graft-versus-host-disease free and relapse-free (HR=0.9, 95% CI: 0.8-1.1, P=0.5) and overall (HR=1.0, 95% CI: 0.8-1.2, P=0.8) survival. They had however, a lower incidence of chronic graft-versus-host disease (HR=0.7, 95% CI: 0.6-0.9; P=0.01). In the cohort of patients receiving grafts from human-leukocyte-antigen matched unrelated donor, patients given peripheral blood stem cells with anti-thymocyte globulin (n=2,318) had better severe graft-versus-host-disease free and relapse-free survival than those given bone marrow without anti-thymocyte globulin (n=303) (HR=0.8, 95% CI: 0.6-0.9, P=0.001). They also had a lower incidence of chronic graft-versus-host disease (HR=0.6, 95% CI: 0.5-0.8, P=0.0006) and better overall survival (HR=0.8, 95% CI: 0.6-1.0, P=0.04). In summary, these data suggest that peripheral blood stem cells with anti-thymocyte globulin results in comparable (in the case of sibling donor) or significantly better (in the case of unrelated donor) severe graft-versus-host-disease free and relapse-free survival than bone marrow without anti-thymocyte globulin in patients with acute myeloid leukemia in complete remission receiving grafts after myeloablative conditioning.
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Comparison of the clinical outcomes of hematologic malignancies after myeloablative haploidentical transplantation with G-CSF/ATG and posttransplant cyclophosphamide: results from the Chinese Bone Marrow Transplantation Registry Group (CBMTRG)
Tang, F., Xu, Y., Chen, H., Xu, L., Zhang, X., Wang, Y., Liu, Q., Wu, D., Huang, X.
Science China. Life sciences. 2019
Abstract
This study compared G-CSF/ATG and PTCy in myeloablative haploidentical hematopoietic stem cell transplantation (haplo-HSCT) for hematologic malignancies between January 2013 and March 2018 reporting to the Chinese Bone Marrow Transplantation Registry Group (CBMTRG). For each PTCy, G-CSF/ATG subjects (1:4) were selected using the nested case-pair method. In total, 220 patients including 176 in G-CSF/ATG group and 44 in PTCy group were analyzed. The incidences of 30-day neutrophil engraftment (88.6% vs. 96.6%, P=0.001), 90-day platelet engraftment (84.1% vs. 94.2%, P=0.04), the median time to neutrophil engraftment (17 days vs. 12 days, P=0.000) and platelet engraftment (22 days vs. 17 days, P=0.001) were significantly inferior in PTCy group. The incidences of grades 2-4 and 3-4 acute graft-versus-host disease (GVHD), chronic GVHD and severe chronic GVHD were comparable. Among G-CSF/ATG and PTCy groups, the 3-year progression-free survival, overall survival, cumulative incidences of nonrelapse mortality and relapse was 74.3% vs. 61% (P=0.045), 78.3% vs. 65.2% (P=0.039), 12% vs. 27.3% (P=0.008), and 14.9% vs. 11.7% (P=0.61), respectively. G-CSF/ATG can achieve better engraftment, PFS and OS, and lower incidence of NRM compared to PTCy in myeloablative haplo-HSCT for hematologic malignancies.
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Haploidentical hematopoietic cell transplantation for severe acquired aplastic anemia: a case-control study of post-transplant cyclophosphamide included regimen vs. anti-thymocyte globulin & colony-stimulating factor-based regimen
Xu, L., Fu, B., Wang, W., Xu, Y., Wu, D., Wang, S., Liu, Q., Xia, L., Gao, S., Jiang, M., et al
Science China. Life sciences. 2019