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1.
Post-transplant сyclophosphamide after matched donor hematopoietic stem cell transplantation in children with acute leukemia
Borovkova, A. S., Paina, O. V., Semenova, E. V., Bykova, T. A., Osipova, A. A., Slesarchuk, O. A., Kozhokar, P. V., Tsvetkova, L. A., Rakhmanova, Z. Z., Kozlov, A. V., et al
Clinical transplantation. 2023;:e15181
Abstract
INTRODUCTION The data on post-transplant cyclophosphamide (PTCy) in pediatric acute leukemia after matched allo-HSCT are limited to case series. The present study aimed to assess the results of PTCy-based GVHD prophylaxis in a large cohort of children with acute leukemia after matched allo-HSCT. METHODS A retrospective analysis of 190 pediatric patients with acute leukemia who had a first allograft between 2008 and 2020 from a matched sibling donor (MSD) or matched unrelated donor (MUD) was carried out. In the MSD setting, GVHD prophylaxis consisted of PTCy alone (n = 28) for the study group, and calcineurin inhibitor (CNI) ± antimetabolite (n = 30) for the control group. In MUD setting, most patients in the study group received GVHD prophylaxis with PTCy+CNI+mycophenolate mofetil (n = 42, 66.7%) or PTCy+CNI+sirolimus (n = 12, 19%). All patients (n = 69) in the control group received ATG+CNI+antimetabolite. RESULTS After MUD allo-HSCT, the incidences of acute GVHD grade III-IV and moderate/severe chronic GVHD were significantly lower in the PTCy group compared to control (6.6% vs. 35.0% and 12.7% vs. 47.1%, respectively, p < .0001). Five-year GVHD-free, relapse-free survival (GRFS) after MUD allo-HSCT was higher in the PTCy group compared to control (35.1% vs. 7.3%, p < .0001). At the same time, there was no significant difference between both groups after MSD allo-HSCT. CONCLUSIONS In pediatric acute leukemia, PTCy-based GVHD prophylaxis for MUD allo-HSCT is a feasible and effective option that results in a low incidence of GVHD. Compared to the ATG-based approach, PTCy provides better control of GVHD in children. In pediatric allo-HSCT from MSD, PTCy demonstrates comparable effectiveness to conventional GVHD prophylaxis.
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2.
Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients
Elnaggar, M., Hafez, H., Abdallah, A., Hamza, M., Khalaf, M. M., El-Haddad, A.
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231192516
Abstract
BACKGROUND/OBJECTIVES Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. PATIENTS AND METHODS This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. RESULTS There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. CONCLUSION This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.
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3.
Lower levels of cyclosporine between days 0 and +21 may reduce later relapses without increasing graft-versus-host disease in children and adolescents with acute lymphoblastic leukemia who undergo myeloablative TBI-based allogeneic hematopoietic cell transplantation
Arcuri, L. J., Lerner, D., Tavares, Rcbds
European journal of haematology. 2022
Abstract
BACKGROUND The degree of immunosuppression required for adequate graft-versus-host disease (GVHD) prevention, while keeping an adequate graft-versus-leukemia effect, in children with acute leukemia has not been established. We report the results of a retrospective comparison of cyclosporine levels and relapse rate in children and adolescents with acute lymphoblastic leukemia (ALL). METHODS Patients<21 y/o with ALL in remission who underwent TBI-based hematopoietic cell transplantation from related or unrelated donors between 2008 and 2021 were included. Cyclosporine levels were measured twice a week and we calculated the area under the curve (AUC) from D0 to D+7, D+14, and D+21. RESULTS We included 76 patients. There was a trend towards a lower incidence of relapse in patients with a mean AUC<200 ng/mL at D+21 (HR=0.41; p=0.08). The five-year relapse rate was 26.9% for patients with a mean AUC<200 ng/mL at D+21 and 43.9% for patients with a mean AUC≥200 ng/mL at D+21. Relapse protection was restricted to relapses happening after D+120 (HR=0.21; p=0.04). CONCLUSIONS Our results show evidence that pediatric patients with ALL might benefit from lower cyclosporine levels between D0 and D+21 without a detectable increase in GVHD. Large prospective studies comparing different cyclosporine levels are awaited.
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4.
Impact of posttransplant cyclophosphamide on the outcome of patients undergoing unrelated single-unit umbilical cord blood transplantation for pediatric acute leukemia
Li, X. Y., Zhan, L. P., Liu, D. D., Han, X. W., Chen, H., Wu, Z. Z., Wang, Y., Que, L. P., Wu, X. J., Liu, S., et al
BMC cancer. 2022;22(1):1190
Abstract
BACKGROUND Umbilical cord blood transplantation (UCBT) from unrelated donors is one of the successful treatments for acute leukemia in childhood. The most frequent side effect of UCBT is peri-engraftment syndrome (PES), which is directly associated with the greater prevalence of acute and chronic graft-versus-host-disease (aGvHD and cGvHD). In haploidentical stem cell transplantation, posttransplant cyclophosphamide (PTCY) has been demonstrated to be an effective method against GvHD. However, the effects of PTCY as a GvHD prophylactic in UCBT had not been investigated. This study aimed to evaluate the effects of PTCY on the outcomes of UCBT for pediatric acute leukemia. METHODS This retrospective study included 52 children with acute leukemia who underwent unrelated single-unit UCBT after myeloablative conditioning regimens. The results from the PTCY and non-PTCY groups were compared. RESULTS The incidence of transplantation-related mortality in non-PTCY and PTCY were 5% and 10% (p = 0.525), respectively. The incidence of relapse in non-PTCY and PTCY were 5% and 23% (p = 0.095), respectively. Second complete remission status (CR2) was an independent risk factor for relapse-free survival (hazard ratio = 9.782, p = 0.001). The odds ratio for sepsis or bacteremia incidence was significantly greater in the PTCY group (9.524, p = 0.017). PTCY group had increased rates of cytomegalovirus activity and fungal infection. The incidence of PES, aGvHD, cGvHD, and hemorrhagic cystitis in the PTCY group was lower than that in the non-PTCY group, although it was not significantly different. Additionally, higher doses of PTCY (29 mg/kg and 40 mg/kg) were associated with lower incidences of aGvHD and severe GvHD (65% and 29%, respectively) than lower doses (93% and 57%, respectively). Engraftment time and graft failure incidence were similar across groups. CONCLUSION The results support the safety and efficiency of PTCY as part of PES controlling and GvHD prophylaxis in single-unit UCBT for children with acute leukemia. A PTCY dosage of 29 mg/kg to 40 mg/kg appears to be more effective in GvHD prophylaxis for UCBT patients.
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5.
Outcomes of Unmanipulated Haploidentical Transplantation Using Post-Transplant Cyclophosphamide (PT-Cy) in Pediatric Patients With Acute Lymphoblastic Leukemia
Ruggeri, A., Galimard, J. E., Paina, O., Fagioli, F., Tbakhi, A., Yesilipek, A., Navarro, J. M. F., Faraci, M., Hamladji, R. M., Skorobogatova, E., et al
Transplantation and cellular therapy. 2021;27(5):424.e1-424.e9
Abstract
HLA-haploidentical transplantation (haplo-HCT) using post-transplantation-cyclophosphamide (PT-Cy) is a feasible procedure in children with malignancies. However, large studies on Haplo-HCT with PT-Cy for childhood acute lymphoblastic leukemia (ALL) are lacking. We analyzed haplo-HCT outcomes in 180 children with ALL. Median age was 9 years, and median follow-up was 2.7 years. Disease status was CR1 for 24%, CR2 for 45%, CR+3 for 12%, and active disease for 19%. All patients received PT-Cy day +3 and +4. Bone marrow (BM) was the stem cell source in 115 patients (64%). Cumulative incidence of 42-day engraftment was 88.9%. Cumulative incidence of day-100 acute graft-versus-host disease (GVHD) grade II-IV was 28%, and 2-year chronic GVHD was 21.9%. At 2 years, cumulative incidence of nonrelapse mortality (NRM) was 19.6%. Cumulative incidence was 41.9% for relapse and 25% for patients in CR1. Estimated 2-year leukemia free survival was 65%, 44%, and 18.8% for patients transplanted in CR1, CR2, CR3+ and 3% at 1 year for active disease. In multivariable analysis for patients in CR1 and CR2, disease status (CR2 [hazard ratio {HR} = 2.19; P = .04]), age at HCT older than 13 (HR = 2.07; P = .03) and use of peripheral blood stem cell (PBSC) (HR = 1.98; P = .04) were independent factors associated with decreased overall survival. Use of PBSC was also associated with higher NRM (HR = 3.13; P = .04). Haplo-HCT with PT-Cy is an option for children with ALL, namely those transplanted in CR1 and CR2. Age and disease status remain the most important factors for outcomes. BM cells as a graft source is associated with improved survival.
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6.
Efficacy of low dose antithymocyte globulin on overall survival, relapse rate, and infectious complications following allogeneic peripheral blood stem cell transplantation for leukemia in children
Kang, H. M., Kim, S. K., Lee, J. W., Chung, N. G., Cho, B.
Bone marrow transplantation. 2020
Abstract
Antithymocyte globulin (ATG) and anti-T lymphocyte globulin (ATLG) have been widely used to prevent graft-versus-host disease (GvHD), each with distinct properties and noninterchangeable doses. However, the optimal dose of ATG in children undergoing allo-PBSCT for leukemia has not yet been established. Therefore, the impact of ATG dose on overall survival (OS), relapse, GvHD, and infectious complications was investigated. Patients administered high dose (unrelated: 7.5?mg/kg, haploidentical: 10.0?mg/kg) and low dose (unrelated: 3.75?mg/kg, haploidentical: 5.0?mg/kg) ATG during two consecutive time periods were compared. There were 78 (39.8%) patients in the low dose group and 118 (60.2%) in the high dose group. OS was superior in the low dose group compared to the high dose group (P?=?0.017), and relapse incidence was significantly lower in the low dose group (P?=?0.022). Cumulative incidences of acute and chronic GvHD were similar between the groups (P?=?0.095 and P?=?0.672, respectively). Cytomegalovirus reactivation (70.3% vs. 51.3%, P?=?0.007), Epstein-Barr virus reactivation (81.4% vs. 39.7%, P?0.001), and invasive bacterial infections (12.7% vs. 0%, P?=?0.001) post transplant were more frequent in the high dose group compared to the low dose group. Therefore, low dose ATG is more optimal in pediatric allo-PBSCT providing better OS while lowering the risk of relapse and infectious complications.
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7.
Control of graft-versus-host disease with rabbit anti-thymocyte globulin, rituximab, and bortezomib in TCRalphabeta/CD19-depleted graft transplantation for leukemia in children: a single-center retrospective analysis of two GVHD-prophylaxis regimens
Shekhovtsova, Z., Shelikhova, L., Balashov, D., Zakharova, V., Ilushina, M., Voronin, K., Kurnikova, E., Muzalevskii, Y., Kazachenok, A., Pershin, D., et al
Pediatric transplantation. 2019;:e13594
Abstract
Both acute GVHD and chronic GVHD remain the leading cause of morbidity and death after allogeneic HSCT. We conducted a retrospective analysis comparing two GVHD-prophylaxis regimens: 35 patients received "Regimen 1" (horse ATG, tacrolimus, and methotrexate) and 46 "Regimen 2" (rabbit ATG, rituximab, and peritransplant bortezomib). All 81 patients with a median age of 9 (0.6-23) years with ALL (n = 31) or AML (n = 50) in complete remission received TCRalphabeta/CD19-depleted transplants between May 2012 and October 2016, from 40 HLA-matched unrelated and 41 haploidentical donors. After a median follow-up of 3.9 years, the CI of acute GVHD II-IV was 15% (95% CI: 7-30) in the "Regimen 2" group and 34% (95% CI: -54) in the "Regimen 1" group, P = .05. "Regimen 2" was also more effective in the prevention of chronic GVHD; the CI at 1 year after HSCT was 7% (95% CI: 2-19) vs 31% (95% CI: 19-51), P = .005. The CI of relapse at 3 years adjusted for the GVHD-prophylaxis regimen groups 31% (95% CI: 19-51) for the "Regimen 1" vs 21% (95% CI: 11-37) for the "Regimen 2", P = .3. The retrospective observation suggests that the use of the rATG, rituximab, and bortezomib was associated with significantly lower rate of GVHD without the loss of anti-leukemic activity.
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8.
Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation
Oostenbrink, L. V. E., Jol-van der Zijde, C. M., Kielsen, K., Jansen-Hoogendijk, A. M., Ifversen, M., Muller, K. G., Lankester, A. C., van Halteren, A. G. S., Bredius, R. G. M., Schilham, M. W., et al
Frontiers in immunology. 2019;10:315
Abstract
Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6-10 mg/kg; ATG-FRES at 45-60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6-8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III-IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.
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9.
T-cell-replete haploidentical stem cell transplantation using low-dose antithymocyte globulin in children with relapsed or refractory acute leukemia
Sano, H., Mochizuki, K., Kobayashi, S., Ohara, Y., Ito, M., Waragai, T., Takahashi, N., Ikeda, K., Ohto, H., Kikuta, A.
International journal of hematology. 2018
Abstract
We evaluated the efficacy and toxicity of T-cell-replete haploidentical stem cell transplantation (TCR-haploSCT) using low-dose antithymocyte globulin (ATG) in children with refractory/relapsed (R/R) acute leukemia. From October 2009 to April 2016, 39 consecutive patients with R/R acute leukemia who underwent TCR-haploSCT were included. At the time of TCR-haploSCT, 17 patients were in complete remission (CR), but 22 had active disease. Thirty-three patients received a myeloablative regimen and six received a reduced-intensity conditioning regimen. Graft-versus-host disease (GvHD) prophylaxis comprised tacrolimus, methotrexate, prednisolone, and low-dose ATG (thymoglobulin 2.5 mg/kg). Neutrophil engraftment (> 0.5 x 10(9)/L) was 95% after a median of 13 days. The median follow-up period was 527 days, with mean 3-year overall and disease-free survival rates of 45.1% [standard deviation (SD), +/- 8.5%) and 33.8% (SD, +/- 7.9%), respectively. The cumulative incidence of acute GvHD was 73.0%, but that of grade III-IV acute GvHD was 34.1%. The 3-year cumulative incidences of relapse and transplant-related mortality were 50.3 and 15.9%, respectively. Age < 10 years at transplantation was associated with a better overall survival in the multivariate analysis. These data suggest that TCR-haploSCT using a low-dose ATG combined with the GvHD prophylaxis described here has a significant anti-leukemic activity, particularly in younger patients.
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10.
Influence of Age on Acute and Chronic GVHD in Children Receiving HLA-Identical Sibling BMT for Acute Leukemia: Implications for Prophylaxis
Qayed, M., Wang, T., Hemmer, M. T., Spellman, S., Arora, M., Couriel, D., Alousi, A., Pidala, J., Abdel-Azim, H., Aljuf, M., et al
Biology of Blood & Marrow Transplantation. 2017
Abstract
Relapse remains the major cause of mortality post hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research suggests that reducing the intensity of calcineurin inhibitor based graft versus host disease (GVHD) prophylaxis may be an effective strategy in abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk for GVHD, to risk stratify patients based on age. Patients <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 entered into the Center for International Blood and Marrow Transplant Research registry were included. Cumulative incidence of grade 2-4 acute GVHD was 19%, grade 3-4 acute GVHD 7%, and chronic GVHD 16%. Compared to age 13-18 years, age 2-12 years was associated with a lower risk for grade 2-4 acute GVHD (hazard ratio [HR] 0.42, confidence interval [CI] 0.26-0.70, p=0.0008), grade 3-4 acute GVHD (HR 0.24, CI 0.1-0.56, p=0.001) and chronic GVHD (HR 0.32, CI 0.19-0.54, p<0.001). The risk of grade 2-4 acute GVHD was lower for children undergoing transplantation in 2005-2008 (HR 0.36, CI 0.2-0.65, p=0.0007), and 2009-2013 (HR 0.24, CI 0.11-0.53, p=0.0004) compared to 2000-2004. Similarly, the risk of grade 3-4 acute GVHD was lower for children undergoing transplantation in 2005-2008 (HR 0.23, CI 0.08-0.65, p=0.0056) and 2009-2013 (HR 0.16, CI 0.04-0.67, p=0.0126) compared to 2000-2004. We conclude that acute GVHD rates have decreased significantly over time, and children 2-12 years are at very low risk for acute and chronic GVHD. These results should be validated in an independent analysis, as these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis. Copyright © 2017. Published by Elsevier Inc.