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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.
Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation
Penack, O., Marchetti, M., Aljurf, M., Arat, M., Bonifazi, F., Duarte, R. F., Giebel, S., Greinix, H., Hazenberg, M. D., Kröger, N., et al
The Lancet. Haematology. 2024
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Full text
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Editor's Choice
Abstract
Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic haematopoietic stem-cell transplantation (HSCT). In the last 3 years, there has been regulatory approval of new drugs and considerable change in clinical approaches to prophylaxis and management of GVHD. To standardise treatment approaches, the European Society for Blood and Marrow Transplantation (EBMT) has updated its clinical practice recommendations. We formed a panel of one methodologist and 22 experts in the field of GVHD management. The selection was made on the basis of their role in GVHD management in Europe and their contributions to the field, such as publications, presentations at conferences, and other research. We applied the GRADE process to ten PICO (patient, intervention, comparator, and outcome) questions: evidence was searched for by the panel and graded for each crucial outcome. In two consensus meetings, we discussed the evidence and voted on the wording and strengths of recommendations. Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD. The EBMT proposes to use these recommendations as the basis for routine management of GVHD during allogenic HSCT. The current recommendations favour European practice and do not necessarily represent global preferences.
PICO Summary
Population
Panel of 22 experts and one methdologist convened by the European Society for Blood and Marrow Transplantation (EBMT)
Intervention
Update of the EBMT consensus recommendations
Comparison
Outcome
Key updates to the recommendations include: (1) primary use of ruxolitinib in steroid-refractory acute GVHD and steroid-refractory chronic GVHD as the new standard of care, (2) use of rabbit anti-T-cell (thymocyte) globulin or post-transplantation cyclophosphamide as standard GVHD prophylaxis in peripheral blood stem-cell transplantations from unrelated donors, and (3) the addition of belumosudil to the available treatment options for steroid-refractory chronic GVHD.
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Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor
Paviglianiti, A., Ngoya, M., Peña, M., Boumendil, A., Gülbas, Z., Ciceri, F., Bonifazi, F., Russo, D., Fegueux, N., Stolzel, F., et al
Bone marrow transplantation. 2024
Abstract
Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III-IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed.
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4.
Outcomes of ATG-PTCY-CSA vs. ATG-based Prophylaxis for 10/10 HLA Matched Unrelated Donor Allogeneic Hematopoietic Cell Transplantation: ATG-PTCY-CsA for PB MUD allo-HCT
Queralt Salas, M., Alfaro-Moya, T., Atenafu, E. G., Datt Law, A., Lam, W., Pasic, I., Novitzky-Basso, I., Santos Carreira, A., Chen, C., Michelis, F. V., et al
Transplantation and cellular therapy. 2024
Abstract
In 2015, dual T-cell depletion with ATG and PTCY combined with CsA replaced our prior institutional GVHD prophylaxis composed by 4.5mg/kg of ATG, CsA, and MMF (ATG-based) in 10/10 HLA MUD peripheral blood allo-HCT. The initial ATG dose was 4.5mg/kg [ATG(4.5)/PTCY], and in 2018, was lowered to 2mg/kg [ATG(2)/PTCY]. This study compares the results obtained from 444 adults undergoing MUD allo-HCT at our institution who used ATG(4.5)/PTCY (n=127) and ATG(2)/PTCY (n=223) with those who used ATG-based prophylaxis without PTCY (n=84). Incidences of grades II-IV and III-IV aGVHD at day +100, and moderate/severe cGVHD at 1 year were: 35.7%, 21.6%, and 14.7% in patients receiving ATG-based without PTCY, 16.5%, 4.9%, and 4.3% in patients receiving ATG(4.5)/PTCY, and 23.3% (P=0.004), 8.0% (P<0.001), and 14.1% (P=0.006) in patients receiving ATG(2)/PTCY. One-year OS, NRM, and GRFS were 69.8% 25.3% and 52.0% for patients receiving ATG-based, 82.7%, 17.3%, and 59.8% for patients receiving ATG(4.5)/PTCY, and 78.3% (P=0.446), 14.7% (P=101), and 56.2% (P=0.448) for patients receiving ATG(2)/PTCY. On univariate analyses, using ATG(2)/PTCY was associated with a lower risk of NRM (HR 0.54, P=0.023) than using ATG-based. ATG(2)/PTCY prophylaxis effectively prevents GVHD, results in comparable relapse risk, OS, and GRFS than using ATG(4.5)/PTCY and ATG-based (without PTCY).
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Impact of post-transplant cyclophosphamide (PTCy)-based prophylaxis in matched sibling donor allogeneic haematopoietic cell transplantation for patients with myelodysplastic syndrome: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT
Salas, M. Q., Eikema, D. J., Koster, L., Maertens, J., Passweg, J., Finke, J., Broers, A. E. C., Koc, Y., Kröger, N., Ozkurt, Z. N., et al
Bone marrow transplantation. 2024
Abstract
We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n = 66) or other "conventional prophylaxis" (n = 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p = 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p = 0.011) and platelet (Day +100: 89% vs. 97%, p < 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p = 0.3), 13% (p = 0.4) and 31% (p = 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p = 0.6) and GRFS (33% vs. 25%, p = 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p = 0.06), not confirmed on multivariable analysis (p = 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p = 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p = 0.18), and there was no resultant effect on OS (HR 1.20, p = 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT.
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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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Cmv reactivations in allogeneic hematopoietic stem cell transplant from hla-matched and haploidentical donors with post-transplant cyclophosphamide
Chorão, P., Henriques, M., Villalba, M., Montoro, J., Balaguer-Roselló, A., González, E. M., Gómez, M. D., Gómez, I., Solves, P., Santiago, M., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Graft-versus-host disease prophylaxis (GVHD) with post-transplant cyclophosphamide (PTCy) is associated with an increased risk of CMV infections, with limited data on HSCT with PTCy assessing together matched sibling donors (MSD), matched unrelated donors (MUD), and haploidentical donors (HAPLO). OBJECTIVES Characterize CMV reactivation and recurrences, in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and HAPLO using PTCy as GVHD prophylaxis in the pre-letermovir era. Analyze risk factors of CMV reactivations, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. STUDY DESIGN We analyzed CMV reactivations in patients undergoing HSCT from 160 MSD, 124 MUD and 82 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type. RESULTS Overall, 46% of patients had at least one CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for HAPLO donors (p<0.001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including HAPLO donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age and grade II-IV acute GVHD remained the adverse factors for second CMV reactivation in multivariate analysis, but not type of donor. The 1-year cumulative incidence of third reactivation from HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the hazard for NRM was superior for patients who had a CMV reactivation in multivariate time-dependent Cox-model analysis. CONCLUSIONS CMV reactivation is frequent in HSCT with PTCy among patients not receiving letermovir prophylaxis. Identified risk factors include the use of HAPLO donor, recipient CMV seropositivity, and acute grade II-IV GVHD. The prevalence of recurrent CMV reactivations pose a noteworthy issue, especially after acute GVHD, warranting trials for secondary prophylaxis strategies.
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8.
Severity and organ distribution of chronic graft-versus-host disease with posttransplant cyclophosphamide-based versus methotrexate/calcineurin inhibitor-based allogeneic hematopoietic cell transplantation
Chhabra, S., Jerkins, J. H., Monahan, K., Szabo, A., Shah, N. N., Abedin, S., Runaas, L., Fenske, T. S., Pasquini, M. C., Shaw, B. E., et al
Bone marrow transplantation. 2024
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Full text
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Editor's Choice
Abstract
The reduced risk of chronic graft-versus-host-disease (GVHD) with posttransplant cyclophosphamide (ptCy) in the setting of haploidentical related donor and more recently, with HLA-matched related and matched and mismatched unrelated donor allogeneic transplantation has been established. There is, however, paucity of data to show if ptCy impacts chronic GVHD pathogenesis, its phenotype and evolution after HCT regardless of the donor status. We examined the differences in chronic GVHD incidence and presentation in 314 consecutive patients after receiving their first allogeneic transplantation (HCT) using ptCy-based GVHD prophylaxis (ptCy-HCT; n = 120; including 95 with haploidentical related donor) versus conventional calcineurin inhibitor-based prophylaxis (CNI-MUD; n = 194) between 2012 and 2019. The 1-year cumulative incidence of all-grade chronic GVHD and moderate/severe chronic GVHD was 24% and 12%, respectively, after ptCy-HCT and 40% and 23% in the CNI-MUD recipients (p = 0.0003 and 0.007). Multivariable analysis confirmed that use of CNI-based GVHD prophylaxis and peripheral blood stem cell graft as the risk factors for chronic GVHD. The cumulative incidence of visceral (involving ≥1 of the following organs: liver, lungs, gastrointestinal tract, serous membranes) chronic GVHD was significantly higher with CNI-MUD vs. ptCy-HCT (27% vs. 15% at 1 year, p = 0.009). The incidence of moderate/severe visceral chronic GVHD was 20% in CNI-MUD group vs. 7.7% in the ptCy-HCT group at 1 year (p = 0.002). In addition, significantly fewer ptCy-HCT recipients developed severe chronic GVHD in ≥3 organs (0.8%) vs. 8.8% in the CNI-MUD group at 1-year posttransplant (p = 0.004). There was no significant different in relapse, non-relapse mortality, and relapse-free and overall survival between the two groups. Further investigation is needed to confirm that reduced risk and severity of chronic GVHD, less visceral organ distribution with ptCy-HCT leads to improved quality of life.
PICO Summary
Population
Adults who received their first allogeneic transplantation at a single centre in USA with a matched unrelated donor or haploidentical donor (n=314)
Intervention
Post-transplant cyclophosphamide based GVHD prophylaxis (ptCy-HCT, n =120)
Comparison
Conventional calcineurin inhibitor-based prophylaxis (CNI-MUD, n=194)
Outcome
The 1-year cumulative incidence of all-grade chronic GVHD and moderate/severe chronic GVHD was 24% and 12%, respectively, after ptCy-HCT and 40% and 23% in the CNI-MUD recipients. Multivariable analysis confirmed that use of CNI-based GVHD prophylaxis and peripheral blood stem cell graft as the risk factors for chronic GVHD. The cumulative incidence of visceral (involving ≥1 of the following organs: liver, lungs, gastrointestinal tract, serous membranes) chronic GVHD was significantly higher with CNI-MUD vs. ptCy-HCT (27% vs. 15% at 1 year). The incidence of moderate/severe visceral chronic GVHD was 20% in CNI-MUD group vs. 7.7% in the ptCy-HCT group at 1 year. In addition, significantly fewer ptCy-HCT recipients developed severe chronic GVHD in ≥3 organs (0.8%) vs. 8.8% in the CNI-MUD group at 1-year posttransplant. There was no significant different in relapse, non-relapse mortality, and relapse-free and overall survival between the two groups.
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Impact of early cyclosporine A levels on acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation using in vivo T-cell depletion
Nikoloudis, A., Buxhofer-Ausch, V., Aichinger, C., Binder, M., Hasengruber, P., Kaynak, E., Wipplinger, D., Milanov, R., Strassl, I., Stiefel, O., et al
Cytotherapy. 2024
Abstract
BACKGROUND AIMS Cyclosporin A (CsA) remains a major component of immunosuppressive regimens applied in allogeneic hematopoietic stem cell transplantation (HSCT). The impact of CsA trough levels during the first weeks after HSCT has not yet been investigated specifically in anti-T-lymphocyte globulin (ATLG)-based HSCT from matched related and unrelated donors. METHODS To address this issue, we have retrospectively examined 307 consecutive matched related (n = 145) and unrelated (n = 162) HSCTs, using peripheral blood stem cells or bone marrow. HSCTs for active, uncontrolled malignancies were excluded. The initial three weeks' average mean CsA trough levels were analyzed in landmark and multi-state models, using a cut-off of 200 ng/mL. RESULTS CsA levels >200 ng/mL were associated with a reduced risk of acute graft-versus-host disease (GVHD) grade 3-4 at the first-week landmark (subdistribution hazard ratio [SHR] 0.59, P = 0.03) and the second-week landmark (SHR 0.48, P = 0.004), whereas there was no impact at the third-week landmark (HR 0.87, P = 0.69). This was supported by a multi-state model, in which week 1 (hazard ratio [HR] 0.53, P = 0.006) and week 2 (HR 0.48, P = 0.003), but not week 3 (HR 0.80, P = 0.44) CsA levels >200 ng/mL were associated with a reduced acute GVHD 3-4 risk. Relapse incidence was not significantly affected by week 1 through 3 CsA levels. Despite ATLG's inherent GVHD-preventive properties, week 1 CsA trough levels >200 ng/mL following ATLG-based HSCT (n = 220) were associated with a significantly reduced risk of non-relapse mortality (SHR 0.52, P = 0.02) and improved overall survival (HR 0.61, P = 0.02). CONCLUSIONS Our findings emphasize the continuing importance of ensuring CsA levels ≥200 ng/mL immediately post-transplant in the setting of ATLG-based HSCT.
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10.
Association between CYP3A4, CYP3A5 and ABCB1 genotype and tacrolimus treatment outcomes among allogeneic HSCT patients
Ho, T. T., Perkins, J. B., Gonzalez, R., Hicks, J. K., Martinez, R. A., Duranceau, K., North, B., Kim, J., Teer, J. K., Yao, J., et al
Pharmacogenomics. 2024
Abstract
Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.