-
1.
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.
-
2.
Factors affecting day-to-day variations in tacrolimus concentration among children and young adults undergoing allogeneic hematopoietic stem cell transplantation
Maruyama, Y., Maejima, Y., Hirabayashi, K., Morokawa, H., Okura, E., Saito, S., Nakazawa, Y.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Tacrolimus is widely used as prophylaxis for graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-HSCT). It has a narrow therapeutic index range. High tacrolimus concentrations are associated with toxicity, while low concentrations are associated with an increased risk of GVHD. Although dose adjustments based on therapeutic drug monitoring are performed, unexpected large variations in tacrolimus concentration are sometimes encountered. Thus far, the available evidence suggests that the factors affecting tacrolimus concentration are not fully understood. OBJECTIVES This study was primarily aimed at investigating the factors affecting day-to-day variations in tacrolimus concentration among children and young adults who received continuous tacrolimus infusion after allo-HSCT. The secondary objective was identifying the factors causing large variations (> 20%) in tacrolimus concentrations. STUDY DESIGN This was a retrospective cohort study of 123 consecutive pediatric and young adult patients, aged < 25 years, who received continuous intravenous tacrolimus infusion after allo-HSCT at Shinshu University Hospital, Matsumoto, Japan, between January 2009 and December 2021. To compare day-to-day variations in tacrolimus concentrations without consideration of the tacrolimus dose, two consecutive days when the tacrolimus dose was not changed were selected from the first day when the tacrolimus concentration was higher than 7 ng/mL after allo-HSCT to day 28 after allo-HSCT. Subsequently, information for the following 24-h was collected in addition to the tacrolimus concentrations and hematocrit values. Tacrolimus concentration was determined using whole blood samples. RESULTS Tacrolimus concentrations significantly increased in patients who received red blood cell concentrate (RCC) transfusion (p < 0.0001) and methotrexate (p = 0.0162), patients with persistent fever (p = 0.0056), and patients with a decline in fever (p = 0.0003). In contrast, tacrolimus concentrations decreased significantly in patients who received platelet concentrate (PC) transfusion (p < 0.0001), redeveloped fever (p = 0.0261), and received replaced tacrolimus administration route set (p = 0.0008). Variations in tacrolimus concentration significantly correlated with variations in hematocrit (r = 0.556, p < 0.0001). Body weight (p < 0.0001), RCC transfusion (p < 0.0001), methotrexate use (p = 0.0333), persistent fever (p = 0.0150), and decline in fever (p = 0.0073) were associated with a sharp increase in tacrolimus concentration. In contrast, body weight (p < 0.0001), PC transfusion (p = 0.0025), and replacement of the tacrolimus administration route set (p = 0.0025) were associated with a sharp decrease in tacrolimus concentration. CONCLUSIONS RCC and PC transfusions, fever, methotrexate administration, and replacement of the tacrolimus administration route set were independent factors affecting day-to-day variations in tacrolimus concentration. In addition to these factors, low body weight was a risk factor for both a sharp increase and decrease in tacrolimus concentration. These findings suggest the need for better control of tacrolimus concentrations using whole blood samples.
-
3.
Early recovery of myeloid-derived suppressor cells after allogeneic hematopoietic cells: comparison of post-transplantation cyclophosphamide to standard graft-versus-host disease prophylaxis
Oshrine, B., Innamarato, P., Branthoover, H., Nagle, L., Verdugo, P., Pilon-Thomas, S., Beatty, M.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (alloHCT) using haploidentical donors (haploHCT) with post-transplantation cyclophosphamide (PTCy) for augmented graft-versus-host disease (GVHD) prophylaxis has emerged as a robust platform to expand donor options with acceptable levels of GVHD and graft failure. The mechanism by which PTCy mitigates GVHD risk is partly explained by preferential cytotoxicity based on aldehyde dehydrogenase levels and up-regulation of regulatory T cells, but is incompletely understood. Myeloid-derived suppressor cells are important mediators of T-cell function and are up-regulated by cyclophosphamide exposure. OBJECTIVES We hypothesized that this cell type may play a role in GVHD protection in children undergoing haploHCT/PTCy. STUDY DESIGN We prospectively collected samples in the first month after alloHCT from children undergoing standard of care (SOC) alloHCT with matched donors and tacrolimus-based GVHD prophylaxis (N=11) and PTCy recipients (N=11). MDSC recovery was compared using flow cytometry, and MDSC suppressive function was assessed at the peak of MDSC quantitative recovery post-alloHCT. RESULTS Groups were well matched for conditioning regimen and stem cell source. PTCy recipients exhibited more robust MDSC recovery, particularly polymorphonuclear-MDSCs than SOC recipients, with preservation of T-cell suppressive function. This corresponded to significantly lower incidence of Grade II-IV acute GVHD (9.1% versus 27.3%) and moderate/severe chronic GVHD (0% versus 27.3%) in PTCy recipients. Patients who developed GVHD had decreased MDSC-mediated T-cell suppression, as well as higher levels of IL-10, a cytokine closely linked to GVHD biology. CONCLUSION Overall, these findings provide support for the role of MDSCs in mediating GVHD protection after PTCy-based haploHCT.
-
4.
Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients
Liu, X. L., Guan, Y. P., Wang, Y., Huang, K., Jiang, F. L., Wang, J., Yu, Q. H., Qiu, K. F., Huang, M., Wu, J. Y., et al
Frontiers in pharmacology. 2022;13:891648
Abstract
Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C(0)) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C(0) of 5-15 ng mL(-1). Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h(-1) (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg(-1) d(-1) (q12h), respectively. Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.
-
5.
Switching from Intravenous to Oral Tacrolimus Reduces its Blood Concentration in Paediatric Cancer Patients
Ujiie, H., Nihei, S., Nishiya, N., Goto, S., Asakura, Y., Miura, S., Hirai, D., Endo, M., Oyake, T., Ito, S., et al
Anticancer research. 2021;41(5):2591-2596
Abstract
BACKGROUND/AIM: Tacrolimus is an essential immunosuppressant for successful allogeneic haematopoietic stem cell transplantation (Allo-HSCT). This study aimed to examine the change in the blood concentration of tacrolimus during switching from intravenous to oral administration in allo-HSCT for paediatric cancer to predict the optimal dosage. PATIENTS AND METHODS We retrospectively examined the medical records of 63 patients who received allo-HSCT and were administered tacrolimus. To compare bioavailability among different dose ranges, the blood concentration was divided by the dose (C/D). RESULTS Thirty-nine patients (age range=children 1-15 years, adults 17-67 years) were switched to oral administration of tacrolimus. The C/D after switching was significantly lower in children than in adults (p=0.039). There was a strong positive correlation between age and C/D in children, whereas no correlation was observed in adults. CONCLUSION In paediatric cancer patients, switching tacrolimus administration route may result in reduced blood concentrations. This tendency is more prominent in younger children.
-
6.
Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients
Carlone, G., Simeone, R., Baraldo, M., Maestro, A., Zanon, D., Barbi, E., Maximova, N.
Journal of clinical medicine. 2021;10(3)
Abstract
Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC(0-12). We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = -0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC(0-12) concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.
-
7.
Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD
Watkins, B., Qayed, M., McCracken, C., Bratrude, B., Betz, K., Suessmuth, Y., Yu, A., Sinclair, S., Furlan, S., Bosinger, S., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;:Jco2001086
-
-
-
Free full text
-
-
Editor's Choice
Abstract
PURPOSE Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.
PICO Summary
Population
Adults and children with haematologic malignancies enrolled in the ABA2 trial (n=185)
Intervention
8/8 matched unrelated donor transplantation with CNI/MTX plus abatacept prophylaxis (abatacept, n=73)
Comparison
CNI/MTX plus placebo (placebo, n=69); non-randomised cohort: 7/8 mismatched unrelated donor (7/8, n=43)
Outcome
ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%), and the SGFS was better (97.7% v 58.7%). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients.
-
8.
Evaluating risk factors for acute graft versus host disease in pediatric hematopoietic stem cell transplant patients receiving tacrolimus
Phan, M., Chavan, R., Beuttler, R., Benipayo, N., Magedman, G., Buchbinder, D., Tomaszewski, D., Yang, S.
Clinical and translational science. 2021
Abstract
To identify the clinical and pharmacological risk factors associated with tacrolimus pharmacodynamics for acute GVHD (aGVHD) in pediatric patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) from a matched related donor. A retrospective cohort single center chart review study was conducted with pediatric patients who received tacrolimus prophylaxis after allogeneic HSCT between 01/01/2017 and 12/31/2019. Potential risk factors were tested separately between aGVHD and non-aGVHD cohorts and were further analyzed in a logistic regression model with backwards elimination and a partial least squares discriminant analysis. Thirty-three patient cases were included in our study and 52% (17/33) developed aGVHD while on tacrolimus prophylaxis. When tested independently, donor age and sibling versus parent donor/recipient relation were shown statistically significant between aGVHD and non-aGVHD patients (p<0.005). Pharmacological factors associated with tacrolimus treatment failed to demonstrate a significant impact on patient's risk of aGVHD. Using a best fit logistic regression model that tested all the variables together, donor age was the only significant variable predicting patient's risk of aGVHD (p<0.01). Donor relationship and donor age were unable to be evaluated separately and are therefore confounding variables. Among pediatric patients receiving allogeneic HSCT, aGVHD risk is significantly decreased by either sibling donor and/or younger donors. While no conclusions were drawn on the effect of tacrolimus therapy (p=0.08), results warrant additional research with a larger sample size to evaluate the accuracy of monitoring tacrolimus serum trough levels.
-
9.
Pediatric acute graft-versus-host disease prophylaxis and treatment: Real-life approach reveals dissimilarities compared to published recommendations
Lawitschka, A., Lucchini, G., Strahm, B., Dalle, J. H., Balduzzi, A., Gibson, B., Diaz De Heredia, C., Wachowiak, J., Dalissier, A., Vettenranta, K., et al
Transplant international : official journal of the European Society for Organ Transplantation. 2020
Abstract
Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable non-malignant diseases and the lower incidence of Graft-versus-Host-Disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with ≥75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: single-agent cyclosporine A (CsA) was used for matched-sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in non-malignant diseases. Most centers used additional anti-thymocyte globulin for matched-unrelated and mismatched donor HCT, but not for matched-siblings. Regarding prophylaxis in non-myeloablative conditioning (mainly for non-malignant diseases) responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches towards aGVHD prophylaxis/treatment differentiated for malignant and non-malignant underlying diseases.
-
10.
Haploidentical stem cell transplant with post-transplantation cyclophosphamide and mini-dose methotrexate in children
Medina, D., Estacio, M., Rosales, M., Manzi, E.
Hematology/oncology and stem cell therapy. 2020
Abstract
BACKGROUND Haploidentical stem cell transplantation (haplo-SCT) is an option for patients without human leukocyte antigen-matched related or unrelated donor. Post-transplantation cyclophosphamide (PTCy) is an effective method of graft versus host disease (GVHD) prophylaxis and permits the use of T-cell replete grafts in settings were ex vivo manipulation is not feasible. METHODS A retrospective study among patients younger than 18 years, with a history of hematologic malignancies who underwent haplo-SCT between 2012 and 2016. All patients received a preparative regimen of fludarabine, busulfan, and 400 cGy total body irradiation or melphalan. Post-transplant GvHD prophylaxis consisted either of PTCy (50 mg/kg on Days + 3 and + 4) and cyclosporine (CSA) plus mycophenolate (MMF) (15 mg/kg/dose, thrice daily, per os), or mini-dose methotrexate (MTX; 5 mg/m(2) dose) on Days + 5, +7, +10, and + 15. RESULTS A total of 52 children were included, whose median age was 9 years (interquartile range, 4.9-14; range, 1.2-17 years), and 63% were males. The most common complications were cytomegalovirus reactivation (57%) and hemorrhagic cystitis (36%). The acute GVHD prophylaxis was PTCy, CSA, and mini-dose MTX in 42 (81%) patients, and 10 (19%) patients received PTCy, CSA, and MMF. The cumulative incidence of acute GvHD II-IV, acute GvHD III-IV, and chronic GvHD were 42%, 8.5%, and 19%, respectively. Grades I-IV acute GvHD occurred in 100% of the patients who received prophylaxis with CSA and MMF, and 62% who received CSA and mini-dose MTX (p = .055). The transplant-related mortality at 100 days was 18%. The 5-year overall and event-free survival were 59% and 57%, respectively. CONCLUSIONS Haplo-SCT with PT/Cy can be an available, safe, and feasible option for children with hematologic malignancies; meanwhile, the use of mini-dose of MTX was associated with lower rates of acute GVHD. However, our results require further support from prospective randomized studies to improve the efficacy of this prophylactic strategy.