Differential Elimination of Anti-Thymocyte Globulin of Fresenius and Genzyme Impacts T-Cell Reconstitution After Hematopoietic Stem Cell Transplantation

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

Thymoglobulin (R) Exposure Is Influencing CD4+Immune Reconstitution As a Predictor for Improved Overall Survival in Pediatric Haematopoietic Cell Transplantation : Towards Individualized Dosing

Transplantation and immunomodulatio

Population Pharmacokinetic Modeling of Thymoglobulin (R) in Children Receiving Allogeneic-Hematopoietic Cell Transplantation : Towards Improved Survival Through Individualized Dosing

Background and Objectives To prevent graft-versus-host disease and rejection in hematopoietic cell transplantation (HCT), children receive Thymoglobulin (R), a polyclonal antibody acting mainly by depleting T cells. The therapeutic window is critical as over-exposure may result in delayed immune reconstitution of donor T cells. In this study, we describe the population pharmacokinetics of Thymoglobulin (R) as a first step towards an evidence-based dosing regimen of Thymoglobulin (R) in pediatric HCT. Methods Serum active Thymoglobulin (R) concentrations were measured in all pediatric HCTs performed between 2004 and 2012 in two pediatric HCT centers in The Netherlands. Population pharmacokinetic analysis was performed using NONMEM (R) version 7.2. Results A total of 3,113 concentration samples from 280 pediatric HCTs were analyzed, with age ranging from 3 months to 23 years old. The cumulative Thymoglobulin (R) dose was 10 mg/kg in 94 % of the patients given in 4 consecutive days. A model incorporating parallel linear and concentration-dependent clearance of Thymoglobulin (R) was identified. Body weight [for linear clearance (CL) and central volume of distribution] as well as lymphocyte count pre-Thymoglobulin (R) infusion (for CL) were important covariates. As such, the current dosing regimen results in higher exposure in children with a higher bodyweight and/ or a lower lymphocyte count pre-Thymoglobulin (R) infusion. Conclusion This model can be used to develop an individual dosing regimen for Thymoglobulin (R), based on both body weight and lymphocyte counts, once the therapeutic window has been determined. This individualized regimen may contribute to a better immune reconstitution and thus outcome of allogeneic HCT

The Diagnostic Value of Interleukin-8 for the Detection of Bacteremia in Pediatric Hematopoietic Stem Cell Recipients With Febrile Neutropenia

Transplantation and immunomodulatio

Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation : a multicentre, retrospective pharmacodynamic cohort analysis

BACKGROUND: Anti-thymocyte globulin (ATG) was introduced into the conditioning regimen in haemopoietic cell transplantation (HCT) to prevent graft-versus-host-disease (GvHD) and graft failure. However, ATG can also cause delayed immune reconstitution of donor T cells. We studied the relation between exposure to active ATG and clinical outcomes in children. METHODS: In this retrospective analysis, all patients (age 0·2-23 years) receiving their first HCT between April 1, 2004, and April 1, 2012, who received ATG (thymoglobulin) in two Dutch paediatric HCT programmes were included. The cumulative dose of ATG was chosen according to local protocols and was given intravenously over 4 days consecutively. ATG exposure measures (maximum concentration, concentration at time of HCT, clearance, days to reach a concentration below the lympholytic concentration of one arbitrary unit [AU] per mL, total area under the curve [AUC], AUC before HCT, and AUC after HCT) were calculated using a validated population pharmacokinetic model. The main outcome of interest was immune reconstitution (defined as CD4+ T cells >0·05 × 10(9) cells per L in two consecutive measurements within 100 days). Other outcomes of interest were survival, acute and chronic GvHD, and graft failure. We used Cox proportional hazard models, logistic regression models, and Fine-Gray competing risk regressions for analyses. FINDINGS: 251 patients were included. The chance of successful immune reconstitution decreased as the ATG AUC after HCT increased (odds ratio 0·991, 95% CI 0·987-0·996; p<0·0001). Within the cord blood group, we noted decreased immune reconstitution above the lowest AUC quartile (≥20 AU × day/mL; p=0·0024), whereas in the bone marrow or peripheral blood stem cell group, decreased immune reconstitution was noted only in the highest quartile (≥100 AU × day/mL; p=0·0024). Successful immune reconstitution by day 100 was associated with increased overall survival (hazard ratio [HR] 0·49, 95% CI 0·29-0·81; p=0·0047) caused by reduced non-relapse mortality (0·40, 0·21-0·77; p=0·0062), and relapse-related mortality in myeloid leukaemia (0·25, 0·08-0·76; p=0·015). An AUC before transplantation of at least 40 AU × day/mL resulted in a lower incidence of acute GvHD (grade 2-4 HR 0·979, 95% CI 0·963-0·994; p=0·0081; and grade 3-4 0·975, 0·952-0·998; p=0·033), chronic GvHD (0·983, 0·968-0·998; p=0·029), and graft failure (0·981, 0·965-0·997; p=0·020) compared with an AUC of less than 40 AU × day/mL. INTERPRETATION: These results stress the importance of improving the efficacy and safety of ATG in HCT by amending dosage and timing. Individualised dosing and timing of ATG to aim for optimum exposure before and after HCT could result in improved outcomes after paediatric HCT. FUNDING: Dutch Organization for Scientific Research

Impact of Serotherapy on Immune Reconstitution and Survival Outcomes After Stem Cell Transplantations in Children : Thymoglobulin Versus Alemtuzumab

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly affected by the kinetics of reconstitution of the immune system. This study compared the effects of antithymocyte globulin (ATG) and alemtuzumab on various outcome parameters after HSCT. The study cohort consisted of 148 children, with a median age of 9.6 years (range, .4 to 19.0), who underwent HSCT for malignant and benign hematological disorders in a single HSCT unit. Conditioning included ATG (n= 110) or alemtuzumab (n= 38). Cox proportional hazard regression analysis showed that alemtuzumab significantly delayed the recovery of CD3+ T cells and CD4+as well as CD8+ T cell subsets (P ≤ .001) and natural killer (NK) cells (P= .008) compared with ATG. In both ATG- and alemtuzumab-treated patients, shorter drug exposure lead to significantly faster recoveryof T cells. Alemtuzumab was associated with lower donor chimerism 3 and 6 months after transplantation and a higher risk of disease relapse (P= .001). The overall survival and event-free survival risks were significantly lower for alemtuzumab-treated patients (P= .020 and P <.001, respectively). Patients who received alemtuzumab showed a trend to lower risk of acute graft-versus-host disease, more human adenovirus, and less Epstein-Barr virus reactivations compared with patients who received ATG. These data indicate that children treated with alemtuzumab as part of the conditioning regimen have a slower T cell and NK cell reconstitution compared with those treated with ATG, which compromises the overall and event-free survival. Prolonged length of lympholytic drug exposure delayed the T cell recovery in both ATG- andalemtuzumab-treated patients. Therefore, we recommend detailed pharmacokinetic/pharmacodynamic (PK/PD) analyses in a larger cohort of patients to develop an algorithm aiming at optimization of the serotherapy containing conditioning regimen