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Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation.

ABSTRACT: Residual antithymocyte globulin (ATG; Thymoglobulin) exposure after allogeneic hematopoietic (stem) cell transplantation (HCT) delays CD4+ T-cell immune reconstitution (CD4+ IR), subsequently increasing morbidity and mortality. This effect seems particularly present after cord blood transplantation (CBT) compared to bone marrow transplantation (BMT). The reason for this is currently unknown. We investigated the effect of active-ATG exposure on CD4+ IR after BMT and CBT in 275 patients (CBT n = 155, BMT n = 120; median age, 7.8 years; range, 0.16-19.2 years) receiving their first allogeneic HCT between January 2008 and September 2016. Multivariate log-rank tests (with correction for covariates) revealed that CD4+ IR was faster after CBT than after BMT with <10 active-ATG × day/mL (P = .018) residual exposure. In contrast, >10 active-ATG × day/mL exposure severely impaired CD4+ IR after CBT (P < .001), but not after BMT (P = .74). To decipher these differences, we performed ATG-binding and ATG-cytotoxicity experiments using cord blood- and bone marrow graft-derived T-cell subsets, B cells, natural killer cells, and monocytes. No differences were observed. Nevertheless, a major covariate in our cohort was Filgrastim treatment (only given after CBT). We found that Filgrastim (granulocyte colony-stimulating factor [G-CSF]) exposure highly increased neutrophil-mediated ATG cytotoxicity (by 40-fold [0.5 vs 20%; P = .002]), which explained the enhanced T-cell clearance after CBT. These findings imply revision of the use (and/or timing) of G-CSF in patients with residual ATG exposure.

SUBMITTER: de Koning C

PROVIDER: S-EPMC5851423 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation.

de Koning Coco C Gabelich Julie-Anne JA Langenhorst Jurgen J Admiraal Rick R Kuball Jurgen J Boelens Jaap Jan JJ Nierkens Stefan S

Blood advances 20180301 5

Residual antithymocyte globulin (ATG; Thymoglobulin) exposure after allogeneic hematopoietic (stem) cell transplantation (HCT) delays CD4+ T-cell immune reconstitution (CD4+ IR), subsequently increasing morbidity and mortality. This effect seems particularly present after cord blood transplantation (CBT) compared to bone marrow transplantation (BMT). The reason for this is currently unknown. We investigated the effect of active-ATG exposure on CD4+ IR after BMT a ...[more]

PMID: 29535105

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Project description:Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell-depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (<30 AU × day/mL) was associated with lower risk of NRM (P < .01) and higher probability of achieving CD4+ IR (P < .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P < .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the <30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the <30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the <30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.

Dataset Information

Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation.

Publications

Filgrastim enhances T-cell clearance by antithymocyte globulin exposure after unrelated cord blood transplantation.

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