Importance of Individualized Conditioning in Allogeneic Hematopoietic Cell Transplantation

Background and Aim: Allogeneic hematopoietic (stem) cell transplantation(HCT) is a last-resort treatment for patients with primary immunedeficiencies (PIDs), metabolic disorders, or refractory hematologicalmalignancies. T-cell immune reconstitution (IR) after HCT is pivotal fordisease control and reduces the probability of transplantation-relatedmortality. However, adequate immune reconstitution is criticallydependent on chemo- and serotherapy (anti-thymocyte globulin (ATG))used in the conditioning phase. We studied the relationship betweenexposure to ATG and clinical outcomes in adult and pediatric HCTpatients.Methods: We performed a retrospective, pharmacokineticpharmacodynamicanalysis of data from patients undergoing anallogeneic-HCT with ATG (thymoglobulin) as part of non-myeloablative conditioning (2004-2016). Active ATG concentrations were measuredusing a validated bioassay and pharmacokinetic exposure measures werecalculated with a population pharmacokinetic model. We compared theprobability of CD4 T-cell reconstitution, previously defined as having> 50×106 cells/L in 2 consecutive measurements within 100 days afterHCT, according to cell source (BM vs CB) and ATG exposures. Coxproportional hazard models were used to identify covariates affectingCD4 IR, including age, sex, diagnosis (malignancy, PID, BM failuresyndromes, or benign non-PID), treatment period steroid- treated (gradeII-IV) aGVHD, and ATG exposure after HCT. To address why IR after CBis more affected by residual ATG exposure than IR after bone marrow(BM) transplantation, we performed complement- and cell-dependentcytotoxicity assays (NK and neutrophils) in addition to phagocytosisassays using patient’s neutrophils.Results: For adult patients, ATG exposure post-HCT was the best predictorfor 5-year overall survival. Optimum exposure post-transplantation was60–95 AU per day/mL. Estimated 5-year overall survival in the optimumexposuregroup was significantly higher than under- or overexposedpatients, resulting in a greater event-free survival chance. In children,the ATG exposure post-CBT predicted successful CD4 T-cell IR andevent-free survival chances were significantly higher in patients withsuccessful IR and lower ATG exposure. In both populations modeleddosingbased on absolute lymphocyte counts led to higher optimumtarget attainment than did weight-based dosing. Multivariate log-ranktests (with correction for covariates) revealed that IR was faster after CBTthan after BMT in patients with low levels (<10 AU/day) residual ATGexposure, but vice versa in patients with higher active-ATG exposures.We found no differences in ATG-binding and ATG-cytotoxicity butidentified that Filgrastim treatment (only given after CBT) increasedneutrophil cytotoxicity by 40-fold.Conclusion: We show that exposure to residual-ATG affects survival afterHCT in pediatric and adult patients, stressing the importance of optimumATG-dosing. Individualized ATG dosing, based on lymphocyte countsrather than bodyweight, might improve survival chances after HCT.Filgrastim (G-CSF) exposure explained the enhanced T-cell clearanceafter CBT. These findings imply a revision of the use (and/or timing) ofATG and G-CSF.

کلیدواژه ها:

Hematopoietic cell transplantation ، Individualized ، Conditioning ، ATG ، Busulfan ، Fludarabine