High exposure to fludarabine in conditioning prior to allogeneic hematopoietic cell transplantation predicts impaired CD4 reconstitution and lower probability of survival
J.B. Langenhorst (1,2), C. van Kesteren (1,2,3),T.P. Dorlo (5), E.M. van Maarseveen (3),S. Nierkens (1,2), J. Kuball (4), M.A. De Witte (4), J.J Boelens (1,2), A.D.R Huitema (3,5)
1 Pediatric Blood and Marrow Transplant Program, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands; 2 U-DANCE, Laboratory of Translational Immunology, UMCU, Utrecht, The Netherlands; 3 Department of Clinical Pharmacy, UMCU, Utrecht, The Netherlands; 4Department of Hematology, UMCU, Utrecht, The Netherlands; 5Department of Pharmacy & Pharmacology, , Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands
Objectives: Allogeneic hematopoietic cell transplantation (HCT) is a procedure where healthy donor cells are infused to replace a diseased bone marrow. Fludarabine (Flu) is a drug widely used together with busulfan (Bu) in conditioning, a part of the procedure where high dose chemo- and serotherapy and/or irradiation are used to allow engraftment of the donor cells and to eradicate residual disease. Whilst targeting Bu to optimal exposure has been shown to increase survival(1), to date there is no optimal exposure known for Flu. As Flu has strong cytotoxic and immunosuppressive properties, this study aims to relate Flu exposures with CD4+ T-cell reconstitution (IR) and overall survival (OS).
Methods: In this retrospective single-centre study, the circulating metabolite of Flu (F-ara-A) was quantified in samples acquired for routine Bu therapeutic drug monitoring (TDM, from 2010). With these data, a pharmacokinetic model was developed in NONMEM 7.3 and the cumulative Flu area under the curve (AUC) was determined.
Main outcomes of interest were OS and IR. A value of 50 million CD4+ T-cells per litre was chosen as dichotomous measure for IR.(2-3) The time point at which a patient had the second consecutive measurement above threshold was defined as time of IR. Statistical analyses were done using Kaplan-Meier estimation (R 3.3) and parametric time-to-event (TTE) models (NONMEM 7.3).
Results: For the outcome analyses 197 patients were included (128 adults, 69 children), with a median age of 38 (0.23-73.5 years). To find an optimal cut-off for Flu exposure regarding the impact on OS, receiver-operating characteristic curves were used. A cut-off of 21.2 mg*h/L was found to be optimal, resulting in 2-year OS of 39% OS above and 65% below this cut-off. (p<0.001)
A Weibull TTE model, with covariates age and anti-thymocyte globulin exposure was found to best describe IR. Herein Flu AUC continuously impaired rate of IR. (OR 0-50 mg*h/L: 0.13, p=0.01). In a sequential analysis, where IR probability was imputed into an OS TTE model, IR was found to have an effect on OS (OR 0-100% IR: 0.41, p<0.001). Independently from IR, Flu exposure above cut-off further decreased OS (HR 2.2, p=0.0035).
Conclusions: High exposure to Flu impairs CD4+ T-cell reconstitution and reduces survival after HCT both via an IR dependent and independent manner. This is the first step in the definition of a target exposure for Flu in this setting. Dose individualization and/or TDM-based corrections towards the Flu target is warranted to reduce overexposure and improve survival after HCT.
References:
[1] Bartelink, I.H. et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol 3, e526-e36 (2016).
[2] Admiraal, R. et al. Association between anti-thymocyte globulin exposure and CD4+ immune reconstitution in paediatric haemopoietic cell transplantation: a multicentre, retrospective pharmacodynamic cohort analysis. Lancet Haematol 2, e194-203 (2015).
[3] Bartelink, I.H. et al. Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. Biol Blood Marrow Transplant 19, 305-13 (2013).
