Soumya Perinparajah (1), S.Y. Amy Cheung (2), James W.T. Yates (3), Nigel Klein (1), Joanna Lewis (1), Helen Payne (1,4), John Booth (5), Reem Elfeky (6), Natalia Builes Restrepo (6), Paul Veys (1,6), Joseph F. Standing (1,7)
(1) UCL Great Ormond Street Institute of Child Health, London, United Kingdom; (2) Certara Ltd, Amsterdam, Netherlands; (3) GlaxoSmithKline, Stevenage, United Kingdom; (4) Clinical Trials Unit, Medical Research Council, London, United Kingdom; (5) Digital Research and Informatics Unit, Great Ormond Street Hospital and Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre, London, United Kingdom; (6) Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London, United Kingdom; (7) Department of Pharmacy, Great Ormond Street Hospital for Children, London, United Kingdom
Objectives: To date, studies of immune reconstitution after paediatric haematopoietic stem cell transplantation (HSCT) have mainly focussed on T cell reconstitution and of these, only a few have taken a mathematical modelling approach to give insight into both the rate and extent of immune reconstitution [1]. There is an unmet need to improve understanding of B cell reconstitution in the post-HSCT setting in children using a modelling approach that can capture the non-linearity of the underlying biological processes and the heterogeneity observed in reconstitution due to the influence of patient-, donor- transplant-, disease- and drug-related factors.
The aim of the present study was to develop a mathematical model for CD19+ B cell reconstitution in children post-HSCT that incorporates scaling of model parameters for age-related effects and assesses clinically relevant covariates.
Methods: Retrospective electronic data were collected from children who underwent HSCT at a tertiary paediatric hospital between 2004 and 2016. CD19+ B cell counts were available before and after HSCT. In order to delineate age-related effects on CD19+ B cell reconstitution, a priori scaling was applied to the CD19+ B cell production and death parameters in the model using a B cell maturation function [2][3]. In addition, parameters were included to estimate the time to CD19+ B cell output from the bone marrow following HSCT. Proportional and combined residual error models were tested, and both M5 and M3 methods were tested for handling CD19+ B cell counts below the lower limit of quantification (LLOQ). The maturation function was developed using R version 3.5.1, and models were fitted using NONMEM® version 7.4.3 using the first-order and Laplacian conditional estimation with interaction algorithms. Covariates were identified by implementing the stepwise covariate modelling approach in Perl-speaks-NONMEM version 4.8.1.
Results: 4115 measurements of CD19+ B cell counts were available from 359 children who underwent HSCT. The median age at HSCT was 3.2 years (range, 1 month to 17 years). The final model which best described the data used a Hill-type equation to estimate the time delay between HSCT and half-maximal CD19+ B cell output, had a combined residual error model and used the M3 method for handling CD19+ B cell counts that were below the LLOQ (n = 363). The parameter estimates showed good precision, and were as follows (% residual standard error); CD19+ B cell production rate constant (λ), 1.68×106 cells/day (1.09); CD19+ B cell death rate constant (μ), 0.015 cells day-1 (1.17); Hill co-efficient, 4.17 (0.13); time to half-maximal CD19+ B cell output (T50), 58 days (1.19). The setpoint CD19+ B cell count was calculated to be 112×106cells/L, given by dividing λ by μ. The following covariates were found to be significant on the T50 parameter (effect size); HSCT indication of primary immunodeficiency (-0.55), receiving a myeloablative conditioning regimen (0.17) and having a matched donor (0.01).
Conclusions: A mechanistic model was developed to reflect the age-dependant nature of CD19+ B cell reconstitution post-HSCT in children. The final model adequately described CD19+ B cell dynamics in the post-HSCT study cohort and the effect of clinically relevant covariates has been assessed, highlighting its potential to be used in clinical management to predict post-HSCT patient trajectories of CD19+ B cell reconstitution.
References:
[1] Hoare RL, Veys P, Klein N, Callard R, Standing JF. Predicting CD4 T-cell reconstitution following pediatric hematopoietic stem cell transplantation. Clinical Pharmacology & Therapeutics. 2017 Aug;102(2):349-57.
[2] Payne H, Chain G, Adams S, Hunter P, Luckhurst N, Gilmour K, Lewis J, Babiker A, Cotton M, Violari A, Gibb D. Naïve B cell output in HIV-infected and HIV-uninfected children. AIDS research and human retroviruses. 2019 Jan 1;35(1):33-9.
[3] Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood. Clinical & Experimental Immunology. 2010 Nov;162(2):271-9.
Reference: PAGE 29 (2021) Abstr 9818 [www.page-meeting.org/?abstract=9818]
Poster: Drug/Disease Modelling - Paediatrics