Accepted Manuscript Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients V. Wiegering, M. Eyrich, B. Winkler, P.G. Schlegel PII:
S2468-1245(17)30035-9
DOI:
10.1016/j.phoj.2017.05.002
Reference:
PHOJ 38
To appear in:
Pediatric Hematology Oncology Journal
Received Date: 19 April 2017 Accepted Date: 25 May 2017
Please cite this article as: Wiegering V, Eyrich M, Winkler B, Schlegel PG, Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients, Pediatric Hematology Oncology Journal (2017), doi: 10.1016/j.phoj.2017.05.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Comparison of immune reconstitution after allogeneic vs. autologous stem cell transplantation in 182 pediatric recipients Wiegering V1, Eyrich M1, Winkler B1,2* and Schlegel PG1* Department of Pediatric Hematology and Oncology, University Hospital Würzburg,
Germany 2
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Department of Pediatric Hematology and Oncology, University Hospital Hamburg, Germany
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*Both authors contributed equally to the manuscript
PD Dr. Verena Wiegering Josef-Schneider-Str. 2, D31 97080 Würzburg, Germany Phone: +49-931-201-27728
[email protected]
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Fax: +49-931-20127730
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Correspondence:
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Figures/Tables: 2 Tables, 1 Supplemental file
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Running title: Immune reconstitution after pediatric hematopoietic stem cell
transplantation
Keywords: stem cell transplantation * immune reconstitution * pediatric patients
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Comparison of immune reconstitution after allogeneic vs. autologous stem
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cell transplantation in 182 pediatric recipients ABSTRACT
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Background
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Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a
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variety of malignant and non-malignant conditions. However, even if immune reconstitution
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after HSCT has been studied in extensively, until now data on the comparison of immune
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reconstitution after autologous vs. allogeneic HSCT is scarce, but might provide important
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clinical implications.
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Patient and Methods
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We examined immune reconstitution (T-, B-and NK-cells) at defined time points in 147
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children who received 182 HSCT. Differences in the time course of immune reconstitution
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were analyzed in autologous vs. allogeneic HSCT.
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Results
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We identified a quicker immune reconstitution in the T-cell compartment, especially in the
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CD4 and naïve subset after autologous HSCT, whereas recipients of allogeneic transplants
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showed a higher TCRgd proportion. B-cell reconstitution showed a delayed immune
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reconstitution after allogeneic HSCT in the first two years after HSCT. However, a
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reconstitution of all lymphocyte subsets after HSCT could be achieved in all patients.
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Conclusion
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Children undergoing a HSCT show a different pattern of immune reconstitution in the
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allogeneic and autologous setting. This might influence the outcome and should affect the
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clinical handling of infectious prophylaxis and re-vaccinations.
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Introduction
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Hematopoeitic stem cell transplantation (HSCT) has become an established therapy strategy
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for various diseases. There are two different approaches of HSCT: autologous and allogeneic.
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High-dose chemotherapy followed by autologous stem cell transplantation is designed to
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eliminate higher numbers of chemosensitive residual tumor cells. The efficacy of this
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treatment modality is based on the chemosensitivity of the malignant tumor cells with a steep
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dose–response curve as well as the choice of drugs for which bone marrow impairment is the
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dose-limiting toxicity (1). To rescue the hematopoietic system, patients receive cryopreserved
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autologous hematopoietic stem cells. Autologous HSCT has become an established treatment
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for distinct advanced pediatric tumors as brain tumors, neuroblastoma and sarcoma (2-4). In
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contrast the autologous setting, allogeneic HSCT represents a unique immunotherapeutic
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modality in which donor-derived T-cells exert a graft versus host response, which when
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directed at host-derived malignancy, can result in long-lasting immunologic tumor / leukemia
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control (5). However, when this phenomenon extends to normal host tissue, it results in the
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single most dreaded complication of this procedure, graft versus host disease (GVHD), which
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causes a significant morbidity and mortality after allogeneic HSCT.
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Immune reconstitution after HSCT has been studied in various studies (6, 7) (6, 8). However,
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the comparison of autologous and allogeneic reconstitution seems to be of clinical interest
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because differences might provide (I) new insights in the pathophysiologic basis of graft
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versus tumor effect, (II) in the pathophysiologic basis of GvHD, (III) might be used as
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prognostic marker and (IV) therefore might have clinical implications. In the presented study
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we analyzed immune reconstitution after 182 pediatric stem cell transplantations with regard
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to clinical characteristics and differences in immune reconstitution. These will have clinical
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implications in tailored prophylactic regimes.
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Methods
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Subsets of peripheral blood lymphocytes were analyzed by flow cytometry. Anti-CD3-
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phycoerythrin (PE), anti-CD19-fluorescein isothiocyanate (FITC) and anti-CD16/CD56-FITC
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monoclonal antibodies were used to identify T-, B and NK-cells, respectively. T-cell subsets
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were further characterized by 4-colour flow cytometry to measure the expression of CD4,
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CD8, TCRab, TCRgd, CD45RA and CD45RO. All monoclonal antibodies were purchased
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from Becton-Dickinson (Heidelberg, Germany). Flow cytometry was performed on a FACS
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Calibur, and data analyzed with CellQuest Software (Becton–Dickinson, Heidelberg,
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Germany).
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Statistical analysis
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Student’s paired t-test for mean differences was used to analyze data for levels of statistical
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significance among two groups (e.g. autologous vs. allogeneic). Kaplan–Meier Plots were
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used for survival probability. Statistical correlations between parameters were analyzed using
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a bivariate fit model. Additional multivariate analysis was performed against conventional
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outcome predictors (age, gender, disease status, and stem cell dosage) between multiple
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groups by using repeated measures analysis of variance (ANOVA) and Bonferroni’s multiple
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comparison test. For timely courses a hierarchic linear analysis were used. In all statistical
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applications a p-value of