Comparison of immune reconstitution after allogeneic ...

1 downloads 0 Views 742KB Size Report
Peggs KS, Krauss AC, Mackall CL. Clinical implications of immune reconstitution following. 18 hematopoietic stem cell transplantation. Cancer treatment and ...
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

RI PT

1

Department of Pediatric Hematology and Oncology, University Hospital Hamburg, Germany

SC

*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]

TE D

Fax: +49-931-20127730

M AN U

Correspondence:

EP

Figures/Tables: 2 Tables, 1 Supplemental file

AC C

Running title: Immune reconstitution after pediatric hematopoietic stem cell

transplantation

Keywords: stem cell transplantation * immune reconstitution * pediatric patients

ACCEPTED MANUSCRIPT 1

Comparison of immune reconstitution after allogeneic vs. autologous stem

2

cell transplantation in 182 pediatric recipients ABSTRACT

4

Background

5

Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure for children with a

6

variety of malignant and non-malignant conditions. However, even if immune reconstitution

7

after HSCT has been studied in extensively, until now data on the comparison of immune

8

reconstitution after autologous vs. allogeneic HSCT is scarce, but might provide important

9

clinical implications.

10

Patient and Methods

11

We examined immune reconstitution (T-, B-and NK-cells) at defined time points in 147

12

children who received 182 HSCT. Differences in the time course of immune reconstitution

13

were analyzed in autologous vs. allogeneic HSCT.

14

Results

15

We identified a quicker immune reconstitution in the T-cell compartment, especially in the

16

CD4 and naïve subset after autologous HSCT, whereas recipients of allogeneic transplants

17

showed a higher TCRgd proportion. B-cell reconstitution showed a delayed immune

18

reconstitution after allogeneic HSCT in the first two years after HSCT. However, a

19

reconstitution of all lymphocyte subsets after HSCT could be achieved in all patients.

20

Conclusion

AC C

EP

TE D

M AN U

SC

RI PT

3

ACCEPTED MANUSCRIPT 1

Children undergoing a HSCT show a different pattern of immune reconstitution in the

2

allogeneic and autologous setting. This might influence the outcome and should affect the

3

clinical handling of infectious prophylaxis and re-vaccinations.

AC C

EP

TE D

M AN U

SC

RI PT

4

ACCEPTED MANUSCRIPT

Introduction

2

Hematopoeitic stem cell transplantation (HSCT) has become an established therapy strategy

3

for various diseases. There are two different approaches of HSCT: autologous and allogeneic.

4

High-dose chemotherapy followed by autologous stem cell transplantation is designed to

5

eliminate higher numbers of chemosensitive residual tumor cells. The efficacy of this

6

treatment modality is based on the chemosensitivity of the malignant tumor cells with a steep

7

dose–response curve as well as the choice of drugs for which bone marrow impairment is the

8

dose-limiting toxicity (1). To rescue the hematopoietic system, patients receive cryopreserved

9

autologous hematopoietic stem cells. Autologous HSCT has become an established treatment

10

for distinct advanced pediatric tumors as brain tumors, neuroblastoma and sarcoma (2-4). In

11

contrast the autologous setting, allogeneic HSCT represents a unique immunotherapeutic

12

modality in which donor-derived T-cells exert a graft versus host response, which when

13

directed at host-derived malignancy, can result in long-lasting immunologic tumor / leukemia

14

control (5). However, when this phenomenon extends to normal host tissue, it results in the

15

single most dreaded complication of this procedure, graft versus host disease (GVHD), which

16

causes a significant morbidity and mortality after allogeneic HSCT.

17

Immune reconstitution after HSCT has been studied in various studies (6, 7) (6, 8). However,

18

the comparison of autologous and allogeneic reconstitution seems to be of clinical interest

19

because differences might provide (I) new insights in the pathophysiologic basis of graft

20

versus tumor effect, (II) in the pathophysiologic basis of GvHD, (III) might be used as

21

prognostic marker and (IV) therefore might have clinical implications. In the presented study

22

we analyzed immune reconstitution after 182 pediatric stem cell transplantations with regard

23

to clinical characteristics and differences in immune reconstitution. These will have clinical

24

implications in tailored prophylactic regimes.

AC C

EP

TE D

M AN U

SC

RI PT

1

ACCEPTED MANUSCRIPT

Methods

2

Subsets of peripheral blood lymphocytes were analyzed by flow cytometry. Anti-CD3-

3

phycoerythrin (PE), anti-CD19-fluorescein isothiocyanate (FITC) and anti-CD16/CD56-FITC

4

monoclonal antibodies were used to identify T-, B and NK-cells, respectively. T-cell subsets

5

were further characterized by 4-colour flow cytometry to measure the expression of CD4,

6

CD8, TCRab, TCRgd, CD45RA and CD45RO. All monoclonal antibodies were purchased

7

from Becton-Dickinson (Heidelberg, Germany). Flow cytometry was performed on a FACS

8

Calibur, and data analyzed with CellQuest Software (Becton–Dickinson, Heidelberg,

9

Germany).

M AN U

SC

RI PT

1

Statistical analysis

11

Student’s paired t-test for mean differences was used to analyze data for levels of statistical

12

significance among two groups (e.g. autologous vs. allogeneic). Kaplan–Meier Plots were

13

used for survival probability. Statistical correlations between parameters were analyzed using

14

a bivariate fit model. Additional multivariate analysis was performed against conventional

15

outcome predictors (age, gender, disease status, and stem cell dosage) between multiple

16

groups by using repeated measures analysis of variance (ANOVA) and Bonferroni’s multiple

17

comparison test. For timely courses a hierarchic linear analysis were used. In all statistical

18

applications a p-value of