Immune reconstitution in children following chemotherapy for acute leukemia.

Anthony P Williams,Thomas Maishman,Stuart C Clarke,Paul T Heath,Rachael Brooks,Elizabeth Dixon,Juliet C Gray,Sam A Wilding,Saul N Faust,Ajay Vora,Angeliki Galanopoulou,Susan Mapstone,Jessica Bate,Soonie R Patel,Julia Chisholm

doi:10.1002/jha2.27

Abstract

Although survival rates for pediatric acute lymphoblastic leukemia are now excellent, this is at the expense of prolonged chemotherapy regimens. We report the long‐term immune effects in children treated according to the UK Medical Research Council UKALL 2003 protocol. Peripheral blood lymphocyte subsets and immunoglobulin levels were studied in 116 participants, at six time points, during and for 18‐month following treatment, with 30‐39 patients analyzed at each time point.Total lymphocytes were reduced during maintenance chemotherapy and remained low 18 months following treatment completion. CD4 T cells remained significantly reduced 18 months after treatment, but CD8 cells and natural killer cells recovered to normal values. The fall in naïve B‐cell numbers during maintenance was most marked, but numbers recovered rapidly after cessation of treatment. Memory B cells, particularly nonclass‐switched memory B cells, remained below normal levels 18 months following treatment. All immunoglobulin subclasses were reduced during treatment compared to normal values, with IgM levels most affected.This study demonstrates that immune reconstitution differs between lymphocyte compartments. Although total B‐cell numbers recover rapidly, disruption of memory/naïve balance persists and T‐cell compartment persist at 18 months. This highlights the impact of modern chemotherapy regimens on immunity, and thus, infectious susceptibility and response to immunization.

Highlights

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, with approximately 400 new cases each year in the UnitedKingdom
Absolute counts for total lymphocytes, total B cells, naïve B cells, unswitched memory B cells, switched memory B cells, CD4 T cells, CD8 T cells, and natural killer (NK) cells were assessed for normality at each time point, using a combination of tests along with the graphical representation of the data
We demonstrated the impact of a contemporary chemotherapy regimen for ALL on long-term immune reconstitution in a large pediatric patient cohort

Summary

Introduction

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, with approximately 400 new cases each year in the United. In the United Kingdom, current regimens entail just over 2 years of chemotherapy for girls, and just over 3 years of treatment for boys. 2011, the majority of pediatric patients in the United Kingdom with ALL were recruited to the MRC UKALL 2003 trial [4]. This protocol, similar to other treatment regimens internationally, entailed 6-12 months of relatively intensive blocks of chemotherapy, followed by maintenance chemotherapy (oral 6-mercaptopurine and methotrexate and four weekly vincristine and steroid pulses) for the remainder of the treatment period. Treatment was stratified according to conventional clinical, cytogenetic, and morphological response criteria, with three treatment regimens (A, B, and C), of increasing intensity

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