Reduced versus intensive chemotherapy for childhood acute lymphoblastic leukemia: Impact on lymphocyte compartment composition

Abstract

Chemotherapy for childhood acute lymphoblastic leukemia may cause severe immune damage. The lymphocyte compartment of 140 patients during and after a new strongly reduced (standard risk (SR), n = 43) and intensive chemotherapy regimen (medium risk (MR), n = 97) was studied between 2006 and 2009. Transitional and naive B cells and IgG⁺/A⁺, IgM⁺ and IgM only memory B cells were significantly reduced during chemotherapy; significantly more in MR group. One year after treatment CD27⁺IgG⁺/A⁺, IgM⁺ and IgM only memory B cells had still not fully recovered, but this was not confined to the MR group. The T cell compartment was less but also significantly affected during chemotherapy and recovered to normal levels. In the MR group, NK cells had not fully recovered to normal levels 1 year after treatment. Thus, intensive chemotherapy regimens cause severe, mainly B cell memory damage that persists even 1 year after treatment.

Introduction

Although tailored and intensive therapy leads to a cure rate higher than 90% for childhood acute lymphoblastic leukemia (ALL) [1], [2], [3], there are concerns about the immune damage induced by these intensive chemotherapy regimens [4], [5], [6]. However, the consequences of the currently used intensive ALL chemotherapy regimens for immune damage and reconstitution are largely unknown and hampered by the lack of age matched reference values. Earlier studies only described a selection of early and memory subpopulations and showed that chemotherapy for ALL led to a considerable B cell loss in bone marrow [7], [8], [9] and blood followed by a rapid recovery after cessation of chemotherapy [6], [10], [11], [12]. Especially, the number of naive B cells had decreased during chemotherapy, while memory B cells seemed only mildly affected. The rapid recovery after cessation of chemotherapy was accompanied by a rapid increase in naive B cells [6]. Some studies on T cells showed that chemotherapy reduces particularly naive CD4⁺ but also CD8⁺ T cell numbers, with a relative sparing of memory T cells [11], [13], [14], while other studies showed that the overall T cell compartment was only mildly affected [6].

Recently we described a detailed characterization of the B and T lymphocyte compartments during childhood in a large population of healthy children including early and memory B and T cell subsets according to age [15]. We now evaluated 140 children who were treated for ALL according to the Dutch childhood oncology group (DCOG) ALL 10 protocol, using Minimal Residual Disease (MRD) directed tailored therapy, during and 1 year after cessation of chemotherapy. Patients were stratified into 3 arms based on therapy response identical to BFM-2000 criteria [16] with a new strongly reduced intensification and maintenance treatment for standard risk patients (SR), an intensive intensification and maintenance treatment for medium risk patients (MR) and series of intensive courses of chemotherapy often combined with allogeneic stem cell transplantation for high risk patients (HR) (Fig. 1). In this study we compared various early and memory B and T cell subpopulations in SR and MR group during and 1 year after cessation of chemotherapy to each other and to a healthy control cohort (HC) after correction for age on the basis of reference values [15].