Reduced versus intensive chemotherapy for childhood acute lymphoblastic leukemia: Impact on lymphocyte compartment composition
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].
Section snippets
Study population
Between December 2006 and June 2009 140 children with ALL (1–19 years of age) treated according to the DCOG ALL 10 trial were studied (Table 1). All Dutch University Medical Centers participated in this study. The study was approved by the medical ethics committee and written informed consent was obtained from all study participants or their legal guardians. Of 43 SR and 97 MR patients respectively 89 and 231 peripheral blood samples were obtained at 6 different time points: 11 (after
The lymphocyte compartment in general
Total lymphocyte counts gradually decreased in both the SR and MR group to a median of 18% (SR) and 23% (MR) of reference values at 104 weeks of treatment (SR and MR vs. HC; both p < 0.001) (Fig. 2A, Tables S3 and S4). One year after cessation of chemotherapy, levels had restored to normal levels. B cell numbers remained stable (around 4%) during the reduced SR intensification/maintenance therapy (20 weeks – end of treatment) while during the intensive MR intensification/maintenance therapy B
Discussion
This study provides for the first time detailed data about early and memory B and T cell subsets during and after intensive compared to strongly reduced childhood ALL chemotherapy in a large cohort. During chemotherapy, transitional and naive B cells were more affected than memory B cell subpopulations, especially in the MR group, indicating severe bone marrow suppression. Apparently, memory B cells have a relative survival advantage over transitional and naive B cells during chemotherapy. One
Conflict of interest statement
All authors have no conflict of interest to report.
Acknowledgements
The authors would like to thank E.E. Nibbelke (University Medical Center Utrecht) for study support and Dr. P. Westers (University Medical Center Utrecht) for statistical advice. Furthermore, we thank B.E. van der Linden-Schrever (DCOG), A. van der Sluijs (DCOG), I. Bronmans-Smit (Erasmus MC), R. Jugooa (Erasmus MC) and B. Beukenkamp (Erasmus MC) for their excellent technical support. In addition, we would like to thank Dr E.R. van Wering (DCOG) for her kind cooperation.
This work was
References (42)
- et al.
Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch childhood oncology group (DCOG) protocol ALL-9 (1997–2004)
Lancet Oncol
(2009) Chemotherapy-induced immunosuppression and reconstitution of immune function
Leuk Res
(2002)- et al.
Changes in host defence induced by malignancies and antineoplastic treatment: implication for immunotherapeutic strategies
Lancet Oncol
(2008) - et al.
Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia
Blood
(2005) - et al.
Decreased numbers of CD4+ T lymphocytes in peripheral blood after treatment of childhood acute lymphoblastic leukemia
Leuk Res
(2006) - et al.
Refined characterization and reference values of the pediatric T- and B-cell compartments
Clin Immunol
(2009) - et al.
Identification and characterization of circulating human transitional B cells
Blood
(2005) - et al.
Phenotypic and functional heterogeneity of human memory B cells
Semin Immunol
(2008) - et al.
Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire
Blood
(2004) - et al.
A new CD21low B cell population in the peripheral blood of patients with SLE
Clin Immunol
(2004)
Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations
J Pediatr
Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study
J Allergy Clin Immunol
The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency
J Allergy Clin Immunol
Treating childhood acute lymphoblastic leukemia without cranial irradiation
New Engl J Med
Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia – an individual patient data meta-analysis involving 5659 children
Br J Haematol
Immune function in children under chemotherapy for standard risk acute lymphoblastic leukaemia – a prospective study of 20 paediatric patients
Br J Haematol
Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: implications for monitoring of minimal residual disease
Br J Haematol
Regeneration pattern of precursor-B-cells in bone marrow of acute lymphoblastic leukemia patients depends on the type of preceding chemotherapy
Leukemia
Current chemotherapy protocols for childhood acute lymphoblastic leukemia induce loss of humoral immunity to viral vaccination antigens
Pediatrics
Profound abnormality of the B/T lymphocyte ratio during chemotherapy for pediatric acute lymphoblastic leukemia
Leukemia
Immune reconstitution after childhood acute lymphoblastic leukemia is most severely affected in the high risk group
Pediatr Blood Cancer
Cited by (14)
Clinical and genetic spectrum from a prototype of ciliopathy: Joubert syndrome
2023, Clinical Neurology and NeurosurgeryCitation Excerpt :Our patient did not exhibit global developmental delay, but he had hypophyseal hormone deficiencies without the classical molar tooth sign. Sanders et al.[18], for the first time, have identified pathogenic variants in the KATNIP gene associated with Joubert syndrome in three siblings with primarily hypophyseal hormone deficiencies. Their index patient had global developmental delay with central hypothyroidism and growth hormone deficiency, and her MRI indicated an ectopic posterior pituitary with severe hypoplasia/aplasia of the anterior pituitary and vermis hypoplasia.
Insights into defective serological memory after acute lymphoblastic leukaemia treatment: The role of the plasma cell survival niche, memory B-cells and gut microbiota in vaccine responses
2018, Blood ReviewsCitation Excerpt :Indeed, several studies show an impact of chemotherapy on phenotypic alterations and distribution of MBC subsets in the re-emerging MBC compartment following ALL treatment (summarized in Table 2). In a study following children during and after ALL treatment, the authors found that switched (CD27+ IgG+/IgA+), non-switched IgM+ (CD27+ IgM+ IgD+), IgM-only (CD38− CD27+ IgM+ IgD−) and non-classical (CD27− IgG+/IgA+) MBC proportions had dropped to 0–7% of healthy control values during the course of therapy and recovered to 22–65% of control values one year after completed chemotherapy [79]. In line with this, the same group as well as others performed a long-term follow of children with haematological malignancies, including those with ALL diagnosis, and demonstrated that it could take several years after cessation of chemotherapy for peripheral MBC numbers to normalize [9,21].
Adequate immune responses to vaccines after chemotherapy for leukaemia diagnosed in childhood
2024, Acta Paediatrica, International Journal of PaediatricsRecovery of lymphocyte subpopulations is incomplete in the long-term setting in pediatric solid tumor survivors
2022, Pediatrics InternationalT Cell Subsets During Early Life and Their Implication in the Treatment of Childhood Acute Lymphoblastic Leukemia
2021, Frontiers in Immunology