Childhood cancer and its treatment compromise immune functions bearing implications for the risk of infections and effectiveness of revaccinations. A plethora of studies describe the immune reconstitution after allogeneic HSCT and provide recommendations for infection prophylaxis and revaccination strategies. According to the frequency of the disease, analyses of the immune recovery after the end of therapy in pediatric patients who did not undergo HSCT focused on ALL. In this context, an early report by Alanko et al. described the recovery of blood B-lymphocytes and serum immunoglobulins7. The authors found that, based on these parameters, a sufficiently functioning immune system was established 6months after cessation of chemotherapy and concluded that prophylactic antibiotics can be withdrawn and immunizations started. In a subsequent publication, the same group later described a differential and age-dependent recovery of blood T cell subsets posttherapy9. Although their analysis showed a mean reversion to normal values by 6months, some individual patients continued to have subnormal values for up to 1year after therapy, some of whom exhibited increased susceptibility to infections. Such observations were largely confirmed in later studies in ALL11,14,19,20. Some of these analyses showed that in comparison, B-cells were reduced more significantly and for longer periods than T-cells. In a long-term follow-up, van Tilburg and colleagues showed that whereas naive B and T cells exhibited a relatively fast recovery, memory B-cells regenerated significantly slower and memory T-cells did not fully recover during the entire 5-year follow-up12. In a more recent large study including 116 participants, Williams and colleagues underlined that immune reconstitution differs between lymphocyte compartments21. Concerning the influence of treatment intensity, Ek et al. found that immune reconstitution after childhood ALL was most severely affected in the high-risk group10.

The immune reconstitution after therapy for solid tumors in children and adolescents has been characterized less extensively as compared to ALL.

In an early orienting pilot study, Cranendonk et al. retrospectively determined the effects of various chemotherapeutic drug regimens on the numbers of different blood cell types in 131 children treated for solid tumors. Apart from the general cytoreductive effects during treatment, they observed that, in the majority of the children, the lymphocyte count became normal between 1 and 12months after cessation of therapy22. Later, Alanko and coworkers focused on the hematologic and immunologic recovery in a small analysis including 11 children who had been treated for HD (n=3), Nephroblastoma (n=4), Burkitt`s Lymphoma (n=2), clear cell sarcoma (n=1) and rhabdomyosarcoma (n=1). The group described that the lymphocyte counts of most patients normalized during the first 12months after therapy. The recovery in patients with HD or Burkitt`s lymphoma was slower than in patients with nephroblastoma and radiotherapy appeared to prolong immune reconstitution15. In a later investigation, Kovacs and colleagues assessed immune recovery in 88 children receiving chemotherapy for ALL (n=43), lymphoma (n=15), bone tumors (n=20), and other solid tumors (n=10). The group determined serum immunoglobulin levels (Ig), natural killer activity (NK), antibody-dependent cellular cytotoxicity (ADCC), and T and B cell proliferation 1year after cessation of therapy. They found, that cytotoxic therapy can lead to long-term depression of the immune system, which was most prominent in patients with ALL.

For adults with HD, a treatment-associated marked long-term dysregulation of T-cell subset homeostasis has long been described17 and it had been shown that radiation therapy decreases the absolute CD4 T-cell counts23. As a consequence, antibody responsetopneumococcal vaccinewas profoundly impaired in patients who had received intensive treatment for HD24.

Comparable larger studies in pediatric cohorts have not been performed.

To illustrate varying characteristics of the cellular reconstitution after completion of chemotherapy in pediatric patients with ALL and other disease entities, we here present a comparative analysis of the course of total leukocyte, neutrophil and lymphocyte counts from 4months before until twelve months after therapy in a large pediatric cohort of n=132 patients who had been treated for ALL, HD and ES. Depending on the underlying disease and the resulting treatment regimens and modalities, we describe significant differences mainly affecting the total lymphocyte counts.

In contrast to earlier reports10, we found no differences in the cellular reconstitution between patients with ALL belonging to the HR group and those belonging to the MR or SR group. This might be explained, however, by the relatively small proportion of patients with HR in this study.

In particular, we saw a marked and prolonged post-therapeutic lymphocyte depression in patients with HD and ES as compared to patients with ALL. Lymphopenia was most distinct in individuals with HD who had received radiation therapy. This appears obvious because in the vast majority of cases the radiation field comprised the mediastinum and thus the thymic region with direct influence on T lymphocyte regeneration. In patients with HD, these findings are in line with earlier investigations in adult cohorts17,23,24.

In addition to these entity, treatment, and modality specific differences in cellular reconstitution, we observed a clear age dependency with patients aged11years showing an earlier recovery of the total lymphocyte count than patients aged 1218years. An age dependency of the post-therapeutic immune reconstitution has been proposed in different contexts in some earlier studies9,25 whereas others did not report comparable differences12. Considering the lower median age of patients with ALL compared to patients with HD and ES, this finding could contribute to the differences in lymphocyte reconstitution described between the disease entities in this study.

Overall, our study underlines that immune reconstitution after chemotherapy for childhood cancer highly depends on the underlying disease entity, the therapeutic regimen, and treatment modality as well as patient age and differs significantly between ALL and solid tumors. These discrepancies might at least in part be a consequence of the less intensive maintenance therapy applied in ALL but not in HD or ES. However, at the same time, current recommendations for infection prophylaxis and revaccination in childhood cancer have been mainly derived from pediatric patients with ALL4,26,27,28, are still rather uniform, and do not consider potential differences for patients with solid tumors. In pediatric patients, who have been treated for childhood cancers without autologous or allogeneic HSCT, infection prophylaxis is generally withdrawn between 3- and 6months2,3, and inactivated vaccines are administered from 3months and live vaccines from 6months after cessation of conventional antineoplastic therapy4.

The results of our study could potentially contribute to discussions about adjusting the recommendations and establishing differentiated disease-, therapy- and modality-specific guidelines considering the differences in cellular reconstitution and in particular the clear and long-lasting effect of irradiation on lymphocyte total counts.

We are aware that our study bears some limitations. Above all, due to the retrospective design, we could not investigate any additional immunological parameters and therefore focused on absolute leukocyte, neutrophil, and lymphocyte blood counts as surrogate parameters of immunological recovery. Moreover, we could not draw any clinical correlations, especially between the evolution of cell counts and infectious complications. In addition, the recent implementation of the bispecific T cell engager blinatumomab in the treatment protocols might further influence and thus alter cellular reconstitution after therapy in patients with ALL.

As a consequence, future joint large studies are essential to cover these aspects in a disease- and treatment-specific manner. For a few treatment protocols, such investigations have already been initiated.

Continue reading here:
Temporal evolution and differential patterns of cellular reconstitution ... - Nature.com