Although the pathogenesis of acquired AA is still unclear, it was proposed that T cell mediated hematopoietic stem cell injury plays an important role in the pathogenesis of AA. During the course of AA, the patients' bone marrow are attacked by their own T lymphocytes, causing apoptosis of hematopoietic stem cells and subsequent insufficient blood cells [16–18]. CsA is a well-established T cell suppressant, the immunosuppressive mechanism of CsA mainly involves the activation of calcineurin (CN), c-Jun N-terminal kinase (JNK) and p38 signal pathway that activate the T cell pathway. These mechanisms selectively regulate the function of peripheral blood lymphocyte subsets, block the activation of cytotoxic T cells, and reduce interleukin 2 (IL-2) and interferon γ (INF-γ), tumor necrosis factor α (TNF-α) and other hematopoietic negative regulatory factors to play its immunosuppressive role [19–21]. CsA has long been one of the main drugs for AA immunosuppressive therapy. In previous reports, the response rate of children’s AA to IST (combined use of ATG and CsA) was 30.0–70.0%, and the overall long-term survival rate was 90.0% [8, 22, 23]. However, there are few clinical reports on children with NSAA treated with CsA monotherapy (without ATG). The current study analyzed the role of CsA monotherapy and showed that the total effective rate of CsA in NSAA in the current cohort was 75.0% (CR + PR), indicating that CsA has a definite effect on NSAA.
In the study of NSAA’s natural history, Nishio et al observed in 22 children that there was no spontaneous remission in children with NSAA (without immunosuppressive treatment) after a median follow-up period of 86 months (11–198 months), and 55% of them developed transfusion dependent AA after the median time of 51.5 months (9-175 months) after diagnosis [24]. This evidence suggested that the prognosis of children with NSAA without immunosuppression treatment was poor. The studies also found that age, sex, ANC, platelet, ARC, Hb and other factors at the time of diagnosis had no significant correlation with disease progression. In the current study, we also find that the efficacy of CsA was not associated with the age of disease diagnosis, patients’ gender, WBC and ANC at the time of diagnosis, immune cellularity, as well as CsA blood trough concentration. However, the efficacy of CsA treatment was associated with higher levels of RBC, Hb and Plt at the time of diagnosis. These results suggested that the remaining hematopoietic ability is probably need for a better CsA response. Kwon et al found in the study of adult NSAA that patients whose Plt did not respond to 60 days of CsA treatment were more likely to progress to SAA [25]. These studies, along with our study, suggested that the initial response to CsA treatment is suggestive to the long-term prognosis.
The therapeutic index of CsA in immunosuppressive therapy is narrow therefore the use of CsA requires therapeutic drug monitoring (TDM) and dose adjustment. However, the exact effective blood concentration of CsA in treating AA is not clear. Studies have shown that the inhibition of CsA on CN activity peaked at CsA blood concentration > 700 µg/L [26]. In our study, it was found that the average dose of CsA and peak concentration gradually increased in CR, PR and NR group, however there was no difference in the trough concentration of the three groups. The above results suggest that it can be difficult for some children to increase the trough concentration correspondingly by increasing the CsA dose, meanwhile increasing the peak concentration may not improve the efficacy of CsA. In addition, in our previous IST studies on AA in children, we did not find that early (1–2 weeks after treatment) titration of a high trough concentration has a positive effect on the prognosis [15]. Higher concentration of CsA may bring more toxic and side effects, and increasing the dosage of CsA may not be a good method to improve the curative effect for patients who did not respond. However, there are many factors affecting the pharmacokinetics (PK) of CsA, including age, serum creatinine, clinical factors and concomitant drugs. The variability of pharmacokinetics in children is greater than that in adults, so the PK parameters based on adults may not be applicable to children [27–29]. Although the initial dose of CsA in this study was recommended as 5 mg/kg/d according to the Chinese guidelines, but during dose titration, there was a 4.4 times difference between the maximum and minimum doses of CsA, which also confirmed that CsA was applied to children with large individual differences in PK. Not long ago, we also established the PK model of children’s AA CsA to better guide the use of children’s CsA with more clinical parameters [30].
The current guidelines recommend HSCT from fully matched sibling bone marrow donors as the first treatment for AA. Studies showed that the overall survival rate of AA patients after AA exceeded 90% [31–34]. Although HSCT from fully matched unrelated donors is the second choice [35], advance in recent years greatly improved the effective rate, survival rate and failure free survival rate of fully compatible unrelated donor transplantation, making it the first choice for HSCT in AA. In the past, unrelated donor umbilical cord blood transplantation had a high probability of failure [36]. In recent years, the survival rate has been greatly improved. For unrelated donors lacking full compatibility or compatibility of their compatriots or in emergencies, unrelated donor umbilical cord blood transplantation is a potential treatment option. Haploid HSCT has a low survival rate in the past, and the survival rate has been significantly improved in recent years. It can also be used as an alternative treatment for patients with acquired AA [37–39]. In this study, there was a higher rate of patient receiving matched donor transplantation, and the success rate was high. Nevertheless, two patients died after transplantation, the control of infection and GvHD complications after AA transplantation is still a matter of concern that restrains the use of HSCT in NSAA.
Long term application of CsA may cause a variety of toxic effects, including damage to kidney, liver, nerve, heart and other tissues. Among them, the renal toxicity and liver toxicity of CsA are the most relevant to clinical monitoring [40]. CsA toxicity increases significantly at serum CsA trough concentration > 250 µg/L [41, 42]. A total of 40 pediatric patients included in the study, the most common toxic reaction is hair hyperplasia, which can be as high as 75.0%. Gingival hyperplasia is the second most common toxic reaction, which is 35.0%. The proportion of liver and kidney damage is low, which is 10%. The proportion of other observed adverse reactions, such as obesity and joint pain, is 5% or less, indicating that monitoring the concentration of CsA plays a good role in controlling adverse reactions of important organs. All toxic reactions of patients in this group can be gradually relieved after drug withdrawal or dosage reduction, and generally no further intervention is required.
Although the current study showed that CsA is generally effective for NSAA. However, our findings could be biased due to the design (single center retrospective study), small number of subjects and relative short duration. Further studies with large samples in the future is required to identified the characteristics of children with NSAA for CsA treatment.