Comparison of long-term outcomes between children with aplastic anemia and refractory cytopenia of childhood who received immunosuppressive therapy with antithymocyte globulin and cyclosporine

Abstract

The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.

Hematopoietic stem cell transplantation for acquired aplastic anemia

“…However, 19% developed cytogenetic abnormalities including -7, a poor prognosis finding(25). These results are similar to the observation that G-CSF treatment concurrent with IST increased the risk of development of -7 abnormalities and progression to MDS/AML(26–28). …”

Recent advances in understanding clonal haematopoiesis in aplastic anaemia

“…While there is no evidence that granulocyte colony stimulating factor (G-CSF) potentiates transformation to MDS or changes overall survival in AA (Teramura, et al 2007, Tichelli, et al 2011), this may be a reflection of the relatively short duration of G-CSF therapy given to most patients, as compared to patients with severe congenital neutropenia where long-term high dose G-CSF therapy has been definitively linked to leukemogenesis through the acquisition of CSF3R mutations (Link, et al 2007). In the case of AA, multiple groups found an association between the use and duration of G-CSF therapy and subsequent emergence of monosomy 7 (Desmond, et al 2014, Hama, et al 2015, Kaito, et al 1998, Kojima, et al 2002, Li, et al 2011). A possible mechanistic link was reported by Sloand et al (2006), where pharmacological doses of G-CSF were shown to preferentially stimulate the growth of monosomy 7 clones through abnormal signalling by the GCSF class IV receptor.…”

The current perspective of low-grade myelodysplastic syndrome in children

“…IST consisting of antithymocyte globulin (ATG) and cyclosporine has proven to be effective in a subset of children with low-grade MDS, with response rate ranging from 30 to 70 % [5,6,14,15,21]. Some patients with chromosomal abnormalities or multilineage dysplasia were also reported to respond to IST [5,6,14,15,21].…”

“…Low-grade MDS is diagnosed in all age groups with median age at diagnosis ranging from 6 to 12 years from three representative reports (Table 1) [3,5,6]. Boys and girls are equally affected.…”