In the diagnosis of childhood bone marrow failure (BMF), differentiating aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (MDS) is challenging. The 2008 World Health Organization (WHO) classification has proposed a provisional entity, "refractory cytopenia of childhood (RCC)". The spectrum of patients with RCC is wide, ranging from patients with severe hypocellular bone marrow (BM) and mild dysplasia to those with normocellular BM and distinct dysplasia meeting the criteria of refractory cytopenia with multilineage dysplasia (RCMD) defined for adults with MDS. Currently, it is recommended that children who meet the criteria for RCMD should be classified as RCC in the WHO classification until the number of lineages involved has been fully evaluated with regard to their relative importance as prognostic factors. Until now, no studies have addressed the question whether the current WHO classification reflects clinical outcomes of childhood BMF.

The Japanese Society of Pediatric Hematology and Oncology has established a central review system of morphology. Peripheral blood (PB) and BM smears were reviewed by two pediatric hematologists, and BM trephine biopsies were reviewed by a hematopathologist. In addition, the telomere length of lymphocytes and paroxysmal nocturnal hemoglobinuria (PNH) clones in PB were measured by flowcytometry. RCC is defined as persistent cytopenia with <2% and <5% blasts in PB and BM, respectively. BM aspirate smears show dysplastic changes in >2 cell lineages or >10% within one cell lineage. On the other hand, the criteria of RCMD is defined as persistent cytopenia with <1% and <5% blasts in PB and BM, respectively. BM smears show >10% dysplastic changes in >2 cell lineages. We classified childhood BMF into AA, RCC, and RCMD in our central review.

From February 2009 to February 2015, 1,300 cases were prospectively reviewed. Of the 1,300 cases, 582 were classified as BMF. Among them, 99 were classified as AA, 230 as RCC, 128 as RCMD, 50 as hepatitis-related BMF, 4 as PNH, and 71 as inherited BMF. Of the 71 cases with inherited BMF, 35 were diagnosed as Fanconi anemia, 14 as Shwachman-Diamond syndrome, and 12 as dyskeratosis congenita. To determine the clinical differences among AA, RCC, and RCMD, we compared laboratory and clinical findings for 457 patients classified with AA, RCC, and RCMD. Median ages in the AA, RCC, and RCMD groups were 10, 9, and 7 years, respectively (p<0.01). The male/female ratio in AA, RCC, and RCMD groups was 1.3, 1.4, and 1.1. The median of leukocyte, neutrophil, reticulocyte, and platelet count, and mean corpuscular volume were significantly lower in AA than in RCC and RCMD groups (p<0.01). Chromosomal abnormalities were detected in 1 patient with AA (trisomy 8), 6 patients with RCC (trisomy 8, n=4; monosomy 7, n=1; other, n=1), and 18 patients with RCMD (trisomy 8, n=5; monosomy 7, n=4; other, n=9) (p<0.01). Out of the 457 patients, 69 (AA, n=29; RCC, n=34; RCMD, n=6) were treated with immunosuppressive therapy (IST) with rabbit antithymocyte globulin and cyclosporine. Six months after the IST, the response rate to the IST was not significantly different between AA (38%) and RCC (47%) (p=0.47). Although the number of patients was limited, the response rate to the IST was 100% in patients with RCMD. One patient with RCC developed PNH at 26 months after the IST. Stem cell transplantation was performed in 15 patients with AA, 16 with RCC, and 3 with RCMD. Two patients with AA and 1 patient with RCC died of transplant-related toxicities.

In conclusion, the entity of RCMD should be adopted to childhood MDS classification because children with RCMD exhibited a distinct characteristic of morphology and laboratory findings. Further efforts to clarify molecular events and clinical outcomes are necessary to establish the classification system for childhood BMF.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.