Clinical Characteristics and Treatment Outcome of Refractory Cytopenia of Childhood (RCC): A Prospective Registration Through the Japanese Society of Pediatric Hematology

Refractory cytopenia of childhood (RCC) is a subtype of myelodysplastic syndrome (MDS) in children proposed by the World Health Organization (WHO) classification, which is characterized by dysplastic features of hematopoiesis and persistent cytopenia without increased blasts in bone marrow and peripheral blood. Recommendation of the treatment options for RCC, such as immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (SCT), has been proposed base on transfusion dependency, karyotype and the availability of donors. In this study, we retrospectively analyzed clinical characteristics and the outcome of 75 children with RCC and discussed the utility of treatment modalities.

Patients and Methods: Of 222 children with MDS younger than 16 years of age, who were prospectively registered to the Japanese Society of Pediatric Hematology between 1999 and 2008, 75 children were diagnosed with RCC according to the WHO classification and were eligible for analysis. The median age at diagnosis was 7.9 years. Three-fourths of the patients showed cytopenia in multiple lineages. Hypoplastic BM was documented in 74% of the biopsy specimens. Forty-two patients (56%) had normal karyotype, 9 patients (12%) had chromosome 7 abnormalities, and 18 patients (24%) had other abnormal karyotype. As a first-line therapy, 25 patients received SCT and 22 patients IST, respectively. In the SCT group, 14 patients received total-body irradiation as a conditioning regimen. Twenty-six patients who were not transfusion dependent or severely neutropenic were followed without treatment (Watch and Wait; W&W). Patients were divided into 2 subgroups according to the severity of dysplasia in bone marrow: RCC with unilineage or multilineage dysplasia (RCC-UD: n=40, RCC-MD: n=35). The patients with RCC-MD showed hypoplastic BM less frequently (57%) and had monosomy 7 more frequently (20%) than those with the RCC-UD (88% and 5%, respectively). Proportion of patients with trisomy 8 was similar between RCC-UD and RCC-MD (10% and 9%).

The 5-year overall survival (OS) for all patients was 71+/−9%; 31+/−17% in the SCT group, 89+/−8% in the IST group and 100+/−0% in the W&W group. Only 1 patient in the W&W group progressed to advanced MDS 20 months after diagnosis. One patient suffered from relapse after IST. Transplant-related mortality (TRM) was the most common cause of treatment failure in SCT group. In the IST group, 15 patients (68%) including 5 patients who had chromosome abnormalities responded. Cyclosporine (CSA) alone induced comparable response with combination of CSA and anti-thymocyte globulin (6/10 and 9/12, respectively; p=0.65). Of 7 non-responders, 4 patients were rescued by the second-line SCT. In the W&W group, all children were alive and 1 patient suffered from disease progression. Two of 11 children with normal karyotype who underwent SCT died of TRM, whereas 5 of 7 children with monosomy 7 who received SCT died of TRM. There was no difference in OS at 5 years between RCC-UD and RCC-MD (73+/−9% and 72+/−12%, respectively; p=0.07).

Disease progression and relapse were rare in this patient population. We did not observe a clear impact of severity of dysplasia on clinical outcome. Given a high rate of TRM, indication and conditioning regimens of SCT need to be reconsidered. Since IST, even CSA alone, was effective in more than half of the patients and showed a favorable survival rate also in non-responders, IST might be considered as a first-line therapy in a broader population of RCC. W&W strategy seems to be appropriate if patients do not suffer from severe cytopenia.

No relevant conflicts of interest to declare.