Hematopoietic Stem Cell Transplantation for Patients with Refractory Cytopenia of Childhood

Introduction: Refractory cytopenia of childhood (RCC) is an entity of the pediatric myelodysplastic syndrome (MDS) proposed in the World Health Organization (WHO) 2008 classification and is characterized by persistent cytopenia with dysplasia and <5% blasts in the bone marrow (BM). Although the efficacy of immunosuppressive therapy (IST) has been reported in RCC with response rate of 40-60%, hematopoietic stem cell transplantation (HSCT) is still thought as the only curative therapy for children with MDS. However, appropriate setting of HSCT for patients with RCC has not been established. Recently, we described clinical characteristics and treatment outcome in 65 cases with RCC who were prospectively registered through the Japanese Society of Pediatric Hematology/Oncology (JSPHO) (Hasegawa et al, BJH 2014). In this analysis, we focused on a subgroup that underwent HSCT in order to identify the factors that can predict the outcome of patients with RCC after HSCT.

Patients and Methods: From July 1999 to February 2008, 618 children who were suspected of having MDS were prospectively registered into the JSPHO database and 65 were diagnosed based on the central review of morphology as having primary MDS without excess blasts, which was compatible with criteria of RCC. Therapeutic strategy was determined by each physician based on the recommendations provided by the Japanese Childhood MDS Study Group MDS99. As a first-line therapy, 25 patients received IST, 12 patients received HSCT, and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years. Eventually, 28 (11 male and 17 female) children ended up undergoing HSCT.

Results: Median age at HSCT was 10.3 years (range, 1.5 - 17.2 years). Median duration between diagnosis and HSCT was 481 days (range, 123 – 2674 days). Twelve patients had a history of receiving IST. As a stem cell source, 15 patients received BM from an unrelated donor, 5 received BM from matched-sibling donor, 4 received BM from family donor, and 4 received unrelated cord blood. As a conditioning regimen, myeloablative conditioning (MAC) with total-body irradiation regimen was given to 8 patients, MAC with busulfan regimen was given to 7, and 13 patients received reduced intensity conditioning (RIC). As a GVHD prophylaxis, 22 patients received tacrolimus and 6 received cyclosporine (CyA). Engraftment was confirmed in all patients. Grade III-IV acute GVHD was observed in 3 patients. Of 23 evaluable patients, 7 patients had chronic GVHD. Seventeen patients remained in remission after HSCT. Secondary graft failure was observed in 2 patients who received RIC after failure of IST. Nine patients died due to the following causes: transplantation-related mortality (TRM; n=7), relapse (n=1), and secondary brain tumor (n=1). Seven patients died of TRM at a median time of 103 days after HSCT (range, 44-926 days) and 5-year cumulative incidence of TRM was 28±9%. Grade III-IV acute GVHD and the presence of chronic GVHD were associated with a higher probability of TRM (p=0.03 and 0.02, respectively). Five-year event-free survival (EFS) and overall survival (OS) was 58±10% and 66±9%, respectively. No patient characteristics or transplantation-related variables showed statistically significant difference in EFS or OS. Of 13 children receiving RIC, 7 remained in remission, whereas 3 succumbed to TRM, 2 experienced secondary graft failure, and one developed brain tumor.

Discussion: TRM was the main cause of treatment failure in patients with RCC receiving HSCT. This analysis suggested appropriate prevention of GVHD might be important to succeed in HSCT for patients with RCC.