Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome in children: results of the EWOG-MDS 98 study

Abstract

We report on the outcome of children with advanced primary myelodysplastic syndrome (MDS) transplanted from an HLAmatched sibling (MSD) or an unrelated donor (UD) following a preparative regimen with busulfan, cyclophosphamide and melphalan. Ninety-seven patients with refractory anemia with excess blasts (RAEB, n ¼ 53), RAEB in transformation (RAEB-T, n ¼ 29) and myelodysplasia-related acute myeloid leukemia (MDR-AML, n ¼ 15) enrolled in the European Working Group of MDS in Childhood (EWOG-MDS) 98 study and given hematopoietic stem cell transplantation (HSCT) were analyzed. Median age at HSCT was 11.1 years (range 1.4-19.0). Thirty-nine children were transplanted from an MSD, whereas 58 were given the allograft from a UD (n ¼ 57) or alternative family donor (n ¼ 1). Stem cell source was bone marrow (n ¼ 69) or peripheral blood (n ¼ 28). With a median follow-up of 3.9 years (range 0.1-10.9), the 5-year probability of overall survival is 63%, while the 5-year cumulative incidence of transplantation-related mortality (TRM) and relapse is 21% each. Age at HSCT greater than 12 years, interval between diagnosis and HSCT longer than 4 months, and occurrence of acute or extensive chronic graft-versus-host disease were associated with increased TRM. The risk of relapse increased with more advanced disease. This study indicates that HSCT following a myeloablative preparative regimen offers a high probability of survival for children with advanced MDS.

Allo-SCT using BU, CY and melphalan for children with AML in second CR

“…Within this trial BuCyMel was used for conditioning of children with advanced myelodysplastic syndrome, which was based on Italian data published earlier. 11,12 Taking BU/CY as a standard backbone, there is published experience with three other drugs that were added in an effort to escalate this regimen: thiotepa, 13,14 etoposide 15,16 and Mel. 12,17 Where thiotepa and Mel are strongly myeloablative even as single agents, this is not the case for etoposide.…”

“…Its profound stem-cell toxic properties make it a potentially attractive agent for malignancies whose origin is attributed to a hematopoietic stem cell defect such as in myelodysplastic syndrome (MDS) and AML, and, therefore, are difficult to cure with standard chemotherapy. 11,22 In combination with BU, CY is most commonly dosed at 120 mg/kg. Higher doses used previously were associated with significantly higher toxicity.…”

Response to treatment with azacitidine in children with advanced myelodysplastic syndrome prior to hematopoietic stem cell transplantation

“…The outcome of RCEB in childhood is poor, with a 5-year overall survival (OS) of about 35-63%, [6][7][8][9] which is inferior to survival in MDS without excess blasts 10,11 and de novo AML. 12 Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for RCEB.…”

“…12 Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for RCEB. 8 Earlier HSCT correlates with better outcome, 13 but preparations for HSCT are often lengthy and appropriate stem cell donors may not be readily available. The main causes of poor outcome include progression to leukemia, high treatment-related toxicity and high relapse incidence of MDS or occurrence of MDR-AML after HSCT.…”

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

“…3 Advanced MDS in children can be separated into three categories: 1) refractory anemia with excess blasts (RAEB); 2) RAEB in transformation (RAEB-t); or 3) myelodysplasiarelated acute myeloid leukemia (MDR-AML). 4 In some children, MDS or hypoplastic bone marrow failure is associated with an underlying genetic predisposition (e.g. Fanconi anemia, dyskeratosis congenita or ShwachmanDiamond syndrome).…”