Allogeneic Stem Cell Transplantation for Children with Advanced Primary MDS: Results from the EWOG-MDS Study Group Employing a Pre-Transplant Preparative Regimen with Busulfan, Cyclophosphamide and Melphalan.

MDS in children is a rare disorder characterized by dysplasia and defined genetic abnormalities. In most patients (pts) MDS arises without known predisposing conditions (primary MDS). Here, we report the results of 55 males and 30 females with advanced primary MDS enrolled in the prospective EWOG-MDS trial 97. Data were analysed according to the most advanced FAB-type prior to SCT: 32 pts were classified as RAEB, 40 as RAEB-t and 13 as myelodysplasia-related AML (MDR-AML). Median age at diagnosis was 9.5 yrs (0.1–17.6) and median time from diagnosis of advanced MDS to SCT 4 mo (0.5–31). Cytogenetics revealed monosomy 7 in 32 pts, trisomy 8 in 7, a complex karyotype in 9 and other abnormalities in 9; karyotype was normal in 26 pts and unknown in 2. 31 pts had received AML-like therapy prior to SCT. All pts were given an unmanipulated graft after condititioning with busulfan 16 mg/kg, cyclophosphamide 120 mg/kg and melphalan 140 mg/m. Source of stem cells was bone marrow in 56 pts, peripheral blood in 25, cord blood in 2 and unknown in 2. 36 pts were transplanted from an HLA-identical relative (MFD), 49 pts from an HLA-identical or 1-antigen disparate unrelated donor (UD). GVHD prophylaxis consisted of CSA alone for MFD, whereas recipients of a UD graft generally received CSA, methotrexate and anti-lymphocyte globulin. Two pts suffered graft failure. The cumulative incidence of grade II-IV acute GVHD and chronic GVHD was 40% (SE 5%) and 25% (SE 5%), respectively. 18 pts suffered transplant-related mortality (TRM), the cumulative incidence of TRM in pts grafted from a MFD or UD being 14 and 25%, respectively (p=n.s.). Presence of acute GVHD II-IV (p<0.01), spleen size at SCT ≥ 1 cm below the costal margin (p=0.03) and age ≥ 12 years (p=0.04) predicted an increased risk of TRM. 17 patients relapsed at a median of 12 mo after SCT (1–107). The 5-year probability of leukemia recurrence was 29%, with no difference between MFD and UD transplants. While the highest FAB type prior to SCT predicted relapse with a cumulative incidence rate increasing from RAEB (13%, SE 10%) to RAEB-t (24%, SE 11%) and MDR-AML (69%, SE 20%) (p=0.03), the use of intensive chemotherapy prior to SCT or blast percentage at SCT did not. With a median observation time after SCT of 29 months (6–107) the EFS at 5-years was 62% (SE 12%) and 39% (SE 11%) for pts given SCT from a MFD or an UD, respectively (p=n.s). These results indicate that a large proportion of pts with advanced MDS can be rescued by SCT. Disease recurrence remains the main cause of treatment failure. Intensive chemotherapy prior to SCT should not be routinely employed.