HLA Identical Siblings Are the Best Donors for Children with ALL

Allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors became a common practice during the last years to rescue children and adolescents with high risk acute lymphoblastic leukaemia (ALL) who lack an HLA identical sibling donor (MSD). However, heterogeneous approaches in donor selection and transplantation methods hamper the interpretation of available data. Therefore we compared the influence of donor source under standardized methods. Twenty-nine centres participated in the prospective trial to evaluate whether the results of HSCT from HLA matched donors (MD) are comparable to those of HLA identical siblings in patients with high risk ALL.

118 patients (age 0.5-18 years, med. 10.2) underwent MSD-HSCT and 313 MD-HSCT. 218 pts were in first and 213 beyond 1^st remission. Unrelated donors were compatible for at least 9/10 matches with allelic typing. GvHD-prophylaxis consisted of CSA only after MSD-HSCT and of CSA/MTX/ATG after MD-HSCT. Patients older than 2 years received total body irradiation and etoposide as conditioning regimen. The stem cell source was for 82% of the MSD-group bone marrow (BM), 10% received peripheral blood stem cells (PBSC) and some received cord blood (CB). In the MD-cohort, 66% received BM, 28% PBSC and the remaining CB or combinations.

Results: After a median follow up of 4.2 years, the 4-year disease free survival (DFS) is 0.70±0.04, the overall survival (OS) 0.77±0.04 after MSD-HSCT and after MD-HSCT DFS is 0.66±0.03, OS 0.73±0.03 (n.s.); 4-years relapse-incidence is 0.22±0.04 after MSD-HSCT and 0.23±0.02 after MD-HSCT (n.s.). Non-relapse mortality at 4 years is 0.06±0.02 for MSD and 0.10±0.02 for MD (p-value 0.228). In multivariate analysis the only significant impact on OS and DFS was 1^st remission compared to 2^nd or 3^rd remission with a Hazard ratio of 1.71. However, engraftment was significantly better after MSD-HSCT: the median day to reach ANC >1000/µl/lymphocytes >100/µl/platelets >50.000/µl was 17/14/22 after MSD-HSCT and 22/23/32 after MD-HSCT (p < 0.001). This resulted in significant less severe infections ( ≥ grade 3 CTA 3.0) –18% vs. 40% (p < 0.01) and less severe pulmonary complications: 10% vs. 19% (p = 0.034).

We conclude that despite excellent outcome with low GVHD-incidence and  low NRM after HSCT from MD in children with high risk ALL the HSCT von MSD results in faster engraftment and immunoreconstitution and less severe infections and justifies the use of minor sibling donors.