Allogeneic HSCT From Unrelated and Sibling Donors Are Equal for Children with Acute Lymphoblastic Leukemia

Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA identical sibling donors is standard of care for children with high-risk acute lymphoblastic leukemia (ALL). However, transplant-related mortality remains a serious problem, especially after transplantation from unrelated or HLA-mismatched donors. Heterogeneity regarding patient selection, transplantation procedures and study endpoints hamper the interpretation of the available data. We therefore initiated a prospective trial to evaluate the results of HSCT in a standardised setting.

From September 2003 through September 2010, 471 children with ALL in first, second or subsequent remission (229 in CR1, 242 ≥ CR2) received an allogeneic HSCT from an HLA-matched sibling (MSD), an HLA-matched family/unrelated donor (MD) or, for patients with very high-risk disease, an HLA-mismatched donor (MMD) after conditioning with total body irradiation (TBI) and etoposide or a chemotherapy-only regimen. Two high risk groups with indication for an HSCT were defined according to results with conventional chemotherapy: “high relapse risk group” (HRR) and “very high relapse risk group” (VHRR). HRR was defined by response to front line chemotherapy, amount of minimal residual disease (MRD), phenotype of leukemia and/or time and site of relapse

At a median observation time of 3 years, the 4-year probability of disease-free survival (pDFS) after MD-HSCT was equivalent to that of MSD-HSCT (68% vs. 71%; n.s.). Transplant-related mortality (TRM) after 3 years was 5% for MSD and 10% for MD HSCT (n.s.). Acute GvHD grade I/II occurred in 274 pts (58%) with no difference between MSD and MD or MMD, 117 evaluable pts did not develop any acute GvHD (24%). Grade III and IV aGvHD occurred in 10% of all patients with no difference according to donor type, stem cell source, patient’s age or gender matching.

Forty percent of 439 evaluable patients developed cGVHD. The 2-year cumulative incidence of extensive chronic GvHD was 16% after MSD and 2% after MD HSCT (p< 0.001). After MSD-HSCT, age > 10 years (29% vs. 4%), transplantation of PBSC compared to BM ( 50% vs. 14%) and remission status > CR1 (21% vs. 11%) negatively influenced the 2 years cumulative incidence of extensive cGVHD. Gender match of donor/recipient, year of HSCT, phenotype, and CMV status did not influence the incidence and severity of cGVD after MSD-HSCT. After MD-HSCT, the 2 year cumulative incidence of cGVHD was only 5 % with no difference between BM and PBSC or HLA disparities (9/10 or 10/10 matches).

The 3-year cumulative incidence of relapse was 21% after MSD-HSCT, and 19% after MD-HSCT (n.s.). For patients with VHRR the results for MD/MSD HSCT (n=232) were significantly superior to those of MMD HSCT (n=46) (3-year pDFS 65% vs. 31%; p<0.001; 3-year incidence of TRM 10% vs, 26%; p<0.001).

Allogeneic HSCT from HLA-matched donors is equivalent to HSCT from HLA-identical sibling donors in children with ALL.