Outcome of Children with All Given HSCT from Unrelated Volunteers Has Significantly Improved over Time and Now Is Comparable to That of Children Transplanted from an HLA-Identical Sibling.
Authors: Locatelli Franco , Zecca Marco , Pession Andrea , Uderzo Cornelio , Dini Giorgio , Fagioli Franca , Favre Claudio , Conter Valentino , Rondelli Roberto , Bonetti Federico , Messina Chiara 
Published: October 2019

Abstract
Leukemia recurrence is the most common cause of treatment failure in children with ALL. The prognosis relapsed ALL mainly depends on the site of recurrence, time between diagnosis and relapse and immune-phenotype, children with bone marrow relapse occurring within the first 30 months after diagnosis or with T-ALL being those with the worst prognosis. Allogeneic haematopoietic stem cell transplantation (HSCT) is considered the treatment of choice for many children with relapsed ALL. We report the outcome of 175 children with ALL in second complete remission given HSCT from either a relative or an unrelated donor (UD) in one of the Italian AIEOP Centers from1998 to 2002. Less than 10% of these patients had an isolated extra-medullary relapse. TBI was employed in the preparative regimen in 92% of patients. GVHD prophylaxis consisted of Cs-A alone in the vast majority of children transplanted from a relative, whereas the combination of Cs-A, short-term MTX and either ALG, or Campath-1G in a minority of cases, was used in children transplanted from an UD. The source of stem cells was bone marrow, cord blood and peripheral blood in 150, 20 and 5 children respectively. We used the Berlin-Frankfurt-Munster (BFM) classification of ALL relapses in childhood to subdivide patients according to site of relapse, time from diagnosis to relapse and immune-phenotype. This classification identifies 4 different groups of risk (S1, S2, S3 and S4), the latter being those including patients with the worst prognosis. The 5-year probability of disease-free survival (DFS) of patients transplanted from either a relative or an unrelated donor was 56% and 44% (P=0.05). However, the outcome of the 86 children transplanted from an HLA-identical sibling or an UD beyond 1998 was comparable, the 3-year Kaplan-Meier estimate of DFS being 62% and 59%, respectively. The cumulative incidence of transplant-related mortality (TRM) for patients transplanted either from a relative or from an UD was 15% and 33%, respectively. For children transplanted beyond 1998 we found a reduction in TRM, irrespectively of the type of donor employed. The 5-year cumulative incidence of relapse for patients transplanted either from a relative or from an UD was 30% and 23%, respectively (P=NS). The occurrence of grade I-III acute GVHD was associated with a reduction in the risk of leukemia recurrence, which translated into a significantly better probability of DFS as compared to children with absent or grade IV acute GVHD. Also chronic GVHD was associated with a significantly lower risk of disease recurrence and with a better DFS. Irrespectively of the type of donor emlpoyed, S1 and S2 patients had a significantly better outcome in comparison to those S3 and S4 groups. These data indicate that allogeneic HSCT is able to rescue a significant proportion of patients with ALL in 2nd CR. DFS of unrelated donor HSCT in children with ALL in 2nd CR has improved in the last few years, being comparable to that of patients transplanted from a matched family donor. This information, together with that on the prognostic relevance of BFM classification, is of value for counselling of patients with relapsed ALL. The GVHD-related graft-versus-leukemia effect is important for the eradication of the malignant clone.