Hematopoietic Stem Cell Transplantation (HSCT) after a Myeloablative Conditioning Regimen in Children with Refractory Cytopenia (RC): Results of a Retrospective Analysis from the EWOG-MDS Group.
Authors: Locatelli Franco , Noellke Peter , Fisher Alexandra , Bader Peter , Bernardo Maria Ester , Bergstraesser Eva , Hasle Henrik , van den Heuvel-Eibrink Marry , Korthof Elisabeth , Stary Jan , Strahm Brigitte , Zintl Felix , Sedlacek Petr , Zecca Marco , Niemeyer Charlotte M. 
Published: April 2020

Abstract
RC is one of the most common variants of childhood MDS, characterized by clonal ineffective hematopoiesis and sustained peripheral cytopenia. Allogeneic HSCT represents a widely employed, curative treatment for children with RC. We analyzed the outcome of 48 children (33 males, 15 females; median age at transplantation 11 years, range 2.9–19) affected by RC, given allogeneic HSCT after a myeloablative preparative regimen and reported to the European Working Group on Childhood MDS (EWOG-MDS). Karyotype analysis was available in all patients, but 4. Clonal abnormalities were detected in 17 patients, involving chromosome 7 in 13 children. Bone marrow cellularity was reduced in 34, normal in 8 and increased in the remaining 6 patients. Nineteen patients were transplanted from an HLA-identical sibling, while the remaining 29 were given HSCT from an unrelated donor (UD). Bone marrow, cord blood and peripheral blood stem cells were employed in 38, 1 and 9 patients, respectively. Busulfan (BU) and cyclophosphamide (CY) were used as preparation to the allograft in 12 patients, while 36 children were given a regimen including BU, CY and melphalan (L-PAM). Cyclosporine-A (Cs-A) alone was mainly used as graft-versus-host disease (GvHD) prophylaxis in children transplanted from a relative, while the majority of patients transplanted from an UD were given the combination of Cs-A, short-term methotrexate and anti-thymocyte globulin. All patients engrafted, the median time to neutrophil and platelet recovery being 16 days (range, 9–79) and 26 days (range, 10–170), respectively. Two patients had secondary graft failure at 74 and 93 days after HSCT, respectively; one of them was successfully re-transplanted. The cumulative probability of developing grade II-IV acute GVHD was 37% (95% CI, 26–54%). Thirteen out of the 41 patients at risk developed chronic GVHD, which was limited in 8 patients and extensive in 5. The cumulative incidence of chronic GVHD was 35% (95% CI, 23–55%). With a median follow-up of 3.5 years (range 4 months-7.8 years), 39 patients are alive with sustained donor engraftment (1 after a second transplant), 9 patients having died for either transplant-related complications (8 patients) or disease recurrence (1 child). The 5-year probability of disease-free survival (DFS) is 77% (95% CI, 65–89%). In patients transplanted from an HLA-identical sibling and from an UD the DFS probability at 5 years is 78% (95% CI, 59–97%), and 76% (95% CI, 60–91%), respectively (P=n.s). The 5-year probability of DFS was 61% (95% CI, 38–83%) and 86% (95% CI, 74–99%) for children who did or did not experience grade II-IV acute GvHD (P=0.04). The outcome of patients prepared with either BU/CY or BU/CY/L-PAM was 92% (95% CI, 76–100%) and 71% (95% CI, 56–86%), respectively (P=n.s). These data indicate that a myeloablative allogeneic HSCT is able to cure a large proportion of children with RC, especially if GvHD is successfully prevented. Transplantation-related mortality represents the main cause of treatment failure, while relapse is rarely observed. The addition of L-PAM does not offer any advantage in comparison to BU/CY. Outcome of children with RC given allogeneic HSCT from either a relative or an UD is similar.