Unrelated Cord Blood Transplantation for Children with Juvenile Myelomonocytic Leukemia.
Authors: Locatelli Franco , Madureira Adrienne B.M. , Rocha Vanderson , Teira Pierre , Champagne Martin , O’Brien Tracey A. , Vora Ajay , Stein Jerry , Olive Teresa , Bonfim Carmem S. , Stary Jan , Bertrand Yves , Garnier Federico , Ionescu Irina , Niemeyer Charlotte , Gluckman Eliane 
Published: April 2020

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for children with juvenile myelomonocytic leukemia (JMML). A recent study from the European Working Group of MDS in Childhood (EWOG-MDS) reported a 5-year probability of event free survival of 55% (n=48), and 49% (n=52) in children transplanted from either an HLA identical sibling or an unrelated volunteer, mainly donating bone marrow (BM) cells. As in the EWOG-MDS analysis only 7 children received unrelated cord blood transplantation (UCBT), we decided to further investigate the role of UCBT in 42 children with JMML, reported to the Eurocord-EBMT and EWOG-MDS registries. Median age at transplantation of the 42 children was 2.6 years (range 0.6–7); 29 patients were males and 13 females. Cytogenetic analysis was available in all patients but one: 10 patients had monosomy 7, 4 other abnormalities, while the remaining 27 children had a normal karyotype. Seven patients underwent splenectomy before UCBT. Conditioning included Busulfan in 78% of patients, while the most common graft-versus-host disease (GVHD) prophylaxis consisted of Cyclosporin-A and steroids. In donor-recipient pairs, histocompatibility was determined by serology or low resolution molecular typing for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 locus. The donor was HLA identical in 7 cases, 1-antigen disparate in 18 and with 2 or more disparities in 14. Median number of nucleated cells infused was 6.8 × 107/Kg (range 2–50). The 60-day cumulative incidence (CI) of engraftment was 76%%, with a median time to neutrophil and platelet recovery of 27 (range 14–51) and 50 (range 15–180) days, respectively. In multivariate analysis an age at UCBT younger than 2.6 years (hazard ratio, HR=0.27; 95% confidence interval=0.13–0.57; p=0.0005) and the use of a more HLA-compatible donor (HR=0.38; 95% confidence interval=0.16–0.89; p=0.03) predicted better engraftment. CI of grade II-IV acute and chronic graft-versus-host disease (GvHD), and of transplantation-related mortality (TRM) were 31%, 16%, and 33%, respectively. The CI of TRM of our cohort of patients is higher than the 2-year TRM CI of 16% in children with JMML given unrelated donor HSCT reported in the EWOG-MDS analysis. Eleven children relapsed, the 2-year CI of relapse being 22%. In comparison, in the EWOG-MDS study, the 2-year CI of relapse of unrelated HSCT recipients was 36%. The CI of relapse was 30% in patients with monosomy 7 as compared to 19% in the remaining children (p=0.64). With a median follow-up of 36 months (range 3–102), the 2-year disease-free survival (DFS) of the overall cohort was 45%; patients younger or older than 2.6 years had a DFS of 66% and 26% respectively, p=0.01. In multivariate analysis, only age at UCBT was associated with increased DFS (HR=2.98; 95% confidence interval=1.21–7.34; p=0.02). These data indicate that UCBT is a suitable option for children with JMML lacking an HLA-compatible relative and suggest that the search for an unrelated cord blood unit be initiated simultaneously to that for unrelated BM donors. Cord blood offers the advantage of nearly immediate availability of stem cells and allows to perform HSCT even in the presence of donor HLA disparities.