Outcome of Transplantation for Acute Leukemia in Down Syndrome
Authors: Hitzler Johann K. , He Wensheng , Doyle John J , Bitan Menachem , Cairo Mitchell S. , Camitta Bruce , Chan Ka Wah , Diaz Miguel Angel , Fraser Christopher , Gross Thomas , Horan John T. , Kasow Kimberly A. , Kennedy-Nasser Alana , Kitko Carrie , Kurtzberg Joanne , Lehmann Leslie E. , Mitchell David , O'Brien Tracey , Pulsipher Michael A. , Smith Franklin O. , Yu Lolie C. , Zhang Mei-Jie , Eapen Mary , Carpenter Paul A. 
Published: October 2019

Abstract
Abstract 1991
Children with Down syndrome (DS) have a 10-to 20-fold increased incidence of acute lymphoblastic (ALL) and acute myeloid leukemia (AML) compared to the overall pediatric population. Available data on HCT in children with DS are scarce, suggest unsatisfactory outcomes and are conflicting as far as causes of treatment failure are concerned. All but one case series identified treatment-related mortality (TRM) as the major barrier to success. To better understand factors associated with HCT-outcomes we studied 28 patients with DS-AML and 27 patients with DS-ALL, the largest cohort of DS patients with acute leukemia to date. All transplants occurred in 2000–2009. Transplantations occurred in second remission for 43% of patients with DS-AML and 52%, with DS-ALL. With a median follow-up of 3-years disease-free survival (DFS) was 14% for DS-AML and 24% for DS-ALL. Leukemia recurrence was the predominant cause of treatment failure in the current analysis, 61% for DS-AML and 54% for DS-ALL, both substantially higher than expected for pediatric non-DS AML or ALL. In the subset of patients with DS-AML, we conducted a matched pair analysis. Cases (DS-AML) were matched to non-DS AML controls for age, disease status, cytogenetic risk group, donor-source, donor-recipient HLA match and graft source. The results of multivariate analysis, adjusted for interval from diagnosis to transplantation are shown below. Relapse risk was significantly higher in DS-AML than non DS-AML (62% vs. 37%; p<0.001). TRM was also higher in patients with DS-AML compared to non DS-AML (24% vs. 15%, p=0.04). Consequently, 3-year DFS was significantly lower for DS-AML compared to non DS-AML (14% vs. 48%, p<0.001). The corresponding probabilities of overall survival (OS) were 21% and 52% (p<0.001). Interval from diagnosis to transplant was significantly associated with OS; transplantation that occurred within 12 months from diagnosis was associated with higher mortality (hazard ratio 1.90, p=0.03). Interval between diagnosis and transplantation was not significantly associated with relapse (hazard ratio 1.42, p=0.27) or TRM (hazard ratio 2.17, p=0.15). In conclusion, after adjusting for known risk factors, leukemic relapse and TRM contribute to treatment failure after HCT in the recent treatment era. Cooperative group trials appear warranted that improve the selection of HCT candidates, optimize transplant-conditioning regimen and explore novel therapeutic approaches to improve the depth of remission prior to HCT in these children.
Table Hazard Ratio 95% confidence interval P-value Transplant-related mortality     DS-AML vs. non DS-AML 2.52 (1.06–6.00) 0.04 Leukemia recurrence     DS-AML vs. non DS-AML 2.84 (1.75–4.59) <0.001 Treatment failure (death or relapse; inverse of DFS)     DS-AML vs. non DS-AML 2.75 (1.75–4.31) <0.001 Overall mortality     DS-AML vs. non DS-AML 2.86 (1.77–4.64) <0.001

Disclosures:
No relevant conflicts of interest to declare.