Outcome of Down Syndrome (DS) Children with Acute Myeloid Leukemia (AML) or Myelodysplasia (MDS) Treated with a Uniform Prospective Clinical Trial - Initial Report of the COG Trial A2971.
Authors: Gamis Alan S. , Alonzo Todd A. , Hilden Joanne M. , Gerbing Robert B. , Loew Thomas W. , Hathaway Lois , McGavran Loris , Barnard Dorothy , Taub Jeffrey W. , Ravindranath Yaddanapudi , Smith Franklin O. , Arceci Robert 
Published: October 2019

Abstract
DS children with AML have a superior outcome as compared to nonDS children with AML. For COG A2971, etoposide, dexamethasone, & the 3 month maintenance course from the standard timing DCTER regimen used in the prior CCG 2891 trial, were eliminated. From 1999–2003, A2971 enrolled 130 DS patients(pts) with AML(n= 86) or MDS(N=44). Median followup was 1253 days (290 – 2140). Sixteen pts had previously been enrolled in this trial’s TMD (transient myeloproliferative disorder) arm & transferred to this treatment arm when they later developed AML or MDS. Induction consisted of 2 courses(IND C1 & C2) of 2 cycles each of thioguanine PO, with AraC & daunomycin by 96 hour infusion(CI-TAD). Consolidation(CON) followed with intensively timed high dose AraC & L-asparaginase followed by IT AraC weekly ×3. Median age at diagnosis was 1.6 years (y) (0.3–13.6) with 85 in the 0–2y group, 39 ages 2–4y, & 6 over 4y of age. Median CBC values: WBC: 6,200 (900–164,900), hgb: 9 (2.5–16.8), & platelets: 29,000 (2,000–325,000). No patient had CNS disease at diagnosis or relapse. Induction remission was evaluable in 108 pts. CR & PR were achieved in 84% & 8%, progressive disease occurred in 6.5%, and there was one death during induction(p=NS vs 2891). At least one non-hematologic toxicity was reported in 55%, 29%, and 54% of pts during IND C1, IND C2, and CON, respectively. The following toxicities were seen respectively in IND 1, IND 2, CON: mucositis 7%, 0%, & 10%; infectious complications including neutropenic fever without an identified organism 42%, 20%, 42%; hyperglycemia 7%, 0%, 5%; pulmonary 9%, 3%, 7%. There were no clinically significant differences in toxicity between 2891 & A2971 trials. Among all pts, 3y OS was 84%(vs 80% in 2891), EFS was 79%(vs 77%), TRM was 3%(vs 4%), & DFS(from CR) was 90%(vs 85%). In CCG 2891, increasing age was an adverse risk factor. By age groups 0–2, 2–4, & >4y, A2971 3y OS was 89, 82, & 33%, 3y EFS was 83, 79, & 33%, & DFS was 91, 92, & 33%, respectively(ages 0–2 vs 2–4y, all p=NS, except OS trend: p=.007). In CCG 2891, these 3y outcomes by age group were: OS: 86, 75, & 42%; EFS: 86, 68, & 33%; and DFS: 92, 81, & 43%. Improvements in survival were seen between trials, particularly in the 2–4 yo’s, but none were statistically significant when compared by age cohorts. Among the 16 previously enrolled with TMD, median age at AML/MDS diagnosis was 1.0 y and all achieved CR. Fourteen were diagnosed before age 2y & had similar diagnostic findings and outcomes to newly diagnosed pts of similar age(p=NS). This report shows that the elimination of 2 agents and maintenance was achieved without a decrease in survival. Age as an adverse risk factor persisted though with less impact in the 2 to 4 year old group in this study and failed to consistently reach statistical significance. As OS & EFS remain <90%, upcoming COG studies will focus upon further improving survival in DS children with AML.