Uniform Approach Better Defines Natural History of Transient Myeloproliferative Disorder (TMD) in Down Syndrome (DS) Neonates: Outcomes from Children’ Oncology Group (COG) Study A2971.

TMD is solely found in DS infants in the first few months of life & is distinguished from congenital AML primarily by its spontaneous resolution. A2971, the largest study of TMD conducted to date, defines the natural history of this disorder by utilizing uniform observation & treatment guidelines. A total of 136 DS patients (pts) <90 days (d) of age were enrolled from 1999–2004 with median follow-up of 745d(0–2187). Pts were assigned to observation(n=110) or intervention(n=26) arms based upon clinical severity. Median age at diagnosis was 5d(0–58) with median hematologic values of WBC 32,800(4,800 – 259,100), hemoglobin 15(5–22.5), platelets 125K(10–958K), peripheral blasts 25%(0–92) & bone marrow blasts 15%(0–95). Hepatomegaly (HM) was seen in 59%, splenomegaly in 39%, & pleural or pericardial effusion in 10% & 19%. Pts required intervention due to hyperviscosity(11%), blast count >100,000/μl(25%), organomegaly(OM) with respiratory(resp) compromise(43%), CHF(11%), hydrops fetalis(21%), liver dysfunction(43%), renal dysfunction(14%), or DIC(25%). For pts who required intervention(n=29, 21%), 9 pts(31%) received leukopheresis/exchange transfusion (Leuk/Exch). 26(90%) pts received low-dose AraC (3.33 mg/kg/24 hrs continuous infusion on days 0–4) for OM, organ dysfunction causing resp compromise, or continued symptoms after Leuk/Exch. Among all pts, 3-year overall survival(OS) was 77 ± 8% & event-free survival(EFS) was 73 ± 9%. 28 deaths were noted (15 related, 12 unrelated to TMD or therapy, 1 unknown). Median time to TMD resolution (defined as resolution of peripheral/ bone marrow blasts, OM, effusions & organ dysfunction) was 46d(7–757). Peripheral blast resolution was attained in a median of 35d (2–147). To date, 16 pts (12%), including 4 treated with AraC, developed AML/MDS at a median time of 355d(118–888). We identified 3 distinct groups of TMD pts: low risk (without palpable HM or hepatic dysfunction, n=52, 38%), intermediate risk (HM with non-life threatening hepatic dysfunction, n=55, 40%), & high risk (WBC>100K or life threatening cardio-resp compromise due to TMD, n=29, 21%). The OS for low, intermediate & high risk groups was 92 ± 8%, 82 ± 11% & 49 ± 20% and EFS was 83 ± 11%, 64 ± 15% & 36 ± 19%, respectively(p<0.001 for low vs high & intermediate vs high risk groups for OS & EFS). WBC >100K (Hazards Ratio-HR 3.57, p=0.004) & presence of hepatomegaly (HR 3.6, p=0.009) were significant adverse risk factors for OS in univariate analyses. This study confirms that most TMD pts undergo spontaneous resolution of disease without intervention, further clarifies the natural history of TMD, & provides baseline comparisons for upcoming COG trials.