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in a Different Vein Research from ASH’s online peer-reviewed journal, Blood Advances Can Cytarabine Prevent Progression to Myeloid Leukemia in Children With Down Syndrome and Transient Myeloproliferative Disorders? In pediatric patients with Down syndrome (DS) and transient myeloproliferative disorder (TMD), treatment with low-dose cytarabine lowered early mortality risk, compared with historical controls, according to results published in Blood Advances. However, treatment with cytarabine did not appear to reduce the risk of progression from TMD to my- eloid leukemia (ML-DS) – the study’s primary goal. “The failure to prevent the development of ML-DS suggests that it is not possible to entirely eliminate the preleukemic GATA1-mutated clone via [low-dose cytarabine],” lead author Marius Flasinski, MD, of Hannover Medical School in Germany, and col- leagues wrote. “Therefore, a more targeted therapy that is directed to the preleukemic cells seems to be required to prevent the progression to ML-DS.” The researchers reported results from the multicenter, non-randomized TMD Prevention 2007 (TMD07) trial, which evaluated the effect of low-dose cytarabine on survival and prevention of ML-DS in 102 children (median age = 4 days; range = 0-88 days) with DS and TMD. Patients were eli- gible for inclusion if they had trisomy 21, >5 percent myeloid blasts, or detection of a GATA1 mutation in the peripheral blood and/or bone marrow within the first three months of life. Per the TMD07 study protocol, participants re- ceived cytarabine 1.5 mg/kg for a seven-day period if they presented with the following criteria: • TMD-related signs (white blood cell count >50×10 9 /L, platelets <100×10 9 /L, and liver dysfunction) at time of diagnosis • minimal residual disease (MRD) via flow cytometry at 8 weeks following diagnosis • no adequate response to cytarabine (assessed by MRD positivity and/or detectable blasts following therapy) In total, 28 patients (72%) received treatment be- cause of signs at diagnosis and 11 (28%) because of detection of MRD. The incidence of mortality and progression to ML-DS in the TMD07 were compared with those in a historical cohort of 148 patients enrolled in the Acute Myeloid Leukemia Berlin-Frankfurt-Munster study; patients received preventive cytarabine per study protocol (at doses ranging from 0.5-1.5 mg/kg). During a median follow-up of 36.1 months (range not reported), nine patients died. Causes of death included sepsis (n=2), cardiac events (n=2), liver failure (n=2), asphyxia (n=1), ML-DS (n=1), and unknown (n=1). Overall, the authors noted, “five patients died because of complications that can be directly (n=2) or possibly (n=3) attributed to TMD.” This represented a five-year overall survival (OS) rate of 91 percent and five-year event-free survival (EFS) rate of 72 percent, compared with 85 percent and 63 percent in the historical control group (p=0.15 for each comparison). While this comparison did not reach statistical significance, the cumulative incidence of early mortality (within 6 months of TMD diagnosis) was significantly lower in the TMD07 cohort than in the control group (12% vs. 33%; p=0.02). This reduction in early mortality resulted in a trend toward better five-year EFS and five-year OS in the cytarabine- treated group: • EFS: 59% vs. 44% (p=0.097) • OS: 80% vs. 67% (p=0.10) Seventeen children in the TMD07 trial developed ML-DS, at a mean age of 15.3 months. There was no statistically significant difference in five-year rates of ML-DS between these patients and the historical controls (19% vs. 22%; p=0.88). The authors also noted that “no clinical or laboratory parameters present at diagnosis were associated with the devel- opment of ML-DS.” Among the MRD-positive patients who received cytarabine, the five-year incidence of ML-DS did not differ significantly between asymptomatic patients that were either MRD-positive or MRD-negative at eight weeks after TMD diagnosis (31% vs. 14%; p=0.25). “The trial demonstrates that the progression to ML-DS cannot be prevented by low-dose cytara- bine,” the researchers concluded. “Even an MRD monitoring–based treatment approach was not able to lower the occurrence of ML-DS.” Although the authors reported that “the treat- ment was well-tolerated,” treatment-related adverse events observed in the treatment group included: • nausea (n=6) • severe thrombocytopenia (<20×10 9 /L) (n=10) • severe neutropenia (<0.5×10 9 /L) (n=12) • fatigue (n=13) The authors made the following recommendations for treatment with cytarabine: “Patients [who] present with TMD-related clinical [signs] benefit from low-dose cytarabine treatment to prevent early death, [while] patients [without signs] instead should not receive treatment as they are not at risk of TMD-related early death.” The study’s findings are limited by its non- randomized design and reliance on a historical control to draw comparisons, as well as the relatively small number of patients in both the treatment and historical control groups. The authors report financial relationships with Pfizer, Amgen, Novartis, Bristol-Myers Squibb, and GlaxoSmithKline. The study was supported by the German Research Foundation and the European Research Council. REFERENCE Flasinski M, Scheibke K, Zimmermann M, et al. Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study. Blood Advances. 2018;2:1532-40. PERSPECTIVES “These findings add to