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Clinical Trial
. 2018 Jul 10;2(13):1532-1540.
doi: 10.1182/bloodadvances.2018018945.

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

Marius Flasinski  1 , Kira Scheibke  1 , Martin Zimmermann  1 , Ursula Creutzig  1 , Katarina Reinhardt  2 , Femke Verwer  3 , Valerie de Haas  3 , Vincent H J van der Velden  4 , Christine von Neuhoff  5 , C Michel Zwaan  3   6 , Dirk Reinhardt  2 , Jan-Henning Klusmann  7
Affiliations
Clinical Trial

Low-dose cytarabine to prevent myeloid leukemia in children with Down syndrome: TMD Prevention 2007 study

Marius Flasinski et al. Blood Adv. .

Abstract

Approximately 5% to 10% of children with Down syndrome (DS) are diagnosed with transient myeloproliferative disorder (TMD). Approximately 20% of these patients die within 6 months (early death), and another 20% to 30% progress to myeloid leukemia (ML-DS) within their first 4 years of life. The aim of the multicenter, nonrandomized, historically controlled TMD Prevention 2007 trial was to evaluate the impact of low-dose cytarabine treatment on survival and prevention of ML-DS in patients with TMD. Patients received cytarabine (1.5 mg/kg for 7 days) in case of TMD-related symptoms at diagnosis (high white blood cell count, ascites, liver dysfunction, hydrops fetalis) or detection of minimal residual disease (MRD) 8 weeks after diagnosis. The 5-year probability of event-free and overall survival of 102 enrolled TMD patients was 72 ± 5% and 91 ± 3%, respectively. In patients eligible for treatment because of symptoms (n = 43), we observed a significantly lower cumulative incidence (CI) of early death as compared with symptomatic patients in the historical control (n = 45) (12 ± 5% vs 33 ± 7%, PGray = .02). None of the asymptomatic patients in the current study suffered early death. However, the treatment of symptomatic or MRD-positive patients did not result in a significantly lower CI of ML-DS (25 ± 7% [treated] vs 14 ± 7% [untreated], PGray = .34 [per protocol analysis]; historical control: 22 ± 4%, PGray = .55). Thus, low-dose cytarabine treatment helped to reduce TMD-related mortality when compared with the historical control but was insufficient to prevent progression to ML-DS. This trial was registered at EudraCT as #2006-002962-20.

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Conflict of interest statement

Conflict-of-interest disclosure: D.R. has consulting or advisory roles for Celgene, Pfizer, MSD, Astellas Pharma, BlueBirdBio, Amgen, Novartis, and Boehringer and receives research funding from Celgene. C.M.Z. has consulting or advisory roles for Pfizer, Daiichi Sankyo, Celgene, Novartis, Bristol-Myers Squibb, and Gilead Sciences and receives research funding from Karyopharm Therapeutics, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Overview of the TMD Prevention 2007 study. (A) Treatment plan of the TMD07 study. (B) Flowchart of patients enrolled in the TMD07 study.
Figure 2.
Figure 2.
Outcome of TMD07 patients compared with the historical control. (A) OS. (B) EFS. (C) CI of early death. Five-year probabilities are given in panels A and B.
Figure 3.
Figure 3.
Outcome of symptomatic TMD07 patients (intention-to-treat at diagnosis) compared with symptomatic patients in the historical control. (A) OS. (B) EFS. (C) CI of early death. Five-year probabilities are given in panels A and B.
Figure 4.
Figure 4.
Progression to ML-DS. CI of ML-DS: (A) TMD07 patients compared with the historical control. (B) Per protocol analysis: Treated TMD07 patients compared with asymptomatic, MRD-negative, untreated TMD07 patients and to the historical control. (C) MRD-positive TMD07 patients compared with MRD-negative TMD07 patients in week 12. Five-year probabilities are given in panels A through C.
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References

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