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