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22 DECEMBER 2011 I VOLUME 118, NUMBER 26
CLINICAL TRIALS
Enigmatic
variation
---------------------------------------------------------------------------------------------------------------Irene Roberts and Paresh Vyas
Molecular, biologic, and clinical data, such as the study by Gamis et al,1 indicate that transient myeloproliferative disorder (TMD) and Down syndromeassociated acute myeloid leukemia (ML-DS) are initiated before birth
when fetal liver hematopoietic stem and/or progenitor cells trisomic for chromosome 21 acquire GATA1
mutations. TMD usually presents around birth with a spectrum of clinical features from life-threatening hepatic
fibrosis to asymptomatic leukocytosis. Although most cases of TMD spontaneously and permanently remit by
the age of 6 months, in 15% to 30% of cases additional genetic events lead to further expansion of the trisomic
GATA1-containing clone(s) resulting in ML-DS before the age of 5 years.
blood 2 2 D E C E M B E R 2 0 1 1 I V O L U M E 1 1 8 , N U M B E R 2 6
From www.bloodjournal.org by guest on July 29, 2015. For personal use only.
mosaicism for Hsa21, confirming that phenotypically normal neonates with hematologic
findings consistent with TMD should be
screened for trisomy 21 because Gamis and colleagues study confirms others indicating they
are similarly at risk of ML-DS.1,4,10 More than
75% of infants underwent bone marrow examination. Because it is unclear what additional information was obtained, it could be argued that
marrow examination is unnecessary in infants
with trisomy 21 where clinical and hematologic features are typical of TMD, particularly
where GATA1 mutations confirm a (pre)leukemic clone.7,8,10
An important dilemma in TMD management is identifying which infants will benefit
from treatment and what treatment is most
effective in the short- and long-term. Gamis
and colleagues approached the first question
using prospectively defined criteria for the
presence of one or more life-threatening
symptoms (LTS), including hepatic dysfunction, hydrops fetalis, or blast count
( 100 000/L), as sole criteria for instituting treatment at the physicians discretion.1
Almost half of those with LTS treated according to the guidelines (13/29) succumbed to
TMD or treatment complications. By contrast, TMD resolved completely without
treatment in all patients without LTS, as
found previously where similar treatment
guidelines were used.4 These data support the
conclusion that neonates without LTS
(at diagnosis or while hematologic evidence of
TMD persists) can safely be monitored without treatment because their outcome is
favorable.
Previous reports confirmed here show that
TMD patients with high-risk features defined
as organ infiltration, especially hepatic, and/or
high leukocyte count ( 100,000/uL) have a
mortality of more than 30%.1,3,4 Klusmann et
als study showed that treatment of patients
with high-risk features (which also included
ascites, prematurity, and failure of remission
of TMD), improved survival in the first
months of life. Gamis and colleagues did not
find improved survival of TMD patients with
treatment (cytarabine 3.33 mg/kg/24 hours
by continuous infusion for 5 days), perhaps
because their guidelines permitted treatment
for less severe TMD (a single LTS) and/or
because cytarabine-related toxicity was high
(96% grade 3/4 toxicity). Although the main
aim of treating high-risk TMD is improvement in short-term survival, eradicating the
6724
(pre)leukemic clone(s) and consequent reduction in risk of later ML-DS is a potential longterm benefit. Unfortunately, no studies, including that of Gamis and colleagues, have yet
demonstrated a significant impact of treatment
on the likelihood of developing ML-DS.1,4
Thus, further studies are needed to refine
treatment intervention criteria for TMD and
the most effective treatment regimen for
short-term and long-term benefit.
The findings of Gamis et al are nevertheless helpful for clinicians caring for neonates
and children with DS and go some way to answering important clinical questions. However, many other questions remain: What is
the relationship between TMD, as clinically
defined, and the presence of GATA1 mutation(s)? Does the presence of GATA1 mutation(s) in the absence of typical clinical and
hematologic features constitute TMD and
does this carry the same risk of transformation
to ML-DS? Can patients without GATA1
mutations at birth develop ML-DS, and does
this share the same characteristic time window
of presentation ( 5 years of age) and immunophenotypic (typically megakaryoblastic)
and genetic features, characteristically seen in
patients with GATA1 mutations in the neonatal period? Answers to such questions continue to fascinate all interested in Hsa21 and
its many enigmatic links to leukemia.
Conflict-of-interest disclosure: The authors
declare no competing financial interests.
REFERENCES
1. Gamis AS, Alonzo TA, Gerbing RB, et al. Natural
history of clinically diagnosed transient myeloproliferative disorder in Down syndrome neonates: a report from
the Childrens Oncology Group study A2971. Blood. 2011;
118(26):6752-6759.
2. Hasle H, Niemeyer CM, Chessells JM, et al. A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia. 2003;
17(2):277-282.
3. Massey GV, Zipursky A, Chang MN, et al. A prospective study of the natural history of transient leukemia (TL)
in neonates with Down syndrome (DS): Childrens Oncology Group (COG) study POG-9481. Blood. 2006;107(12):
4606-4613.
4. Klusmann JH, Creutzig U, Zimmermann M, et al. Treatment and prognostic impact of transient leukemia in neonates
with Down syndrome. Blood. 2008;111(6): 2991-2998.
5. Wechsler J, Greene M, McDevitt MA, et al. Acquired
mutations in GATA1 in the megakaryoblastic leukemia of
Down syndrome. Nat Genet. 2002;32(1):148-152.
6. Rainis L, Bercovich D, Strehl S, et al. Mutations in
exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood. 2003;102(3):
981-986.
7. Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A.
GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood. 2003;101
(11):4301-4304.
8. Ahmed M, Sternberg A, Hall G, et al. Natural history
of GATA1 mutations in Down syndrome. Blood. 2004;103
(7):2480-2489.
9. Tunstall-Pedoe O, Roy A, Karadimitris A, et al. Abnormalities in the myeloid compartment in Down Syndrome fetal liver precede acquisition of GATA1 mutations.
Blood. 2008;112(12):4507-4511.
10. Alford KA, Reinhardt K, Garnett C, et al. Analysis of
GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia. Blood. 2011;118 (8):
2222-2238.
IMMUNOBIOLOGY
Romer and colleagues in this issue of Blood report that the density of T cells during
culture increases sensitivity to the CD28 cosignaling agent TGN1412, providing
an improved means of predicting cytokine release syndrome (CRS).1
RS is a common clinical event with antibody therapies such as rituximab and
anti-CD3 antibody. After the infusion of the
CD28 superagonist TGN1412 all 6 healthy
recipients unexpectedly suffered a severe
form of CRS, often referred to as a cytokine
storm.2 The massive release of proinflammatory cytokines rapidly progressed to
blood
From www.bloodjournal.org by guest on July 29, 2015. For personal use only.
Enigmatic variation
Irene Roberts and Paresh Vyas
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
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Copyright 2011 by The American Society of Hematology; all rights reserved.