● ● ● CLINICAL TRIALS

Comment on Gamis et al, page 6752

Enigmatic variation----------------------------------------------------------------------------------------------------------------

Irene Roberts and Paresh Vyas IMPERIAL COLLEGE LONDON; UNIVERSITY OF OXFORD

Variability in presentation and prognosis of transient myeloproliferative disorder(TMD) in infants with Down syndrome (DS) has perplexed clinicians and scien-tists for decades and is explored in this issue of Blood by Gamis and colleagues fromthe Children’s Oncology Group (COG).1

TMD is a clonal myeloproliferation uniqueto neonates with DS that is characterized

by increased circulating blast cells morpho-logically indistinguishable from those in DS–myeloid leukemia (DS-ML).2-4 Indeed, 20%to 30% of infants with TMD subsequentlydevelop ML-DS; fortunately, in most casesTMD spontaneously resolves without latertransformation.4 Although TMD is diagnosedin 5% to 10% of neonates with DS, its exactfrequency is expected to be determined bypopulation-based studies currently in prog-

ress. Identification of N-terminal mutations inthe key megakaryocyte transcription factorGATA1 in both ML-DS and TMD providedimportant insight into their pathogenesis.5-8

Molecular, biologic, and clinical data indicatethat ML-DS is initiated before birth whenfetal liver hematopoietic stem and/or progeni-tor cells trisomic for chromosome 21 (Hsa21)acquire GATA1 mutations.3,4,6,8,9 Cases withpaired ML-DS and TMD samples show thesame GATA1 mutation, indicating they areclonally linked conditions.8 Thus, TMD and

ML-DS provide a tractable model to investi-gate leukemia intiation and progression(see figure). Nevertheless, many questionsremain to be answered before accumulatingmolecular and clinical data can be assembledinto a model that accounts for the extraordi-nary variability in the natural history of theseconditions.

First, because TMD is only loosely definedeven in the World Health Organization classi-fication,2 any DS or mosaic DS neonate couldhave TMD because there are other causes ofcirculating blasts. Thus, it is essential to accu-rately define TMD and establish useful diag-nostic criteria. Second, because the clinical pre-sentation of TMD varies from life-threateningorgan infiltration to asymptomatic leukocyto-sis,1,4 it is important to identify which factorsreliably predict TMD outcome and thereforewhich patients are likely to benefit from treat-ment. Allied to this is the need to establish themost effective treatment regimens for TMD.While the study by Gamis and colleagues can-not answer all of these questions, it is one ofthe largest prospective studies of the naturalhistory of clinically diagnosed TMD and pro-vides valuable clinical information for hema-tologists and pediatricians.1 Strengths of thestudy are the uniform, albeit broad, clinicaldiagnostic criteria and treatment and monitor-ing guidelines. A limitation, as the authorsadmit, is that the study was designed beforerecognition of GATA1 mutations in TMDwhich, given that TMD may be asymptom-atic, prevents conclusions about the naturalhistory of the full spectrum of this enigmaticdisorder.

Hematologists usually encounter TMDthrough consultation on abnormal hemato-logic findings. Importantly for diagnosis, mostneonates with TMD in the study were notanemic and had platelet counts similar to DSneonates without TMD.1 The principal hema-tologic abnormalities were leukocytosis (median32.8 � 103/uL) and increased peripheral bloodblasts (median 25%). Interestingly 16% had

Molecular, biologic, and clinical data, such as the study by Gamis et al,1 indicate that transient myeloprolifera-tive disorder (TMD) and Down syndrome–associated acute myeloid leukemia (ML-DS) are initiated before birthwhen fetal liver hematopoietic stem and/or progenitor cells trisomic for chromosome 21 acquire GATA1mutations. TMD usually presents around birth with a spectrum of clinical features from life-threatening hepaticfibrosis to asymptomatic leukocytosis. Although most cases of TMD spontaneously and permanently remit bythe age of 6 months, in 15% to 30% of cases additional genetic events lead to further expansion of the trisomicGATA1-containing clone(s) resulting in ML-DS before the age of 5 years.

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mosaicism for Hsa21, confirming that pheno-typically normal neonates with hematologicfindings consistent with TMD should bescreened for trisomy 21 because Gamis and col-leagues’ study confirms others indicating theyare similarly at risk of ML-DS.1,4,10 More than75% of infants underwent bone marrow exami-nation. Because it is unclear what additional in-formation was obtained, it could be argued thatmarrow examination is unnecessary in infantswith trisomy 21 where clinical and hemato-logic features are typical of TMD, particularlywhere GATA1 mutations confirm a (pre)leu-kemic clone.7,8,10

An important dilemma in TMD manage-ment is identifying which infants will benefitfrom treatment and what treatment is mosteffective in the short- and long-term. Gamisand colleagues approached the first questionusing prospectively defined criteria for thepresence of one or more life-threateningsymptoms (LTS), including hepatic dysfunc-tion, hydrops fetalis, or blast count(� 100 000/�L), as sole criteria for institut-ing treatment at the physician’s discretion.1

Almost half of those with LTS treated accord-ing to the guidelines (13/29) succumbed toTMD or treatment complications. By con-trast, TMD resolved completely withouttreatment in all patients without LTS, asfound previously where similar treatmentguidelines were used.4 These data support theconclusion that neonates without LTS(at diagnosis or while hematologic evidence ofTMD persists) can safely be monitored with-out treatment because their outcome isfavorable.

Previous reports confirmed here show thatTMD patients with high-risk features definedas organ infiltration, especially hepatic, and/orhigh leukocyte count (� 100,000/uL) have amortality of more than 30%.1,3,4 Klusmann etal’s study showed that treatment of patientswith high-risk features (which also includedascites, prematurity, and failure of remissionof TMD), improved survival in the firstmonths of life. Gamis and colleagues did notfind improved survival of TMD patients withtreatment (cytarabine 3.33 mg/kg/24 hoursby continuous infusion for 5 days), perhapsbecause their guidelines permitted treatmentfor less severe TMD (a single LTS) and/orbecause cytarabine-related toxicity was high(96% grade 3/4 toxicity). Although the mainaim of treating high-risk TMD is improve-ment in short-term survival, eradicating the

(pre)leukemic clone(s) and consequent reduc-tion in risk of later ML-DS is a potential long-term benefit. Unfortunately, no studies, in-cluding that of Gamis and colleagues, have yetdemonstrated a significant impact of treatmenton the likelihood of developing ML-DS.1,4

Thus, further studies are needed to refinetreatment intervention criteria for TMD andthe most effective treatment regimen forshort-term and long-term benefit.

The findings of Gamis et al are neverthe-less helpful for clinicians caring for neonatesand children with DS and go some way to an-swering important clinical questions. How-ever, many other questions remain: What isthe relationship between TMD, as clinicallydefined, and the presence of GATA1 muta-tion(s)? Does the presence of GATA1 muta-tion(s) in the absence of typical clinical andhematologic features constitute TMD anddoes this carry the same risk of transformationto ML-DS? Can patients without GATA1mutations at birth develop ML-DS, and doesthis share the same characteristic time windowof presentation (� 5 years of age) and immu-nophenotypic (typically megakaryoblastic)and genetic features, characteristically seen inpatients with GATA1 mutations in the neona-tal period? Answers to such questions con-tinue to fascinate all interested in Hsa21 andits many enigmatic links to leukemia.

Conflict-of-interest disclosure: The authorsdeclare no competing financial interests. ■

REFERENCES

1. Gamis AS, Alonzo TA, Gerbing RB, et al. Naturalhistory of clinically diagnosed transient myeloprolifera-tive disorder in Down syndrome neonates: a report fromthe Children’s Oncology Group study A2971. Blood. 2011;118(26):6752-6759.

2. Hasle H, Niemeyer CM, Chessells JM, et al. A pedi-atric approach to the WHO classification of myelodys-plastic and myeloproliferative diseases. Leukemia. 2003;17(2):277-282.

3. Massey GV, Zipursky A, Chang MN, et al. A prospec-tive study of the natural history of transient leukemia (TL)in neonates with Down syndrome (DS): Children’s Oncol-ogy Group (COG) study POG-9481. Blood. 2006;107(12):4606-4613.

4. Klusmann JH, Creutzig U, Zimmermann M, et al. Treat-ment and prognostic impact of transient leukemia in neonateswith Down syndrome. Blood. 2008;111(6): 2991-2998.

5. Wechsler J, Greene M, McDevitt MA, et al. Acquiredmutations in GATA1 in the megakaryoblastic leukemia ofDown syndrome. Nat Genet. 2002;32(1):148-152.

6. Rainis L, Bercovich D, Strehl S, et al. Mutations inexon 2 of GATA1 are early events in megakaryocytic malig-nancies 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 mega-karyoblastic leukemia of Down syndrome. Blood. 2003;101(11):4301-4304.

8. Ahmed M, Sternberg A, Hall G, et al. Natural historyof GATA1 mutations in Down syndrome. Blood. 2004;103(7):2480-2489.

9. Tunstall-Pedoe O, Roy A, Karadimitris A, et al. Ab-normalities in the myeloid compartment in Down Syn-drome fetal liver precede acquisition of GATA1 mutations.Blood. 2008;112(12):4507-4511.

10. Alford KA, Reinhardt K, Garnett C, et al. Analysis ofGATA1 mutations in Down syndrome transient myelopro-liferative disorder and myeloid leukemia. Blood. 2011;118 (8):2222-2238.

● ● ● IMMUNOBIOLOGY

Comment on Romer et al, page 6772

Predicting cytokine storms: it’s aboutdensity----------------------------------------------------------------------------------------------------------------

Matthew J. Frigault and Carl H. June ABRAMSON CANCER CENTER

Romer and colleagues in this issue of Blood report that the density of T cells duringculture increases sensitivity to the CD28 cosignaling agent TGN1412, providingan improved means of predicting cytokine release syndrome (CRS).1

CRS is a common clinical event with an-tibody therapies such as rituximab and

anti-CD3 antibody. After the infusion of theCD28 superagonist TGN1412 all 6 healthyrecipients unexpectedly suffered a severeform of CRS, often referred to as a cytokinestorm.2 The massive release of proinflam-matory cytokines rapidly progressed to

severe multiorgan failure requiring ad-vanced medical resuscitation. The events ofthe March 2006 first-in-human trial ofTGN1412 have since sparked a fundamentaldiscussion regarding the failure of preclini-cal models to predict toxicities and how newbiologics are assessed before first-in-humantesting (see figure).

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doi:10.1182/blood-2011-09-3761452011 118: 6723-6724  

Irene Roberts and Paresh Vyas Enigmatic variation 

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