what's up with down syndrome and leukemia-a lot!

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  • Pediatr Blood Cancer 2011;57:13

    HIGHLIGHTby Jeffrey W. Taub, MD1,2,3* and Yaddanapudi Ravindranath, MBBS1,2,3

    Whats Up With Down Syndrome and Leukemia-A Lot!(Commentary on Taga et al., page 36)

    J ust over 50 years ago, Lejeune et al. [1] identified that theunderlying genetic abnormality in Down syndrome (DS) wasthe presence of three copies of chromosome 21 (trisomy 21). Since

    than, many of the landmark studies that have identified various

    clinical and biological features of DS relate to the patterns of

    malignancies in individuals with DS. Children with DS represent

    approximately 3% and 15% of pediatric acute lymphoblastic

    leukemia (ALL) and acute myeloid leukemia (AML) cases,

    respectively [2,3]. In contrast, there is a paradoxical lower

    incidence of solid tumors in DS individuals [4,5], leading to the

    identification of several chromosome 21-localized genes which

    appear to play a protective role in preventing the development of

    tumors including genes linked to angiogenesis [e.g., ADAMTS1;

    ERG; Down syndrome candidate region 1 (DSCR1)] and

    transcription factors [e.g., ETS2] [68].

    Beginning in the late 1980s, Dr. Alvin Zipursky highlighted

    several of the unique features of myeloid malignancies in children

    with DS, including: (i) the remarkably high predisposition to

    develop acute megakaryocytic leukemia (AMkL), which is

    estimated to be 500-fold greater compared to children without DS

    and (ii) an estimation that up to 10% of neonates with DS are born

    with the transientmyeloproliferative disorder (TMD), a precursor to

    AMkL, which can resolve spontaneously in a high proportion of

    cases with supportive care [911]. Childrenwith DS and TMDhave

    an approximate 30% risk of developing myeloid malignancies

    characterized by either myelodysplasia or AMkL, which are

    frequently referred collectively as myeloid leukemias of DS.

    In 1992, the Pediatric Oncology Group (POG) reported an

    unexpected and remarkable finding that 12 children with DS and

    AML had event-free survival (EFS) rates of 100% compared to 28%

    for a group of children without DS treated in a similar fashion on the

    POG 8498 clinical trial [12]. Since this initial report, multiple

    clinical trials reported by POG, the Childrens Cancer Group

    (CCG), Childrens Oncology Group (COG), Berlin-Frankfort-

    Munster (BFM)-AML, Nordic Society of Pediatric Hematology/

    Oncology (NOPHO), Medical Research Council (MRC), Hospital

    for Sick Children (Toronto), France, and Japanese Childhood AML

    cooperative groups have confirmed that children with DS and

    myeloid leukemias typically have EFS rates of approximately 80%

    associated with low relapse/induction failure rates [3,1320].

    In this issue of Pediatric Blood & Cancer, the results of the

    Japanese Childrens Cancer and Leukemia Study Group AML 9805

    study which enrolled 24 patients with DS were reported. Although

    the number of patients enrolled on the trial was less than other

    reported studies, it still serves to highlight several important issues

    for clinicians treating children with DS. All of the patients were

    younger than 4 years of age (95% of DS AML cases occur before

    the age of 4 years [3]), 7 (29%) patients had a past history of TMD

    and all of the patients were classified as having AMkL. Twenty-one

    patients achieved complete remission, while three patients died

    of infectious complications during induction. Post-induction

    therapy, there were no deaths from toxicity and only one patient

    suffered an off therapy extramedullary relapse. All four patients

    with monosomy 7 remained in remission. The 5-year overall and

    EFS were 87.5% 6.8% and 83.1% 7.7%, respectively.One of the challenges faced in treating children with DS and

    leukemia is balancing curative therapy against potential toxicities,

    which are typically infectious complications secondary to myelo-

    suppression and potential cardiac toxicity against a background of

    individualswho have a high incidence of congenital heart defects. In

    the POG 8498 study, the cumulative cytarabine dose used was

    40,700mg/m2; in the current COGAAML0431 clinical trial AAML

    0431 The Treatment of Down Syndrome Children with Acute

    Myeloid Leukemia and Myelodysplastic Syndrome Under the Age

    of 4 Years, the cumulative cytarabine dose is 27,800mg/m2 and in

    this Japanese study, 12,600mg/m2. What is the minimum effective

    cytarabine dose schedule in DS AMkL cases? A recent study from

    France reported that the results with the ultra low dose schedule as

    originally proposed by Zipursky et al. was less effective than a

    combination of standard 100200mg/m2/dose 7 days courseduring induction and high dose cytarabine (500mg/m2/dose 412) in consolidation [10,20]. The current study from Japan suggests

    that cytarabine doses of 1 g/m2/dose 10 doses for consolidationmay be as effective as regimens using higher cytarabine dose

    schedules and may be associated with less toxicity. Biological

    studies, including minimal residual disease detection, may identify

    subsets of patients with DS and AMLwho could be treated with low

    dose cytarabine regimens.

    Increased cardiac toxicity has been reported in prior studies

    including a 17.5% incidence and three deaths from heart failure in

    patients with DS treated on the POG 9421 AML trial, which used

    daunorubicin and mitoxantrone with a combined cumulative

    anthracycline dose of 535mg/m2 (based on a conversion factor of

    5:1 for mitoxantrone) [14]. In the current Japanese study, nine

    patients had congenital heart defects and no severe cardiac toxicity

    2011 Wiley-Liss, Inc.DOI 10.1002/pbc.23033Published online 7 April 2011 in Wiley Online Library(wileyonlinelibrary.com).

    1Division of Pediatric Hematology/Oncology, Childrens Hospital of

    Michigan, Michigan; 2Developmental Therapeutics Program, Barbara

    Ann Karmanos Cancer Institute, Michigan; 3Departments of

    Pediatrics, Wayne State University School of Medicine, Detroit,


    *Correspondence to: Jeffrey W Taub, Division of Hematology/

    Oncology, Childrens Hospital of Michigan, Department of

    Pediatrics, Wayne State University School of Medicine, 3901

    Beaubien Blvd., Detroit, Michigan 48201, USA.

    E-mail: jtaub@med.wayne.edu

    Received 20 December 2010; Accepted 20 December 2010

  • was reported with the use of a lower cumulative anthracycline dose,

    highlighting the importance of limiting anthracycline dosing.

    Identifying factors associated with DS leukemogenesis accel-

    erated significantly following the identification in 2002 byWechsler

    et al. [21] that somatic mutations in the chromosome X-linked

    hematopoietic factor, GATA1, were present in DS AMkL cases.

    Subsequent studies identified thatGATA1mutations are specific and

    have been detected almost uniformly in all DS AMkL and TMD

    cases and not detected in remission DS marrows, non-DS AML

    cases nor DS ALL cases [2224]. The mutations include deletions,

    missense, non-sense, and splice site mutations at the exon 2/intron

    boundarywith the net effect of introducing early stop codons and the

    synthesis of a shorter 40-kDa GATA1 protein, designated GATA1s,

    that is translated from a downstream initiation site and distinguish-

    able from the full-length 50-kDa GATA1 protein. The GATA1s

    protein has altered transactivation activity, likely contributing to the

    uncontrolled proliferation of megakaryocytes. The acquisition of

    GATA1 mutations are likely early steps in a multistep process of

    leukemogenesis and arise prenatally based on several studies

    including their detection in fetal tissues, and retrospective detection

    in Guthrie newborn screening cards from infants with DS who later

    developed AMkL [25,26]. Trisomy 21 likely contributes to the

    development of GATA1 mutations in DS potentially due to a gene

    dosage effect of several chromosome 21-localized genes including

    cystathionine-b-synthase (CBS), and zinc-copper superoxide dis-mutase (SOD1) which are linked to abnormal intracellular folate

    metabolism, uracil accumulation and increased oxidative stress

    leading to DNA damage [27]. Although GATA1 analysis was not

    performed in the current study, the mutations are specific for the DS

    AMkL phenotype and would likely have been detected.

    The basis for the high EFS rates in patients with DS and AML,

    and in particular, individuals with AMkL, is likely due to increased

    sensitivity of blasts to several drugs including cytarabine,

    daunorubicin, and etoposide [2830]. Overexpression of CBS has

    been correlated with in vitro generation of ara-CTP, the active

    intracellular cytarabine metabolite, and subsequent increased

    cytarabine sensitivity in DSAMkL blast cells [29,31]. The presence

    of GATA1 mutations and the generation of GATA1s, interacts and

    modulates the expression of different genes, such as the cytidine

    deaminase genewhichwould also enhance the activity of cytarabine

    in DS blast cells [32,33]. Differential expression of additional genes

    including GATA1 target genes between DS and non-DS blast cells,

    also likely contributes to the high EFS rates of DS cases [34,35]. DS

    AMkL blast cells exhibit high expression of CD36, a megakar-

    yocyte maturation marker [36]. Interestingly, non-DS AMkL blasts

    with high expression of CD 36 demonstrated a similar pattern of

    in vitro drug sensitivity as DS