Page 1135 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 63 Myelodysplastic Syndromes and Myeloproliferative Neoplasms in Children 1001

treatment but others having a rapidly fatal course despite aggressive delivery are taken into account, the incidence may be as high as
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treatment. 176,177 The patients likely to do well without HCT are those 20%. Currently, it is estimated that approximately 20%–30% of
with somatic NRASG212S or KRASG12V mutations, or germline children with TAM subsequently develop AML, usually by 3 years
mutations in CBL. 178–180 Older age, lower platelet count, and elevated of age. This estimate was validated in a recent prospective study
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hemoglobin F levels have been used to predict a more aggressive conducted by the COG. In this study, AML developed in 16% of
clinical course for patients. 181–185 Currently, the most adverse prog- Down syndrome children who had TAM at a median of 441 days
nostic factor for outcome is the presence of >20% blasts or an (118–1085 days).
AML-like gene expression profile, 181,184 which have survival rates of
<10% even with allogeneic HCT.
A wide variety of agents have been used to treat children with Pathobiology
JMML, including AML-like chemotherapy, 59,186–191 low-dose che-
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motherapy, 192,193 interferon-α (IFN-α), and 13-cis-retinoic acid. The molecular pathogenesis of TAM and ML-DS in children with
Tipifarnib, a farnesyl transferase inhibitor, was tested in a Phase II Down syndrome is now providing valuable insights into myeloid
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window by the Children’s Oncology Group (COG) where it pro- leukemogenesis. Current research suggests that the development of
duced some responses, but did not appear to impact long-term TAM and subsequent progression to ML-DS are the result of a
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survival. Perhaps because the evaluation of these treatment regi- three-step process: perturbation of fetal hematopoiesis by trisomy 21;
mens has been complicated by small patient numbers, a prior lack an acquired GATA1 mutation; and the acquisition of additional
of consistent response criteria, and until recently, lack of assays to oncogenic mutations. 208,209
measure the burden of clonogenic JMML stem cells, the utility of It is increasingly clear that trisomy 21 results in genome-wide
chemotherapy prior to HCT is unclear. One report showed no dif- changes in gene expression that affect, directly or indirectly, most
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ference in univariate post-HCT outcomes in patients who did or chromosomes. This results in perturbed hematopoiesis with
did not receive AML-like chemotherapy, but this was limited by the increased numbers and clonality of HSCs, increased frequency of
inclusion of patients with AML and the lack of multivariate analy- megakaryocyte and erythroid progenitors, and reduced numbers of
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sis. Several newer reports show trends towards better post-HCT granulocyte- and macrophage-committed progenitor cells. 211,212
outcomes in patients who either received AML-like chemotherapy Recent studies have shown that virtually all patients with TAM
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(without mention of response) or who had normalization of and most patients with ML-DS harbor mutations in exon 2 and
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WBC count and organomegaly prior to HCT. With the advent occasionally in exon 3 of the hematopoietic transcription factor
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of uniform response criteria and the ability to follow molecular GATA1. 213–217 GATA1 is a double–zinc finger DNA-binding tran-
disease burden in patients with mutations in PTPN11, NRAS, and scription factor expressed primarily in hematopoietic cells. It is
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KRAS, more definitive data on the role of pre-HCT chemotherapy required for the development of red blood cells, megakaryocytes,
may soon be forthcoming. For most children with JMML, alloge- mast cells, and eosinophils. A number of different mutations in
neic HCT offers the only known potential for cure, with about half GATA1 have been identified, including insertions, deletions, missense
of transplanted children surviving disease free. 182,197,198 Rapid with- mutations, nonsense mutations, and slice site mutations. All of these
drawal of immunosuppression appears to be important in this mutations lead to a block in the expression of the full-length 50-kd
disease, as mounting evidence supports a graft-versus-leukemia isoform of GATA1 but allow for the expression of a smaller, 40-kd
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effect. 199,200 A number of issues related to HCT for JMML remain isoform (GATA1s). This smaller isoform lacks the N-terminal
uncertain. Among these are the value of pretransplant splenectomy transactivation domain but retains both zinc fingers involved in DNA
and the optimal conditioning regimen and graft-versus-host disease binding as well as interactions with its cofactor, friend of GATA1
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prophylaxis. Splenectomy, a procedure not without long-term risks, (FOG1). Recent studies have shown that mutations that alter
had a trend towards improved outcomes in patients undergoing GATA1-FOG1 binding in the N-terminal zinc finger or result in the
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umbilical cord blood transplant, but no benefit in those getting expression of the GATA1s isoform uncouple megakaryocyte growth
transplants from other donors. 181,195 Radiation-containing prepara- and differentiation. 219–221 Similar studies in cell lines derived from
tive regimens, which have significant long-term risks in small chil- children with ML-DS have demonstrated that expression of GATA1
dren, have not shown benefit when compared with other published led to erythroid differentiation whereas expression of GATA1s did not
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reports, although they did decrease the risk of rejection in patients alter the characteristics of the cell line. Taken together, current data
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undergoing cord blood transplant. The most common cause of suggest that the loss of GATA1 and expression of GATA1s directly
death after HCT is recurrent disease, but a second HCT can be contribute to leukemogenesis.
lifesaving for some children. 181,201,202 Donor leukocyte infusions have Although mutations in GATA1 may be sufficient to cause TAM,
variable response rates. 200,203 these mutations are not sufficient for the development of ML-DS, as
evidenced by the latency period between resolution of TAM and the
Down Syndrome–Associated Transient development of ML-DS, as well as the observation that not all chil-
Abnormal Myelopoiesis dren with TAM and GATA1 mutations will ultimately develop
ML-DS. Therefore a multistep pathogenesis model is proposed in
patients with Down syndrome in whom ML-DS develops in clones
Epidemiology with GATA1 mutations and additional cooperating mutations. A large
number of potential target genes have been proposed and are the
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Down syndrome is one of the most common congenital disorders, subject of ongoing investigation. Among this long list of candidate
affecting approximately one in every 800–1000 live births. It has targets are mutations in the gene for JAK3, a member of the JAK
been demonstrated in a recent population-based study that children family of nonreceptor tyrosine kinases. Several gain-of-function
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with Down syndrome have a 10–20-fold overall increased risk mutations 223,224 and loss-of-function mutations in JAK3 have been
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of developing leukemia, a 150-fold increased risk of develop- identified in both TAM and ML-DS patient samples. Although
ing AML, and a 500-fold increased risk of acute megakaryocytic mutations in JAK3 might indeed represent an additional “hit” in this
leukemia. The median age of diagnosis of myeloid leukemia of three-step model, the finding of mutations in TAM patients who have
Down syndrome (ML-DS), as defined by the WHO classification not progressed to ML-DS may argue against JAK3 as a cooperating
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system, in children with Down syndrome is 2 years. TAM, also mutation.
known as transient myeloproliferative disorder (TMD) and transient Another particularly important area of investigation is the interac-
leukemia, is thought to occur in at least 10% of children with tion between GATA1 and chromosome 21. Identification of critical
trisomy 21 Down syndrome, although 7%–16% of TAM cases have interactions between GATA1 and relevant genes on chromosome 21
mosaic trisomy 21. It has also been suggested that when cases of will serve to further inform us about the pathogenesis of leukemia in
TAM that develop and resolve in utero or result in death before children with Down syndrome.