Page 1115 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 62

ACUTE MYELOID LEUKEMIA IN CHILDREN

Tanja A. Gruber and Jeffrey E. Rubnitz

Acute myeloid leukemia (AML) is a complex and heterogeneous entities, with the French-American-British (FAB) classification being
group of malignancies in which genetic and epigenetic alterations the prototype of this approach. This classification scheme, however,
lead to the transformation of myeloid cell precursors. The tremendous was limited in biologic, prognostic, and therapeutic significance. The
diversity of abnormalities across subtypes of AML suggests that we identification of specific cytogenetic alterations and submicroscopic
must strive to develop therapies that target specific subgroups. Nev- molecular genetic lesions led to newer classification schemes, with the
ertheless, intensification of broadly active chemotherapy, the selective most recent widely used approach being the World Health Organiza-
use of hematopoietic stem cell transplantation (HSCT; Box 62.1), tion classification of AML (Table 62.1). With the development of
improvements in supportive care and risk stratification, and the use genome-wide gene expression profiling, array-based comparative
of minimal residual disease (MRD) to monitor response to therapy, genomic hybridization methodologies, and next-generation sequenc-
have contributed significantly to improvements in the treatment ing, newer insights have been gained into the heterogeneity within
outcome for children with this disease. Survival rates for children with AML. These studies have helped to validate the distinct nature of
AML who are treated on contemporary clinical trials are now greater some of the previously described genetic subtypes, including AMKL,
than 60%. A subset of patients, including those with acute promy- APL, the CBF leukemias, and AML with translocations involving the
elocytic leukemia (APL), Down syndrome and acute megakaryoblastic mixed lineage leukemia (MLL) gene. In addition, these approaches
leukemia (AMKL), and core-binding factor (CBF) leukemia, have have identified new genetic subtypes as well as lesions that are
excellent outcomes, with survival rates that approach 90%. However, enriched within leukemias that have normal karyotypes or miscella-
the cure rates for other subtypes of AML are unacceptably low and neous chromosomal alterations (Fig. 62.1). Some of these lesions
cannot be improved simply by further intensification of standard provide prognostic information and may serve as therapeutic targets
chemotherapy. Genomic and biologic insights into the mechanisms for directed therapies.
of leukemogenesis have provided opportunities to develop targeted AML-associated chromosomal translocations are genetic drivers
and less toxic therapies for the treatment of AML. Their ability to that are believed to be initiating lesions, but are generally insufficient
improve outcomes, however, will be dependent on the requirement on their own to induce a full leukemic phenotype. Thus, like all
of the biologic targets for the survival of the leukemic cell. Thus, a cancers, multiple genetic and epigenetic alterations are necessary to
comprehensive understanding of compensatory processes and mecha- convert a normal lineage-restricted stem or progenitor cell into a fully
nisms of resistance are critical for the ultimate success of these agents. transformed leukemia cell. Although the exact number of mutations
necessary to generate a leukemia is likely to differ between specific
subtypes of AML, it has been useful to conceptualize the mutations
EPIDEMIOLOGY as falling into two broad classes: class I mutations confer a prolifera-
tive or survival advantage; and class II mutations block differentiation
AML accounts for approximately 20% of cases of acute leukemia in and result in enhanced self-renewal (Fig. 62.2). It appears that it takes
children and adolescents younger than 20 years of age. The incidence at least one mutation in each class to transform a normal cell into a
rates have remained constant over the past 40 years, are similar leukemic one. Interestingly, many of the class II mutations arise from
between boys and girls and, in general, are highest during the first 2 translocation events that lead to chimeric transcription factors with
years of life. However, the age distribution may vary between sub- oncogenic properties. The recent efforts to more deeply explore the
types. For example, APL and CBF leukemia are rare in children molecular lesions that underlie AML have significantly expanded the
younger than 3 years of age, whereas the incidence of AMKL is list of genes whose alterations contribute to leukemogenesis. One of
highest in this young age group and rare among teenagers. The dis- the most surprising findings from these studies was the identification
tribution of AML subtypes may also vary among ethnic groups, with of a very limited number of somatic mutations in AML compared
some studies suggesting a higher incidence of APL among Hispanic with the much larger numbers seen in other malignancies, such as
populations. breast cancer, pancreatic cancer, small-cell lung carcinoma, and mela-
Although we have learned much about the biology and genetics noma. The number of mutations in pediatric AML is also significantly
of AML, the causes remain elusive. The majority of cases are believed lower than the number of mutations seen in pediatric acute lympho-
to result from interactions among genetic factors that may be blastic leukemia (ALL), with one study finding an average of only
inherited or acquired and environmental factors. Constitutional 2.38 somatic copy-number alterations (CNAs; e.g., deletions and/or
syndromes that are associated with an increased predisposition to amplifications) in AML compared with an average of 6.46 CNAs in
AML include Down syndrome, Fanconi anemia, Bloom syndrome, pediatric ALL. Even more striking was the lack of any CNAs in 34%
neurofibromatosis, Noonan syndrome, congenital neutropenia, and of patients.
germline haploinsufficiency of the RUNX1 gene. Exposure to ionizing One of the early dogmas of cancer biology purports that tumors
radiation, alkylating agents, topoisomerase II inhibitors, and benzene are clonal and arise from single cells. In support of this are cytogenetic
are among the few environmental factors proven to increase the risk studies demonstrating that leukemia cells within a patient are uniform
of AML. In the majority of cases of childhood AML, neither a genetic in their abnormalities. As our ability to detect mutations has increased
nor environmental cause can be identified. with the advent of next-generation sequencing, it has become appar-
ent that while there is typically a founding clone that carries a subset
of mutations present in all tumor cells, there is also significant tumor
PATHOBIOLOGY heterogeneity at diagnosis when taking into account the full comple-
ment of lesions. This is perhaps not surprising, given that cells can
The morphologic and histochemical features of the leukemic cells acquire new mutations with each cellular division. Furthermore, this
served as the initial way to subdivide AML into distinct clinical heterogeneity provides an advantage to the tumor cells in that

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