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C H A P T E R 65

CLINICAL MANIFESTATIONS AND TREATMENT OF CHILDHOOD

ACUTE LYMPHOBLASTIC LEUKEMIA

Sima Jeha and Ching-Hon Pui

INTRODUCTION risk diminishes with increasing age. If the first twin develops ALL by
5 to 7 years of age, the risk to the second twin is approximately twice
5
Serial risk-directed clinical trials have optimized the combination of that in the general population, regardless of zygosity. After the age
chemotherapeutic agents and, along with advances in supportive care, of 7 years, the risk to the unaffected twin is similar to that for persons
have led to current cure rates of childhood acute lymphoblastic leu- in the general population. The majority of infants with ALL have a
kemia (ALL) exceeding 85% compared with those of less than 10% chromosome translocation that results in the fusion of the MLL gene
1
in the 1960s. However, because ALL is the most common cancer in at 11q23 with a variety of partner genes, the most common of which
children, relapsed ALL remains a leading cause of death from a disease is AF4. Identical twin infant pairs with concordant ALL share the
in this age group. Over the last decade, minimal residual disease same acquired MLL gene rearrangements.
(MRD) has become the most important determinant in risk stratifica- The most common chromosome translocation in childhood ALL,
tion. Prophylactic cranial irradiation has been successfully omitted t(12;21), results in ETV6-RUNX fusion. In contrast to MLL-
from virtually all patients in several frontline protocols, and the rearranged ALL, ETV6-RUNX1 leukemias present after infancy and
Abelson (ABL) tyrosine kinase inhibitors imatinib and dasatinib have have a concordance rate of only 10% in identical twins. ETV6-
revolutionized the treatment of patients with Philadelphia chromo- RUNX1 fusion can be found in as many as 1% of cord blood samples
some (Ph)-positive ALL. Significant advances in biotechnology, such of normal newborn babies, a frequency 100 times higher than the
as next generation sequencing (NGS), have led to a deeper under- prevalence of this subtype of leukemia, suggesting that additional
standing of the molecular pathways involved in ALL, which in turn postnatal mutations are necessary for malignant transformation.
2
helped identify new ALL subtypes and their driver mutations. Preci- Analysis of Guthrie cards of 2- to 6-year-old children with ALL
sion medicine ALL strategies based on inherited and leukemia-specific showed that most did have detectable, clonotypic ETV6-RUNX1
genomic features, host pharmacogenomics, and targeted molecular sequences at birth. In addition, identical ETV6 and RUNX1 break-
and immunologic treatment approaches are increasingly implemented points were present in each of the twin pairs with a very asynchronous
to improve cure rates and reduce toxicity. diagnosis supporting the requirement for one or more additional
postnatal events following in utero initiation. This interpretation
suggests that ETV6-RUNX1 initiates leukemogenesis but is insuffi-
EPIDEMIOLOGY cient for overt disease, and further genetic alterations are required.
ETV6 deletions on chromosome 12p, the most frequent additional
ALL accounts for approximately 75% of all cases of childhood leu- genetic abnormalities described in cases of ALL with ETV6-RUNX1,
kemia, and is the most common pediatric cancer, representing 23% appear to be subclonal in fluorescence in situ hybridization (FISH)
of cancer diagnoses among children younger than 15 years of age. analysis of leukemic cells from nontwin patients. These findings
About 3600 children and adolescents are diagnosed with ALL each indicate that ETV6 deletion is a secondary or later event in leukemo-
year in the United States, with an annual rate of 30 to 40 per million. genesis, and suggest that leukemia might be initiated in utero but
6
The peak incidence of ALL occurs around 3 to 5 years of age. This requires at least an essential second postnatal event (two hits).
young age peak historically has been associated with major periods Indeed, recent next generation studies show that virtually all cases of
of industrialization in many countries, suggesting a causative role for ALL, with the exception of MLL-AF4–positive ALL, have 8 to 12
environmental changes. Recent studies disclosed that hyperdiploid cooperative mutations.
(>50 chromosomes) and ETV6-RUNX1 (also known as TEL-AML1) Several genetic, dietary, and environmental factors have been
ALL account for more than half of the cases in this peak age group, proposed to modify the risk of leukemia initiation. Children with
and are associated with specific germline genetic polymorphisms. In various congenital immunodeficiency diseases, including Wiskott-
fact, the differences in the prevalence of specific germline genetic Aldrich syndrome, congenital hypogammaglobulinemia, and ataxia-
polymorphisms can largely explain the racial or ethnic differences telangiectasia, have an increased risk of developing lymphoid
in the incidence and proportion of genetic subtypes of ALL. ALL, malignancies, as do patients undergoing chronic treatment with
especially T-cell subtype, occurs more frequently in boys than in girls. 3 immunosuppressive drugs. The loss of cellular immune surveillance
Certain inherited genetic and acquired factors are associated with capability for tumor antigens and the inability to self-regulate lym-
the development of ALL, but most patients have no recognized risk phoproliferative processes may contribute to malignant transforma-
factors. Children with constitutional trisomy 21 (Down syndrome) tion in these patients. Absence of exposure to common infections in
are up to 15 times more likely to develop leukemia than children the first year of life is associated with a higher risk of developing
without Down syndrome. Genetic instability and DNA repair disor- ETV6-RUNX1–positive or hyperdiploid ALL (>50 chromosomes) in
ders (e.g., Bloom syndrome, ataxia-telangiectasia, Fanconi anemia) older children. A possible explanation is that in the absence of
4
are also associated with an increased risk of developing ALL. Among infection-driven modulation of the naive immune network in infants,
identical twins, if one is diagnosed with ALL during the first year of subsequent infectious exposures could result in a highly dysregulated
life, the risk that the other twin will develop ALL is over 70%, response to infections in older children contributing to leukemogen-
approaching 100% in twins with a single monochorionic placenta. esis. Exposure to ionizing radiation and certain toxic chemicals could
The extraordinarily high concordance rate in monozygotic infant also facilitate the development of acute leukemia. The high incidence
twins compared with dizygotic infant twins or nontwinned siblings of leukemia among survivors of atomic bomb explosions in Japan
results from the metastasis of leukemic cells from one twin to the during World War II is well documented. Among survivors of the
other through shared placental circulation. Highest in infancy, this atomic bomb, there was no increase in the incidence of leukemia in

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