Progress and Prospects in Pediatric Leukemia

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Pediatric leukemia is the single most common malignancy affecting children, representing up to 30% of all pediatric cancers. Dramatic improvements in survival for acute lymphoblastic leukemia (ALL) have taken place over the past 4 decades with outcomes approaching 90% in the latest studies. However, progress has been slower for myeloid leukemia and certain subgroups like infant ALL, adolescent/young adult ALL, and relapsed ALL. Recent advances include recognition of molecularly defined subgroups, which has ushered in precision medicine approaches. We discuss the current understanding of the biology of the various childhood leukemias, recent advances in research, and future challenges in this field.

Introduction

Pediatric leukemia is the most common malignancy affecting children, representing up to 30% of all pediatric cancers.1, 2, 3 Approximately 3000 children are diagnosed with leukemia every year in the United States. Pediatric leukemias span diverse clinical and biological subgroups and recent advances in genomics continue to provide ever increasing insight into the underlying pathogenic mechanisms responsible for malignant transformation. The discovery of tumor specific mutations (targets), the development of targeted therapy, and breakthroughs in immunotherapy offer great promise in improving outcome for all patients. In this article, we will describe individual subtypes of pediatric leukemia, address current challenges, and discuss opportunities for integration of novel therapy.

Section snippets

Epidemiology

Acute lymphoblastic leukemia (ALL) accounts for about 80% of all pediatric leukemia.1 It is the most common in children aged 2–5 years, but occurs across all age groups.1, 2, 3 The incidence is highest among Caucasians and Hispanic populations. ALL is also more common in boys than in girls and boys have a slightly poorer prognosis. In all, 85% of pediatric ALL is of B-precursor origin while the remaining 15% is T-cell derived.4

Biology

An inherited predisposition and environmental exposures are thought

Epidemiology

Acute Myeloid Leukemia (AML) represents 13% of acute leukemias in children less than 10 years of age and in contrast to ALL, the incidence of AML rises in the second decade of life, and it forms up to 36% of acute leukemias between 15 and 19 years of age.1, 43 The overall incidence in the United States in children between 0 and 19 years is about 8.8 per million.44 AML occurs with almost similar frequencies in both males and females, at all age groups.

Pathogenesis

Like ALL, the great majority of pediatric

Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) in children is a very rare disease with an incidence of about 1.3 per million under the age of 20 years.1 Incidence is directly proportional to age with most patients being older than 10 years of age. It biologically resembles adult CML, with a similar breakpoint in the BCR gene leading to the BCR–ABL fusion, t (9; 22) (q34:11), which leads to a constitutively activated tyrosine kinase. This is thought to confer a survival advantage to the Ph+stem cell clone

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia (JMML) is a unique pediatric myeloproliferative/myelodysplastic disease, which arises from a clonal proliferation of monocytic and granulocytic progenitor cells, at all stages of differentiation. It occurs with a frequency of about 1–2 cases per million.77 Median age of diagnosis is 2 years, with a higher incidence in boys than girls. Certain genetic conditions, like neurofibromatosis (NF)-1 and Noonan’s syndrome, have been found to predispose to development of

Long-Term Effects of Therapy

As the survival rates for pediatric leukemia keep rising, so do concerns for long-term effects of therapy. A study looking at long-term effects in a cohort of pediatric leukemia survivors from 1970 to 1986, showed a 25-year mortality rate of 13%, with the majority of deaths due to leukemia recurrence (66.2%) or secondary neoplasms (12.2%).84 At least 50% of survivors also suffered from one or more chronic medical conditions, principally involving musculoskeletal, cardiac, or neurological

Conclusion

Pediatric leukemia continues to uphold its status as one of the greatest success stories in human oncology, with multiple advances since the advent of the genomic era. However, it still remains the single largest cause of cancer-related mortality in children. A major goal is the integration of targeted agents including immunotherapy to improve outcome for high-risk patients and to reduce the burden of therapy for those successfully treated with conventional agents (Fig 2).

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