Topics in Pediatric Leukemia – Acute Lymphoblastic Leukemia

Introduction

Acute leukemia is the most common childhood malignancy, which accounts for approximately one third of all pediatric cancers. Acute lymphoblastic leukemia (ALL) constitutes about 75% of pediatric acute leukemias. The incidence of ALL in the United States is approximately 3.4 cases per 100,000 individuals less than 15 years of age. The peak incidence of childhood ALL occurs between ages 3 and 4.[1,2] In the United States, the incidence of ALL is higher in whites than in African Americans by a ratio of 1.8: 1. In addition, ALL is slightly more common in boys than in girls.[3,4]

Genetic factors may predispose children to develop leukemia. Germline chromosomal abnormalities have been associated with childhood leukemia.[5–7] Environmental factors, eg, exposure to pesticides and herbicides; maternal use of alcohol, cigarettes, and contraceptives; and chemical contamination of groundwater have all been studied, although no definitive link to the development of childhood ALL has been established.[8,9]

Pathophysiology

The development of ALL, like other malignancies of hematologic origin, is believed to involve a transformation event that occurs in a single progenitor cell that has the capability for indefinite clonal expansion. The leukemogenic event may occur in committed lymphoid cells of B- or T-cell lineages or in early precursors, which gives rise to the different subtypes of ALL based on the stage of lymphoid differentiation of the cell in which the event occurred.[9] About 80% of all cases of ALL express cell-surface markers indicative of a precursor B-cell lineage. Only 1% to 2% of cases express a phenotype typical of a mature B cell. T-cell ALL accounts for about 15% to 20% of cases and is commonly associated with features at diagnosis, such as older age, male predominance, high white blood cell (WBC) count, and extramedullary disease, all of which indicate the need for increased intensity of chemotherapy.[10]

The identification of specific chromosomal abnormalities plays an important role in determining therapy and prognosis in certain subtypes of ALL. Some of the more common chromosomal abnormalities in ALL include the TEL-AML1 fusion gene, which by molecular techniques, can be found in 25% of cases of pre-B ALL.[10] The presence of this translocation carries a more favorable prognosis. The bcr-abl t(9,22) p180 translocation is found in only about 3% to 5% of cases of childhood ALL. The presence of this translocation is associated with a high WBC count at diagnosis and a poor response to therapy.[11] Rearrangements of the MLL gene at chromosome band 11q23 are found in 80% of cases of ALL in infants. Unfortunately, young children with this genetic abnormality have a very poor prognosis and a survival of less than 20% despite intensive therapy.[12–15] Children, with MLL gene rearrangements, > 1 year of age at diagnosis were found to have better prognoses than those of infants with the same translocation, but far worse than age-matched patients without rearrangements of the MLL gene.[16]

Diagnosis and Clinical Presentation

Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional symptoms include fever (60%), fatigue (50%), pallor (25%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disruption of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in about 75% of patients. Approximately 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm³ occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection.[15,16] Infiltration of the lymphoid system may cause lymphadenopathy and hepatosplenomegaly. CNS involvement is found in less than 5% of children at presentation. When present, the signs and symptoms include headache, vomiting, papilledema, and sixth-nerve palsy.[17–19]

Although peripheral blasts with anemia and thrombocytopenia are strongly suggestive of ALL, the definitive diagnosis of ALL is based on the bone marrow aspiration or biopsy demonstrating more than 25% lymphoblasts. In patients with large leukemia cell burden, serum chemistries may reveal signs of tumor lysis, including hyperkalemia, hypocalcemia, hyperphosphatemia, and lactic acidosis. Serum uric acid may be elevated due to increased cell turnover. Tumor lysis can be a metabolic emergency at the time of presentation and may be exacerbated by initiation of therapy.[20]

Once the diagnosis of ALL is made, cytogenetic analysis, immunophenotyping by flow cytometry, and immunohistochemical staining are performed to further characterize ALL subtype and guide therapy. A lumbar puncture and cerebrospinal fluid examination are also performed to determine the presence of occult CNS involvement.

Treatment

The currently accepted philosophy behind treatment of pediatric ALL is based on the recognition of the heterogeneity of the disease. Although it is no longer acceptable to treat all cases of childhood ALL with a single treatment regimen, there are 4 basic phases in all treatment protocols. These phases include remission induction, treatment of clinical or occult CNS disease (consolidation), intensification, and maintenance therapy. The goals of induction therapy are to attain remission, defined as the absence of evidence of leukemia, which includes the absence of CNS or testicular disease, and to have bone marrow examination showing normal cellularity with fewer than 5% lymphoblasts. The 3-drug combination of vincristine, a glucocorticoid, and L-asparaginase successfully induces remission in 95% of children with ALL.[21]

Intrathecal therapy has increased event-free survival by preventing relapse in the CNS where the blood-brain barrier provides a “sanctuary” from systemic chemotherapeutic agents.[22,23] Although cranial irradiation is used in some protocols, it is usually restricted to therapy for high-risk ALL and patients with proven CNS disease because of the significant neurotoxic sequelae. Given immediately after remission induction, consolidation therapy is particularly important in high-risk ALL, such as T-cell ALL and the infant form of ALL, in addition to patients with CNS disease. Maintenance chemotherapy usually includes daily administration of 6-mercaptopurine (6MP) in addition to intermittent methotrexate. Duration of therapy differs among centers and protocols, but, on average, therapy lasts 2.5 years. Generally, boys are treated for 3 years and girls 2 years, secondary to the recognition that boys are more likely to relapse.[24] Most relapses are treated with intensified regimens of chemotherapy.

Because of the relatively high rates of disease-free survival in ALL, hematopoietic stem cell transplantation is reserved for patients who fail to respond to induction therapy, those who relapse during treatment, or those who relapse within 1 year following completion of chemotherapy. Risk stratification has classically been based on the 2 prognostic factors that have been most consistent in retrospective analyses: age at presentation and initial WBC count. The future of ALL therapy involves gene-expression profiling and immunophenotyping to classify children into various risk groups that will influence treatment decisions. Although there is a growing consensus that this is feasible, it is not currently the standard of care.[25,26]

Prognosis

Over the past decade, advances in the treatment of childhood ALL have led to the current long-term, event-free survival rates of about 80%. Despite the overall good prognosis, some of the less common subtypes are at high risk of relapse. There is no universally accepted method of stratifying patients into risk groups, but there are clinical features of ALL that are generally acknowledged as prognostic factors. Age, sex, and initial leukocyte count are consistently cited as important prognostic factors.[27]

Patients between the ages of 2 and 10 years tend to have a more favorable prognosis. Infant ALL carries a high risk of early relapse despite intensive chemotherapy. These patients tend to have high initial WBC counts, CNS involvement at presentation, thrombocytopenia, massive organomegaly, and unfavorable karyotypic features, suggesting that this disease may be biologically different from typical ALL.[28] In most studies, girls have more favorable prognoses than boys. The reason is not completely understood. Initial WBC count is accepted as a prognostic indicator at diagnosis. Those with high initial WBC counts (greater than 50,000 per mm³) have poorer prognoses. T-cell ALL commonly presents with a high leukocyte count and has a high rate of lymphoblast proliferation.[29,30]

Race also appears to be a prognostic factor. Despite the lower incidence of childhood ALL in African Americans, prognosis is poorer than for white children. This is thought to be, in part, due to the fact that African American children tend to develop subtypes of ALL considered to be higher risk, such as T-cell ALL. Hispanic children also have an increased incidence of high-risk disease when compared with whites, but less so than African Americans.[31] Patients with a DNA index > 1.16 (eg, hyperdiploid) have better prognoses than those with a DNA index < 1.16.[32]

Future Challenges and Novel Therapies

One of the major problems in pediatric oncology is the need to design better therapy for children with ALL who relapse. This population of children represents the largest group of patients with cancer refractory to current therapies. Although recent improvement in survival is encouraging, there continues to be a subset of patients with childhood ALL who relapse, and about 20% of patients die of the disease.[33] Intensive regimens, including nucleoside analogs (such as gemcitabine and clofarabine), have shown promise in the treatment of heavily pretreated children with relapsed or refractory leukemia. Multicenter, phase 2 trials with a reinduction regimen of topotecan, vinorelbine, thiotepa, dexamethasone, and gemcitabine are ongoing.[34–36] In addition, current modalities of therapy are nonspecific, causing significant risk to normal tissues.

Exciting work is being done to identify target-specific therapies to minimize toxicity and improve event-free survival. Imatinib mesylate is an example of an inhibitor of a tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia that has shown some efficacy, albeit limited, in the treatment of Philadelphia chromosome-positive ALL.[37] As encouraging as these novel approaches may be, they are far from being accepted as the standard of care for a disease that still imparts substantial morbidity and mortality.