Childhood Acute Lymphoblastic Leukemia

by Melissa Adde

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children under 15 years of age and accounts for 25% of all childhood cancers in industrial nations. Incidence data from many developing countries indicates that ALL is also the most common childhood malignancy in most world regions, with some notable exceptions such as equatorial Africa where Burkitt's Lymphoma occurs in greater frequency. In the USA, there is an incidence of three to four new cases of ALL per 100,000 children per year. The incidence of ALL in developing countries tends to be lower than in the USA or Europe, although there is country-to-country variation and some cases may not ever be diagnosed. There is a peak age incidence in children, ages two to five years in most countries, but this age peak, due to a specific sub-type of ALL, varies and is sometimes missing. The incidence continues to decrease throughout adolescence. Males have a higher incidence than females and, in the USA, white children have a higher incidence than black children. Children with Down's syndrome or certain other inherited disorders are more likely to develop ALL than are normal children.

The diagram shows the relative frequencies of various molecular lesions in childhood ALL (both pre-B and pre-T) in the USA (data from Rubnizt and Look, Childhood Leukemias, Ed. Ching-Hon Pui). Most lesions result in fusion proteins derived from genes involved in cell growth, differentiation and survival, the letters stand for the involved genes. Some of them are mentioned in the text. Figure 1

Normal lymphocytes fight infection, in part, by making substances e.g., antibodies that attack viruses and bacteria. There are three types of lymphocytes, B, T and Natural Killer (NK) cells. Lymphocytes are made by the bone marrow and undergo further maturation and differentiation in the organs of the lymphatic system - the spleen, thymus, and lymph nodes. ALL is a malignant disease that results when developing lymphocytes become too numerous and fail to mature. The excess of immature lymphocytes (lymphoblasts) can involve different stages of maturation during the lymphoid differentiation process, giving rise to subtypes of ALL. The leukemic lymphoblasts are found predominantly in the bone marrow and bloodstream but can also be found in the organs of the lymphatic system. The malignant cells may also invade many other organs, including the spinal cord and the brain.

The signs and symptoms of leukemia reflect the degree of bone marrow infiltration and the extent of spread of the disease to other organs. The most common signs and symptoms include fever, pallor, fatigue, bleeding, bone pain, and swollen lymph nodes. The duration of symptoms may be days to months. The early signs and symptoms of ALL may be similar to other illnesses, such as infections or other causes of anemia. Therefore, when a child presents with signs and symptoms that could be caused by ALL, a blood count is usually performed. In a child with ALL, the blood counts typically reveal a high white blood count (WBC) with abnormal circulating lymphoblasts and often a reduced number of normal white cells (granulocytes), predisposing to infection, fewer red blood cells (anemia) and a low platelet count (potentiating bleeding). In the presence of suspicious findings in the peripheral blood an examination of the bone marrow is required to make the diagnosis and to determine the type of leukemia that is present.

Immunophenotyping is a valuable and relatively inexpensive tool that is part of the standard diagnostic work-up of patients with leukemia and is used to determine the sub-group of ALL as well as to differentiate ALL from other types of leukemia. It is more precise than cytochemical tests used in the past, although these are still sometimes used to distinguish ALL from acute myeloid leukemia (AML). The two major sub-groups of ALL are precursor B cell and precursor T cell. Cytogenetics has played an important role in the identification of smaller sub-groups of patients with specific chromosomal abnormalities which have considerable prognostic significance. However, cytogenetics has largely been replaced by molecular techniques (particularly PCR) and flow cytometry (DNA index).

Potential Prognostic Factors
Prognostic factors are those that reliably predict outcome. These are categorized as follows: clinical and laboratory features at diagnosis; molecular characteristics at diagnosis; and response to initial treatment. It is important to point out that prognostic factors are largely treatment-dependent.

Many clinical and laboratory features at diagnosis have been described as having prognostic significance, perhaps the most important being age at diagnosis, WBC at diagnosis, gender, and race. Infants under one year of age are at a very high risk of treatment failure. In western countries, older children and adolescents (10 years and older) have less favorable outcomes, while children ages 1 to 9 years tend to have more favorable outcomes. Patients with high WBCs tend to have a worse outcome. Girls with ALL have a better prognosis than boys in some series. White children have a better prognosis than black children.

Molecular and biological characteristics of leukemia cells at diagnosis that are associated with outcome include immunophenotype, chromosome number, and certain chromosomal translocations. Precursor B cell ALL, one of the two main sub-groups of ALL, can be further divided into early pre-B and pre-B cell ALL. Patients with an early pre-B phenotype (no expression of surface or cytoplasmic immunoglobulin) have the best prognosis. The T cell phenotype used to be associated with a worse outcome, however, when treated with modern treatment protocols, patients with T cell ALL generally have an outcome similar to those with precursor B cell ALL. Hyperdiploidy, which is the presence of additional copies of whole chromosomes, can be evaluated by measuring the DNA content of cells, a measure known as the DNA index. Hyperdiploidy or a DNA index of > 1.16 is associated with a better prognosis. Hypodiploidy (fewer than normal chromosomes) is associated with a higher risk of treatment failure. Recurring chromosomal translocations (see Figure 1) that have prognostic significance include the t(12;21) cryptic translocation (i.e., normally undetectable by cytogenetics), resulting in the fusion of two genes, TEL and AML1, to create a single protein (TEL-AML1). Such patients have a good outcome. The t(9;22), which involves the same genes as in chronic myeloid leukemia, and also results in a fusion protein, BCR-ABL, has an unfavorable prognosis. Several translocations involve the MLL gene, situated on chromosome band 11q23, each being associated with a different prognosis, depending upon other factors such as the age of the patient, the WBC, the immunophenotype, and the specific translocation. One of them, for example, the t(4;11) is associated with up to 80% of infant leukemias, which do poorly.

Early treatment response has proved to be a particularly good measure of outcome, being, in fact, a direct measure of the effect of chemotherapy. Early response has been evaluated by examination of the bone marrow during induction therapy (e.g., 7 or 14 days after the initiation of treatment), or by the clearance of circulating lymphoblasts from the peripheral blood after 7 or 10 days of treatment with corticosteroid alone, or other drugs used in induction. Patients who have a rapid reduction in the percentage of leukemic cells in the bone marrow or those who have a rapid clearance of circulating leukemic blasts have a better prognosis than those who clear leukemic cells more slowly. The adverse impact on prognosis related to slow early response may be overcome by modifying therapy in such patients, e.g., by prolonging and intensifying induction therapy.

Treatment of ALL
Approximately 70 to 80% of patients with ALL diagnosed in industrialized countries can be cured. The primary treatment is chemotherapy. Treatment consists of remission induction, the prevention of spread to the central nervous system (CNS), consolidation, late intensification and maintenance cycles. A typical remission induction consists of a glucocorticoid, vincristine, and l-asparaginase, with or without an anthracycline. Complete remission is achieved in 95-98% of patients in industrial nations. Many variations exist with respect to continuation therapy, but most protocols include agents such as cyclophosphamide, cytarabine, methotrexate and mercaptopurine in addition to the periodic reintroduction of agents used for remission induction. Late intensification, or re-induction therapy, appears to make an important difference to outcome in all risk groups. CNS preventive therapy may include intrathecal therapy with methotrexate and cytarabine and, in some circumstances, cranial radiation. The total duration of therapy is between two to three years.

Acute Lymphoblastic Leukemia in Developing Countries
Patients with ALL in developing countries often present with more advanced disease (see Case History) in which leukemic cells have not only infiltrated the bone marrow, but also invade other organs – in some cases this may be because the ALL was not suspected initially, but the disease may also be more aggressive in poorer socioeconomic groups (see below). Co-morbidities such as hepatitis, malaria and malnourishment are also much more common, which may affect the patients' ability to tolerate treatment. Access to care in cancer centers or pediatric oncology units is much more limited in developing countries, and patients and their families often have to travel long distances to reach hospitals capable of making the diagnosis and/or providing necessary treatment. Further, even when they reach these centers, a family's inability to pay for treatment due to socioeconomic factors or the lack of health insurance often impacts upon the type of therapy that is ultimately provided to the child. Continuation of treatment and follow-up is often difficult, again because of socioeconomic factors, the need to travel long distances, and the lack of trained physicians who can manage their care outside the major cancer center or pediatric oncology unit.

Treatment protocols typically administered to patients in more affluent countries may not necessarily be optimal for the treatment of children with ALL in developing countries, since prognostic factors may differ, and, as studies in India suggest, the proportion of the major sub-types of ALL differ in various world regions or in different ethnic or socioeconomic groups. Preliminary research on the molecular characteristics of ALL in India suggests that chromosomal translocations associated with a poorer prognosis in western series are more frequent, and those associated with a good prognosis, less frequent. Research into the optimal therapy for children with ALL in developing countries needs to take into consideration differences in clinical and laboratory features at diagnosis and molecular and biological characteristics of the leukemia as well as other relevant factors, such as co-morbidities.

INCTR Activities in ALL
INCTR is working to support research on the treatment and characterization of childhood/adolescent ALL in India, including assisting with the development of a cooperative group within India so that more patients with ALL have better access to care. We also hope to extend and further develop this work in other countries such as Brazil, China and Egypt.