Candy is a four-year-old female who has been feeling poorly for the past several weeks. She has complained of bone pain and has started to limp while playing outside. Her mother notes that she tires easily, appears pale, and comes in to take naps. Candy now has a moderate fever in the evening (38.5°C, 101.3°F oral). More alarming, Candy has had repeated nose bleeds (epistaxis) and has developed small purple spots (petechiae) on her arms and legs. Concerned that Candy may have a “summer virus,” her mother brings her to the family pediatrician. On physical examination, the pediatrician determines that Candy has enlarged lymph nodes and possibly an enlarged spleen. Noting the patient’s pallor and signs of a bleeding tendency and fatigue, the pediatrician suspects any of several diseases involving the blood and bone marrow, including anemia, idiopathic thrombocytopenic purpura (ITP, possibly postviral), or a leukemia. An in-office CBC (complete blood count) reveals a very elevated white cell count (30,000 per microliter with below 10,000 considered normal) with a low red cell and platelet count. A peripheral blood smear discloses multiple abnormal cells with very little cytoplasm, which the pediatrician believes are lymphoblasts (neoplastic, immature lymphocytes) (FIGURE 13-15A). The pediatrician refers Candy to a pediatric hematologist at a regional hospital center for further evaluation. The hematologist suspects that Candy has acute lymphoblastic leukemia of childhood and orders several additional tests. These include a bone marrow aspiration (FIGURE 13-15B and C). Candy’s bone marrow has a predominance of lymphoblastic cells and a great reduction of the other cell lineages (developing granulocytes, platelets, and red cells) in the marrow. A normal marrow is provided for comparison. A lumbar puncture is performed to evaluate whether leukemic cells are present in the cerebrospinal fluid. No such cells are found. A chest x-ray shows no abnormality. Immunological studies of Candy’s leukemic cells indicate they are of B cell origin and have cell surface antigens characteristic of immature cells. A karyotypic (chromosome) study of the leukemic cells show the cells are hyperdiploid (have greater than the normal 46 chromosomes, a good prognostic sign).
FIGURE 13-15A, FIGURE 13-15B, FIGURE 13-15C
Candy begins a long course of chemotherapy. Her initial evaluation (based on age, cell number, cell type, and chromosome number) would place her in a standard (not high risk) group; this classification helps determine the particular chemotherapy to be used. Although therapy will continue for at least two years, Candy has an excellent chance of a cure. The five-year survival rate with no evidence of further disease is 95 percent for similar patients, and overall a cure rate of greater than 80 percent is expected.
Discussion The evaluation of childhood leukemia and therapy of the disease is complex and depends on several variables, including the age of the patient, the severity of the disease at diagnosis, and the nature of the leukemic cell and the molecular abnormalities present in those cells. For example, T cell leukemia in children has a worse prognosis. The chest x-ray is performed because T cell leukemia often occurs in the mediastinum (chest) and can compromise cardiac function. Hence the x-ray is part of standard workup. A small percentage of children with ALL have a Philadelphia chromosome and a BCR-ABL fusion gene, as discussed under chronic myelogenous leukemia. These patients have a worse prognosis, but treatment with kinase inhibitors has much improved survival. Chemotherapy for childhood ALL is a multistep process. Initial therapy (remission induction) usually takes place for about four weeks, with some time initially in a hospital setting, and involves the use of several chemotherapeutic agents in combination. Almost all (95 percent) patients have success in achieving remission initially. This is followed by the consolidation phase, with the aim of eliminating any residual disease, which involves continuing outpatient chemotherapy for as long as six to nine months. This is followed by a prolonged maintenance phase with continuing less intense chemotherapy with antimetabolites given orally for up to three years. In addition, therapy against leukemia in the CNS is always included and is started during remission induction. This includes intrathecal medication (administration of drugs within the membranes of the spinal cord) to ensure the drug enters the cerebrospinal fluid. Up to 20 percent of patients will suffer a relapse, which is often treated by redoing the initial remission induction therapy. All of the drugs used have toxic side effects. Five percent of children treated with these agents will get a secondary cancer (AML). A number of other chronic long-term effects including impairment of fertility, learning problems, and heart and lung disease may also occur. For this reason, long-term follow-up of childhood cancer survivors is critical.
Etiology and Pathogenesis
B cell acute lymphoblastic leukemia of childhood.
Questions
1. Are there known predisposing environmental or genetic factors for acute lymphoblastic leukemia?
2. What are some of the potential risks and side effects of the chemotherapy used in the treatment of acute lymphoblastic leukemia?
3. No evidence of leukemic cells were found in Candy’s cerebrospinal fluid. Nevertheless, therapy for CNS disease was performed. Why is such therapy always done in these cases?
4. What psychosocial effects might Candy’s illness have on both her and her family?
5. Can you estimate the economic cost of Candy’s therapy? What would happen if Candy were not covered by medical insurance?