ETIOLOGY

The etiology of childhood leukemia is unknown and is probably multifactorial. Genetics and environmental factors play important roles. There are many recurrent nonrandom chromosomal translocations in leukemia cells. A translocation may lead to the formation of a new gene, whose expression may lead to a novel protein with transforming capabilities. In chronic myeloid leukemia (CML), a translocation between chromosomes 9 and 22 results in a fusion gene incorporating parts of two genes, BCR and ABL. The protein formed by this novel gene plays an important role in the development of CML. In addition, certain constitutional genotypes can predispose a child to the development of acute leukemia. Patients with Down syndrome, Fanconi anemia, Bloom syndrome, ataxia-telangiectasia, Wiskott-Aldrich syndrome, and neurofibromatosis type 1 all have an increased risk of acute leukemia. Siblings of children with leukemia are also at increased risk of developing leukemia (approximately two- to fourfold above the childhood population). This risk increases for twin siblings (up to 25% for monozygotic twins). In certain patients with leukemia, the unique antigen receptor gene rearrangement or the specific chromosomal translocation characterizing the patient’s leukemic clone can be demonstrated in cord blood cells and neonatal blood spots used for screening for metabolic diseases, suggesting a possible in utero etiology. There are reports of familial leukemia. Environmental factors that may increase the risk of leukemia include ionizing radiation and exposure to certain chemotherapy agents, particularly the topoisomerase II inhibitors.

EPIDEMIOLOGY

Each year, 2500 to 3500 new cases of childhood leukemia occur in the United States. The disease affects about 40 per 1 million children under the age of 15 years. Acute lymphoblastic leukemia (ALL) accounts for approximately 75% of cases. The various subtypes of acute myelogenous leukemia (AML) account for 15% to 20%, and types of chronic myelogenous leukemia (CML) account for less than 5% of cases. Other chronic leukemias, including juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, and chronic lymphocytic leukemia, are rare in childhood.

ALL and AML are classified according to the World Health Organization (WHO) system (Table 155-1), although many clinicians and pathologists still use the FAB (French-American-British) system for AML. ALL is classified according to cell lineage as either B-lineage or T-lineage. The incidence of ALL peaks at 2 to 5 years of age and is higher in boys than in girls. T-cell ALL, in particular, is associated with a male predominance as well as an older age of peak incidence. In the United States, ALL is more common in white than in African-American children.

CLINICAL MANIFESTATIONS

Signs and symptoms of acute leukemias are related to the infiltration of leukemic cells into normal tissues, resulting in either bone marrow failure (anemia, neutropenia, thrombocytopenia) or specific tissue infiltration (lymph nodes, liver, spleen, brain, bone, skin, gingiva, testes). Common presenting symptoms are fever, pallor, petechiae or ecchymoses, lethargy, malaise, anorexia, and bone or joint pain. Physical examination frequently reveals lymphadenopathy and hepatosplenomegaly. Symptomatic central nervous system (CNS) involvement is rare at the time of presentation. The testes are a common extramedullary site for ALL; a painless enlargement of one or both testes may be seen. Patients with T-cell ALL are frequently older males (8–10 years), and often have high white blood cell (WBC) counts, anterior mediastinal masses, bulky disease with cervical lymphadenopathy, hepatosplenomegaly, and CNS involvement. In patients with AML, extramedullary soft tissue tumors may be found in various sites. The presence of myeloperoxidase in these tumors may impart a greenish hue; such tumors are known as chloromas.

LABORATORY AND IMAGING STUDIES

The diagnosis of acute leukemia is confirmed by findings of immature blast cells on either the peripheral blood smear, bone marrow aspirate, or both. With rare exception (a physiologically unstable patient), a bone marrow aspirate should be done urgently to confirm the diagnosis. Most patients have abnormal blood counts; anemia and thrombocytopenia are common. The WBC count may be low, normal, or high; 15% to 20% of patients have WBC count greater than 50,000/mm³. The likely diagnosis of the particular type of leukemia (lymphoid or myeloid) can often be determined by evaluating blast morphology on a peripheral smear or a bone marrow aspirate. Definitive diagnosis requires the evaluation of cell surface markers (immunophenotype) by flow cytometry and evaluation of cytochemical staining patterns. Cytogenetic analysis should be undertaken in all cases of acute leukemia. Certain types of both lymphoid and myeloid leukemias have specific chromosomal abnormalities. In ALL, the t(12;21) translocation is most common (approximately 20% of all cases) and is associated with a favorable prognosis. The t(9;22) translocation occurs in less than 5% of cases and is associated with a poor prognosis. The t(4;11) translocation (and other translocations involving the MLL gene on chromosome 11) often occurs in infants and patients with secondary AML and is generally associated with a poor prognosis. Fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) techniques are now employed in most cases of leukemia because many chromosomal abnormalities may not be apparent on routine karyotypes. A lumbar puncture should always be performed at the time of diagnosis to evaluate the possibility of CNS involvement. A chest x-ray should be obtained in all patients to exclude an anterior mediastinal mass, which is commonly seen in T-cell ALL. Electrolytes, calcium, phosphorus, uric acid, and renal and hepatic function should be monitored in all patients.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of acute leukemia includes nonmalignant and malignant diseases. Infection is probably the most common mimicker of acute leukemia, particularly Epstein-Barr virus infection. Other infections (cytomegalovirus, pertussis, mycobacteria) also can produce signs and symptoms common to leukemia. Noninfectious diagnostic considerations include aplastic anemia, juvenile rheumatoid arthritis, immune thrombocytopenic purpura, and congenital or acquired conditions that lead to neutropenia or anemia. Several malignant diagnoses also can mimic leukemia, including neuroblastoma, rhabdomyosarcoma, and Ewing sarcoma. These all may appear to be small, round, blue cell tumors. Newborns with trisomy 21 may have a condition known as transient myeloproliferative disorder, which produces elevated WBC counts with peripheral blasts, anemia, and thrombocytopenia. It usually resolves with supportive care only, but these children have a significantly increased risk (30%) of developing true acute leukemia (ALL or AML) within the next few months and years of life.

Proliferation and accumulation of histiocytes produces the histiocytoses. Langerhans cell histiocytosis manifests with varying degrees of bone, skin, lung, liver, and bone marrow (pancytopenia) involvement; familial erythrophagocytic lymphohistiocytosis and infection-associated (e.g., Epstein-Barr virus, cytomegalovirus, herpes simplex viruses, malaria) hemophagocytic syndromes manifest with fever, weight loss, irritability, hepatosplenomegaly, rash, hypertriglyceridemia, cytopenias, and aseptic meningitis. These histiocytic diseases should be included in the differential diagnosis of leukemia.

TREATMENT

Patients with ALL generally receive three- or four-agent induction chemotherapy based on their initial risk group assignment. Low- and standard-risk patients receive vincristine, prednisone, and L-asparaginase for 4 weeks; high-risk patients also receive an anthracycline (daunorubicin or doxorubicin). During induction, intrathecal instillation of some combination of methotrexate, cytarabine, and hydrocortisone is given to treat existing CNS leukemia or prevent its development. Following induction of successful remission, which is achieved in nearly all patients with ALL, the remission is consolidated along with CNS-directed therapy. For patients with CNS disease detected at diagnosis and those with T-cell ALL, cranial radiation therapy is usually provided. For high-risk patients, the use of intensive systemic chemotherapy in addition to the CNS-directed therapy during consolidation results in significant improvement in overall outcome. Systemic chemotherapy during this phase often includes cyclophosphamide, cytarabine, and 6—mercaptopurine. A delayed intensification improves outcomes in most groups.

After delayed intensification, all patients receive continuation therapy for a total duration of therapy of 2 to 3 years.Continuation therapy generally consists of a monthly dose of vincristine and short courses (5–7 days) of oral corticosteroid therapy, plus daily oral 6-mercaptopurine, and weekly methotrexate (orally or intramuscularly). In most protocols, intrathecal chemotherapy is given approximately every 3 months during continuation therapy.

The treatment of AML is quite different from that of ALL because nonmyelosuppressive drugs (vincristine, prednisone, and asparaginase) are not effective. Several cycles of extremely intensive myelosuppressive chemotherapy are necessary to cure childhood AML; there is little evidence that low-dose continuation therapy is helpful in AML (with the exception of acute promyelocytic leukemia). Induction therapy for AML usually consists of cytarabine, daunomycin, and etoposide (or 6-thioguanine). Induction is most effective for long-term outcome when two courses of drugs are given consecutively (1 to 2 weeks apart) regardless of blood counts, as opposed to waiting for counts to recover after the first course. If a patient has an HLA-matched sibling donor, most experts recommend a stem cell transplantation in the first remission, except in patients with Down syndrome and those with relatively favorable cytogenetics such as inv(16), t(15;17), and t(8;21). Gemtuzumab ozogamicin, a drug composed of recombinant humanized anti-CD33 antibody and the cytotoxic antibiotic calicheamicin, and haplo-identical natural killer cell transplantation are being studied as an adjuvant therapy for newly diagnosed childhood AML.

COMPLICATIONS

Major short-term complications associated with the treatment of leukemia result from bone marrow suppression caused by chemotherapy. Patients may have bleeding and significant anemia that necessitates transfusion of platelets or blood. Neutropenia with fewer than 500 neutrophils/mm³, and especially fewer than 100 neutrophils/mm³, greatly predispose the patient to significant bacterial infection. Cell-mediated immunosuppression increases the risk of Pneumocystis jiroveci (carinii) pneumonia. Prophylaxis with oral trimethoprim-sulfamethoxazole or aerosolized pentamidine can prevent this. Patients who have not previously had varicella or the varicella vaccine are at risk for severe infection. On exposure, a nonimmune patient should receive varicella-zoster immune globulin. Patients with AML have prolonged periods of neutropenia, which increases the risk of bacterial and fungal infections. Prophylaxis with penicillin and fluconazole is frequently instituted. Long-term sequelae of therapy are less common than in previous treatment eras, but are prevalent in long-term survivors treated in the 1980s and earlier. These sequelae include neurocognitive impairment, short stature, obesity, cardiac dysfunction, infertility, second malignant neoplasms, and psychosocial problems (see Table 154-3).

PROGNOSIS

Patients with ALL are classified into four prognostic risk groups (low, standard, high, and very high) based on age, initial WBC count, genetic characteristics, and response to induction therapy. Classification systems are complex and evolving (Table 155-2). In general, low-risk patients are 1 to 9 years old with an initial WBC count less than 50,000/mm³ and favorable cytogenetic findings such as t(12;21). High-risk patients are younger than 1 year of age or 10 years of age and older, have an initial WBC count greater than 50,000/mm³, have CNS or testicular disease at diagnosis, or have unfavorable cytogenetics such as t(4;11). Very high risk patients have a hypodiploid DNA index, a t(9;22) translocation, or fail to achieve remission after 4 weeks of therapy. All other patients are considered to have standard-risk ALL. Immunophenotype, minimal residual disease, and early response to therapy are other factors that influence risk stratification. Infants with ALL generally have a highly undifferentiated immunophenotype, often have a translocation involving the mixed lineage leukemia gene (e.g., t(4;11)), and have a poor prognosis. It was suggested previously that African-American, Native American, and Hispanic children have poorer outcomes compared with white and Asian children; these results have not been confirmed in all studies.

TABLE 155-2 General Prognostic Factors in Acute Lymphoblastic Leukemia

CNS, central nervous system; WBC, white blood cell.

The overall cure rate for childhood ALL with current therapy approximates 80%. Relapse of ALL occurs most commonly in the bone marrow, but also may occur in the CNS, testes, or other extramedullary sites. If relapse occurs while the patient is still receiving treatment, the prognosis is worse than if relapse occurs after discontinuation of therapy. Longer first remissions are associated with higher cure rates with salvage therapy compared with shorter first remissions. Stem cell transplant from a matched sibling donor, matched unrelated donor, or cord blood currently is recommended for patients who have a relapse while receiving initial chemotherapy. The current overall cure rate for childhood AML is approximately 50%. It is higher for patients who receive a matched sibling stem cell transplant in first remission than for patients treated with chemotherapy alone. The prognosis for relapsed AML is poor.