The Leukemias

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Chapter 489 The Leukemias

The leukemias are the most common malignant neoplasms in childhood, accounting for about 31% of all malignancies that occur in children <15 yr of age. Each year leukemia is diagnosed in approximately 3,250 children <15 yr of age in the USA, an annual incidence of 4.5 cases per 100,000 children. Acute lymphoblastic leukemia (ALL) accounts for about 77% of cases of childhood leukemia, acute myelogenous leukemia (AML) for about 11%, chronic myelogenous leukemia (CML) for 2-3%, and juvenile myelomonocytic leukemia (JMML) for 1-2%. The remaining cases consist of a variety of acute and chronic leukemias that do not fit classic definitions for ALL, AML, CML, or JMML.

The leukemias may be defined as a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to an unregulated clonal proliferation of cells. The progeny of these cells have a growth advantage over normal cellular elements, because of their increased rate of proliferation and a decreased rate of spontaneous apoptosis. The result is a disruption of normal marrow function and, ultimately, marrow failure. The clinical features, laboratory findings, and responses to therapy vary depending on the type of leukemia.

489.1 Acute Lymphoblastic Leukemia

Childhood ALL was the first disseminated cancer shown to be curable and consequently has represented the model malignancy for the principles of cancer diagnosis, prognosis, and treatment. It actually is a heterogeneous group of malignancies with a number of distinctive genetic abnormalities that result in varying clinical behaviors and responses to therapy.

Etiology

In virtually all cases, the etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia (Table 489-1). Exposure to medical diagnostic radiation both in utero and in childhood has been associated with an increased incidence of ALL. In addition, published descriptions and investigations of geographic clusters of cases have raised concern that environmental factors can increase the incidence of ALL. Thus far, no such factors other than radiation have been identified in the USA. In certain developing countries, there has been an association between B-cell ALL and Epstein-Barr viral infections.

Cellular Classification

The classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology, phenotypic characteristics as measured by cell membrane markers, and cytogenetic and molecular genetic features. Morphology alone usually is adequate to establish a diagnosis, but the other studies are essential for disease classification, which can have a major influence on the prognosis and the choice of appropriate therapy. The most important distinguishing morphologic feature is the French-American-British (FAB) L3 subtype, which is evidence of a mature B-cell leukemia. The L3 type, also known as Burkitt leukemia, is one of the most rapidly growing cancers in humans and requires a different therapeutic approach than other subtypes of ALL. Phenotypically, surface markers show that about 85% of cases of ALL are derived from progenitors of B cells, about 15% are derived from T cells, and about 1% are derived from B cells. A small percentage of children with leukemia have a disease characterized by surface markers of both lymphoid and myeloid derivation. Immunophenotypes often correlate to disease manifestations (Table 489-2).

Chromosomal and genetic abnormalities are found in most patients with ALL (Table 489-3, Fig. 489-1). The abnormalities, which may be related to chromosomal number, translocations, or deletions, provide important prognostic information. The identification of the leukemia-specific fusion-gene sequences in archived neonatal blood spots of some children who develop ALL at a later date indicates the importance of in utero events in the initiation of the malignant process, but the long lag period before the onset of the disease in some children, reported to be as long as 14 yr, supports the concept that additional genetic modifications also are required for disease expression. The polymerase chain reaction and fluorescence in situ hybridization techniques offer the ability to pinpoint molecular genetic abnormalities and to detect small numbers of malignant cells during follow-up and are of proven clinical utility. The development of DNA microanalysis makes it possible to analyze the expression of thousands of genes in the leukemic cell. This technique promises to further enhance the understanding of the fundamental biology and to provide clues to the therapeutic approach of ALL. Some effectors of critical signal transduction pathways have already been implicated in the pathogenesis of ALL using this technique.

Clinical Manifestations

The initial presentation of ALL usually is nonspecific and relatively brief. Anorexia, fatigue, malaise, and irritability often are present, as is an intermittent, low-grade fever. Bone or, less often, joint pain, particularly in the lower extremities, may be present. Patients often have a history of an upper respiratory tract infection in the preceding 1-2 mo. Less commonly, symptoms may be of several months’ duration, may be localized predominantly to the bones or joints, and can include joint swelling. Bone pain is severe and can wake the patient at night. As the disease progresses, signs and symptoms of bone marrow failure become more obvious with the occurrence of pallor, fatigue, exercise intolerance, bruising, or epistaxis, as well as fever, which may be caused by infection or the disease. Organ infiltration can cause lymphadenopathy, hepatosplenomegaly, testicular enlargement, or central nervous system (CNS) involvement (cranial neuropathies headache, seizures). Respiratory distress may be due to severe anemia or mediastinal node comparison of the airways.

On physical examination, findings of pallor, listlessness, purpuric and petechial skin lesions, or mucous membrane hemorrhage can reflect bone marrow failure (Chapter 487). The proliferative nature of the disease may be manifested as lymphadenopathy, splenomegaly, or, less commonly, hepatomegaly. In patients with bone or joint pain, there may be exquisite tenderness over the bone or objective evidence of joint swelling and effusion. Nonetheless, with marrow involvement, deep bone pain may be present but tenderness will not be elicited. Rarely, patients show signs of increased intracranial pressure that indicate leukemic involvement of the CNS. These include papilledema (see Fig. 487-3), retinal hemorrhages, and cranial nerve palsies. Respiratory distress usually is related to anemia but can occur in patients with an obstructive airway problem (wheezing) due to a large anterior mediastinal mass (e.g., in the thymus or nodes). This problem is most typically seen in adolescent boys with T-cell ALL. T-cell ALL also has a higher leukocyte count.

Precursor B-cell ALL (CD10+ or common acute lymphoblastic leukemia antigen [CALLA] positive) is the most common immunophenotype (see Table 489-2), with onset at 1-10 yr of age. The median leukocyte count at presentation is 33,000, although 75% of patients have counts <20,000; thrombocytopenia is seen in 75% of patients, and hepatosplenomegaly is seen in 30-40% of patients. In all types of leukemia, CNS symptoms are seen at presentation in 5% of patients (5-10% have blasts in the CSF). Testicular involvement is rarely evident at diagnosis, but prior studies have indicated occult involvement in 25% of boys. There is no indication for testicular biopsy.

Diagnosis

The diagnosis of ALL is strongly suggested by peripheral blood findings that indicate bone marrow failure. Anemia and thrombocytopenia are seen in most patients. Leukemic cells might not be reported in the peripheral blood in routine laboratory examinations. Many patients with ALL present with total leukocyte counts of <10,000/µL. In such cases, the leukemic cells often are reported initially to be atypical lymphocytes, and it is only on further evaluation that the cells are found to be part of a malignant clone. When the results of an analysis of peripheral blood suggest the possibility of leukemia, the bone marrow should be examined promptly to establish the diagnosis. It is important that all studies necessary to confirm a diagnosis and adequately classify the type of leukemia be performed, including bone marrow aspiration and biopsy, flow cytometry, cytogenetics, and molecular studies.

ALL is diagnosed by a bone marrow evaluation that demonstrates >25% of the bone marrow cells as a homogeneous population of lymphoblasts. Staging of ALL is based partly on a cerebrospinal fluid (CSF) examination. If lymphoblasts are found and the CSF leukocyte count is elevated, overt CNS or meningeal leukemia is present. This finding reflects a worse stage and indicates the need for additional CNS and systemic therapies. The staging lumbar puncture may be performed in conjunction with the first dose of intrathecal chemotherapy, if the diagnosis of leukemia has been previously established from bone marrow evaluation. The initial lumbar puncture should be performed by an experienced proceduralist, because a traumatic lumbar puncture is associated with an increased risk of CNS relapse.

Treatment

The single most important prognostic factor in ALL is the treatment: Without effective therapy, the disease is fatal. The survival rates of children with ALL since the 1970s have improved as the results of clinical trials have improved the therapies and outcomes (Fig. 489-2). Survival is also related to age (Fig. 489-3) and subtype (Fig. 489-4).

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Figure 489-3 Kaplan-Meier estimates of event-free survival according to age at diagnosis of acute lymphoblastic leukemia.

(From Pui CH, Robinson LL, Look AT: Acute lymphoblastic leukaemia, Lancet 371:1030–1042, 2008.)

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Figure 489-4 Kaplan-Meier analysis of event-free survival according to biological subtype of leukemia.

(From Pui CH, Robinson LL, Look AT: Acute lymphoblastic leukaemia, Lancet 371:1030–1042, 2008.)

The choice of treatment of ALL is based on the estimated clinical risk of relapse in the patient, which varies widely among the subtypes of ALL. Three of the most important predictive factors are the age of the patient at the time of diagnosis, the initial leukocyte count, and the speed of response to treatment (i.e., how rapidly the leukemic cells can be cleared from the marrow or peripheral blood). Different study groups use various factors to define risk, but age between 1 and 10 yr and a leukocyte count of <50,000/µL are widely used to define average risk. Children who are >10 yr of age or who have an initial leukocyte count of >50,000/µL are considered to be at higher risk. The outcome for patients at higher risk can be improved by administration of more-intensive therapy despite the greater toxicity of such therapy. Infants with ALL, along with patients who present with specific chromosomal abnormalities, such as t(9;22) or t(4;11), have an even higher risk of relapse despite intensive therapy. Clinical trials have demonstrated that the prognosis for patients with a slower response to initial therapy may be improved by therapy that is more intensive than the therapy considered necessary for patients who respond more rapidly.

Most children with ALL are treated in clinical trials conducted by national or international cooperative groups. In general, the initial therapy is designed to eradicate the leukemic cells from the bone marrow; this is known as remission induction. During this phase, therapy usually is given for 4 wk and consists of vincristine weekly, a corticosteroid such as dexamethasone or prednisone, and either repeated doses of native L-asparaginase or a single dose of a long-acting, pegylated asparaginase preparation. Intrathecal cytarabine and/or methotrexate also may be given. Patients at higher risk also receive daunomycin at weekly intervals. With this approach, 98% of patients are in remission,