Epidemiology

ALL is diagnosed in approximately 2,400 children <15 yr of age in the USA each year. ALL has a striking peak incidence at 2-3 yr of age and occurs more in boys than in girls at all ages. This peak age incidence was apparent decades ago in white populations in advanced socioeconomic countries, but it has since been confirmed in the black population of the USA as well. The disease is more common in children with certain chromosomal abnormalities, such as Down syndrome, Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia. Among identical twins, the risk to the second twin if one develops leukemia is greater than that in the general population. The risk is >70% if ALL is diagnosed in the first twin during the first year of life and the twins shared the same (monochorionic) placenta. If the first twin develops ALL by 5-7 yr of age, the risk to the second twin is at least twice that in the general population, regardless of zygosity.

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.

Figure 489-1 Estimated frequency of specific genotypes of acute lymphoblastic leukemia (ALL) in children. The genetic lesions that are exclusively seen in cases of T-cell-lineage leukemias are indicated in purple. All other genetic subtypes are either exclusively or primarily seen in cases of B-cell-lineage ALL.

(From Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia, N Engl J Med 350:1535–1548, 2004.)

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.

Differential Diagnosis

The diagnosis of leukemia is readily made in the patient with typical signs and symptoms, anemia, thrombocytopenia, and elevated white blood count with blasts present on smear. Elevation of the lactate dehydrogenase (LDH) is often a clue to the diagnosis of ALL. When only pancytopenia is present, aplastic anemia (congenital or acquired) and myelofibrosis should be considered. Failure of a single cell line, as seen in transient erythroblastopenia of childhood, immune thrombocytopenia, and congenital or acquired neutropenia, sometimes produces a clinical picture that is difficult to distinguish from ALL and that can require bone marrow examination. A high index of suspicion is required to differentiate ALL from infectious mononucleosis in patients with acute onset of fever and lymphadenopathy and from rheumatoid arthritis in patients with fever, bone pain but often no tenderness, and joint swelling. These presentations also can require bone marrow examination.

ALL must be differentiated from acute myelogenous leukemia (AML) and other malignant diseases that invade the bone marrow and can have clinical and laboratory findings similar to ALL, including neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, and retinoblastoma.

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).

Figure 489-2 Kaplan-Meier analyses of event-free survival (A) and overall survival (B) in 2628 children with newly diagnosed ALL. The patients participated in 15 consecutive studies conducted at St. Jude Children’s Research Hospital from 1962-2005. The 5-year event-free and overall survival estimates (±SE) are shown, except for Study 15, for which preliminary results at 4 years are provided. The results demonstrate steady improvement in clinical outcome over the past 4 decades. The difference in event-free and overall survival rates has narrowed in the more recent periods, suggesting that relapses or second cancers that occur after contemporary therapy are more refractory to treatment.

(From Pui CH, Evans WE: Treatment of acute lymphoblastic leukemia, N Engl J Med 354:166–178, 2006.)

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.)

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,