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, as defined by <5% blasts in the marrow and a return of neutrophil and platelet counts to near-normal levels after 4-5 wk of treatment. Intrathecal chemotherapy is usually given at the start of treatment and once more during induction.

The second phase of treatment focuses on CNS therapy in an effort to prevent later CNS relapses. Intrathecal chemotherapy is given repeatedly by lumbar puncture in conjunction with intensive systemic chemotherapy. The likelihood of later CNS relapse is thereby reduced to <5%. A small percentage of patients with features that predict a high risk of CNS relapse may receive irradiation to the brain. This includes patients who, at the time of diagnosis, have lymphoblasts in the CSF and either an elevated CSF leukocyte count or physical signs of CNS leukemia, such as cranial nerve palsy.

After remission has been induced, in conjunction with CNS therapy, many regimens provide 14-28 wk of multiagent therapy, with the drugs and schedules used varying depending on the risk group of the patient. This period of treatment is termed consolidation and intensification. Many patients benefit from administration of a delayed intensive phase of treatment (delayed intensification), approximately 5-7 mo after the beginning of therapy, and after a relatively nontoxic phase of treatment (interim maintenance) to allow recovery from the prior intensive therapy. Finally, patients are given daily mercaptopurine and weekly methotrexate, usually with intermittent doses of vincristine and a corticosteroid. This period, known as the maintenance phase of therapy, lasts for 2-3 yr, depending on the protocol used.

A small number of patients with particularly poor prognostic features, such as those with the t(9;22) translocation known as the Philadelphia chromosome or extreme hypodiploidy, may undergo bone marrow transplantation during the first remission.

Adolescents and young adults with ALL usually have adverse prognostic factors at the time of diagnosis and require more-intensive therapy. A number of studies have proved that patients in this age group have a superior outcome when treated on pediatric as opposed to adult treatment protocols. Although the explanation for these findings may be multifactoral, it is important that these patients be treated on pediatric treatment protocols, ideally in a pediatric cancer center.

In the future, treatment also may be stratified by gene expression profiles of leukemic cells or the presence of minimal residual disease. In particular, gene expression arrays induced by exposure to the chemotherapeutic agent can predict which patients have drug-resistant ALL. Pharmacogenetic testing of the thiopurine S-methyltransferase gene, which converts mercaptopurine or thioguanine (both prodrugs) into active chemotherapeutic agents, can identify rapid metabolizers (associated with toxicity) or slow metabolizers (associated with treatment failure), thus optimizing drug dosing (Chapter 56).

Supportive Care

Close attention to the medical supportive care needs of the patients is essential in successfully administering aggressive chemotherapeutic programs. Patients with high white blood counts are especially prone to tumor lysis syndrome as therapy is initiated. The kidney failure associated with very high levels of serum uric acid can be prevented or treated with allopurinol or urate oxidase. Chemotherapy often produces severe myelosuppression, which can require erythrocyte and platelet transfusion and which always requires a high index of suspicion and aggressive empiric antimicrobial therapy for sepsis in febrile children with neutropenia. Patients must receive prophylactic treatment for Pneumocystis jiroveci pneumonia during chemotherapy and for several months after completing treatment.

The successful therapy of ALL is a direct result of intensive and often toxic treatment. However, such intensive therapy can incur substantial academic, developmental, and psychosocial costs for children with ALL and considerable financial costs and stress for their families. Both long-term and acute toxicity effects can occur. An array of cancer care professionals with training and experience in addressing the myriad of problems that can arise is essential to minimize the complications and achieve an optimal outcome.

Prognosis

Most children with ALL can now be expected to have long-term survival, with the survival rate >80% at 5 yr from diagnosis (see Fig. 489-2). The most important prognostic factor is the choice of appropriate risk-directed therapy, with the type of treatment chosen according to the subtype of ALL, the initial white blood count, the age of the patient, and the rate of response to initial therapy. Characteristics generally believed to adversely affect outcome include age <1 yr or >10 yr at diagnosis, a leukocyte count of >50,000/µL at diagnosis, T-cell immunophenotype, or a slow response to initial therapy. Chromosomal abnormalities, including hypodiploidy, the Philadelphia chromosome, and MLL gene rearrangements, and certain mutations, including deletion of the IKZF1 gene, portend a poorer outcome. More-favorable characteristics include a rapid response to therapy, hyperdiploidy, trisomy of specific chromosomes, and rearrangements of the TEL/AML1 genes.

Patients in clinical remission can have minimal residual disease (MRD) that can only be detected with specific molecular probes to translocations and other DNA markers contained in leukemic cells or specialized flow cytometry. MRD can be quantitative and can provide an estimate of the burden of leukemic cells present in the marrow. Higher levels of MRD present at the end of induction suggest a poorer prognosis and higher risk of subsequent relapse. MRD of 0.01-0.1% on the marrow on day 29 of induction is a significant risk factor for shorter event-free survival for all risk categories, when compared with patients with no MRD.

Epidemiology

AML accounts for 11% of the cases of childhood leukemia in the USA; it is diagnosed in approximately 370 children annually. The relative frequency of AML increases in adolescence, representing 36% of cases of leukemia in 15-19 yr olds. One subtype, acute promyelocytic leukemia (APL), is more common in certain other regions of the world, but incidence of the other types is generally uniform. Several chromosomal abnormalities associated with AML have been identified, but no predisposing genetic or environmental factors can be identified in most patients (see Table 489-1). Nonetheless, a number of risk factors have been identified, including ionizing radiation, chemotherapeutic agents (e.g., alkylating agents, epipodophyllotoxin), organic solvents, paroxysmal nocturnal hemoglobinuria, and certain syndromes: Down syndrome, Fanconi anemia, Bloom syndrome, Kostmann syndrome, Shwachman-Diamond syndrome, Diamond-Blackfan syndrome, Li-Fraumeni syndrome, and neurofibromatosis type 1.

Cellular Classification

The characteristic feature of AML is that >20% of bone marrow cells on bone marrow aspiration or biopsy touch preparations constitute a fairly homogeneous population of blast cells, with features similar to those that characterize early differentiation states of the myeloid-monocyte-megakaryocyte series of blood cells. The most common classification of the subtypes of AML is the FAB system (Table 489-4). Although this system is based on morphologic criteria alone, current practice also requires the use of flow cytometry to identify cell surface antigens and use of chromosomal and molecular genetic techniques for additional diagnostic precision and also to aid the choice of therapy. The World Health Organization (WHO) has proposed a new classification system that incorporates morphology, chromosome abnormalities, and specific gene mutations. This system provides significant biologic and prognostic information.

Table 489-4 FRENCH-AMERICAN-BRITISH (FAB) CLASSIFICATION OF ACUTE MYELOGENOUS LEUKEMIA

Clinical Manifestations

The production of symptoms and signs of AML, as in ALL, is due to replacement of bone marrow by malignant cells and due to secondary bone marrow failure. Thus, patients with AML can present with any or all of the findings associated with marrow failure in ALL. In addition, patients with AML present with signs and symptoms that are uncommon in ALL, including subcutaneous nodules or “blueberry muffin” lesions (especially in infants), infiltration of the gingiva (especially in M4 and M5 subtypes), signs and laboratory findings of disseminated intravascular coagulation (especially indicative of acute promyelocytic leukemia), and discrete masses, known as chloromas or granulocytic sarcomas. These masses can occur in the absence of apparent bone marrow involvement and typically are associated with the M2 subcategory of AML with a t(8;21) translocation. Chloromas also may be seen in the orbit and epidural space.

Diagnosis

Analysis of bone marrow aspiration and biopsy specimens of patients with AML typically reveals the features of a hypercellular marrow consisting of a monotonous pattern of cells with features that permit FAB subclassification of disease. Flow cytometry and special stains assist in identifying myeloperoxidase-containing cells, thus confirming both the myelogenous origin of the leukemia and the diagnosis. Some chromosomal abnormalities and molecular genetic markers are characteristic of specific subtypes of disease (see Tables 489-3 and 489-5).

Treatment

Aggressive multiagent chemotherapy is successful in inducing remission in about 85-90% of patients. Targeting therapy to genetic markers may be beneficial (see Table 489-5). Up to 5% of patients die of either infection or bleeding before a remission can be achieved. Matched-sibling bone marrow or stem cell transplantation after remission has been shown to achieve long-term disease-free survival in 60-70% of patients. Continued chemotherapy for patients who do not have a matched sibling donor is generally less effective than marrow transplantation but nevertheless is curative in about 45-50% of patients. However, for selected patients with favorable prognostic features [t(8;21); t(15;17); inv(16); FAB M3] and improved outcome with chemotherapy, matched sibling stem cell transplantation is recommended only after a relapse. Matched unrelated donor (MUD) stem cell transplants may be effective therapy, but they carry the risk of significant graft versus host disease as well as the complications associated with intensive myeloablative therapy. MUD transplants are usually reserved for patients who have a relapse. However, patients with unfavorable prognostic features (e.g., monosomy 7 and 5, 5q-, and 11q23 abnormalities) who have inferior outcome with chemotherapy might benefit from MUD stem cell transplant in first remission.

Acute promyelocytic leukemia (FAB-M3), characterized by a gene rearrangement involving the retinoic acid receptor [t(15;17); PML-RARA], is very responsive to all-trans-retinoic acid (tretinoin) combined with anthracyclines and cytarabine. The success of this therapy makes marrow transplantation in first remission unnecessary for patients with this disease.

The supportive care needs of patients with AML are basically the same as those for patients with ALL. However, the very intensive therapy required in AML produces prolonged bone marrow suppression with a very high incidence of serious infections, especially streptococcal viridans sepsis and fungal infection.

The most current information on treatment of AML is available in the PDQ (Physician Data Query) on the National Cancer Institute website (www.cancer.gov/cancertopics/pdq/treatment/childAML/healthprofessional/).