Acute Lympholastic Leukemia (ALL)

Background

Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, accounting for about 25% of all cancer diagnoses in patients under age 15 years. The worldwide incidence of ALL is about 1:25,000 children per year, including 2500 children per year in the United States. The peak age at onset is 4 years; 85% of patients are diagnosed between ages 2 and 10 years. Before the advent of chemotherapy, this disease was fatal, usually within 3–4 months, with virtually no survivors 1 year after diagnosis.1

ALL results from uncontrolled proliferation of immature lymphocytes. Its cause is unknown, and genetic factors may play a role. Leukemia is defined by the presence of more than 25% malignant hematopoietic cells (blasts) on bone marrow aspirate. Leukemic blasts from the majority of cases of childhood ALL have an antigen on the cell surface called the common ALL antigen (CALLA). These blasts derive from B cell precursors early in their development. Less commonly, lymphoblasts are of T cell origin or of mature B cell origin. Over 70% of children receiving aggressive combination chemotherapy and early presymptomatic treatment to the central nervous system (CNS) are now cured of ALL.1

Definition

Acute lymphoblastic leukemia (ALL) is an abnormal clonal proliferation of lymphocytic progenitor cells.2

Epidemiology

Approximately 2,800 children are diagnosed with ALL in the United States annually. It has a striking peak incidence between 2–6 yr of age and occurs slightly more frequently in boys than in girls. This peak age incidence was apparent decades ago in white populations in advanced socioeconomic countries, but more recently has also been confirmed in the black population of the United States. The disease is more common in children with certain chromosomal abnormalities such as Down syndrome, Bloom syndrome, ataxia-telangiectasia, and Fanconi syndrome. Among identical twins, the risk to the second twin if one develops leukemia is greater than that in the general population. The risk may be as high as 100% if the first twin is diagnosed 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.3

Etiology

In virtually all cases, the etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia (Table 2-1).3

GENETIC CONDITIONS
Down syndrome
Fanconi syndrome
Bloom syndrome
Diamond-Blackfan anemia
Schwachman syndrome
Klinefelter syndrome
Turner syndrome
Neurofibromatosis
Ataxia-telangiectasia
Severe combined immune deficiency
Paroxysmal nocturnal hemoglobinuria
Li-Fraumeni syndrome

ENVIRONMENTAL FACTORS :
Ionizing radiation
Drugs
Alkylating agents
Nitrosourea
Epipodophyllotoxin
Benzene exposure
Advanced maternal age

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 may increase the incidence of ALL. Thus far, no such factors other than radiation have been identified, except for an association between B-cell ALL and Epstein-Barr viral infections in certain developing countries.3

Acute leukemia is the most common malignancy diagnosed in children and ALL accounts for approximately 75% of the cases. ALL has a peak incidence between 2 and 6 years of age, is more common in whites than in blacks, and occurs more frequently in boys than in girls. A variety of environmental (e.g., ionizing radiation), genetic (e.g., karyotype abnormalities, Down syndrome), viral (e.g., retroviruses), and immunologic (e.g., Wiskott-Aldrich syndrome, ataxia telangiectasia) factors have been associated with the development of ALL. The molecular mechanisms underlying leukemic transformation of lymphocytic progenitor cells is not completely understood. Immunologic marker analysis enables lineage assignment and maturational staging of the lymphoid leukemias. Approximately 65% of patients have early pre–B-cell lymphoblast disease (best outcome), whereas 18% to 20%, 13% to 15%, and 1% have pre–B-cell, T-cell, and B-cell (worst outcome) pheno-types, respectively. Cells from 1% to 3% of children fail to react with any of the antigen tests and are classified as undifferentiated or null-type leukemia.2

Genetic factors are presumed to play a significant role in the cause of acute leukemias, including ALL. Evidence for this is based on several observations, including the association between various constitutional chromosomal abnormalities and childhood ALL, the occurrence of familial leukemia, and the molecular epidemiologic evidence of the importance of various alleles of specific genes.4

Constitutional chromosomal abnormalities are associated with childhood leukemia. Children with trisomy 21 (i.e., Down syndrome) are up to 15 times more likely to develop leukemia than are normal children. Although both ALL and acute myeloid leukemia (AML) are observed, ALL predominates in all but the neonatal age group.4

Other less common preexisting chromosomal abnormalities have been linked to leukemia. Included among these are children with Klinefelter’s syndrome and the trisomy G syndromes. Children with neurofibromatosis and those with Schwachman syndrome are also reported to have an increased risk of leukemia. As noted above, a higher risk of childhood leukemia has been associated with increasing maternal age. This may reflect the increased incidence of subtle karyotypic abnormalities in infants born to older mothers.4

The incidence of acute leukemia among those with Bloom syndrome and Fanconi’s anemia is well documented. These rare, autosomal recessive disorders are characterized by increased chromosomal fragility. Although AML is more common in those with Bloom syndrome, ALL also occurs. There is some evidence that the development of leukemia in these patients is a consequence of genetic recombination of somatic cell chromosomes. Defective replication and repair of DNA appears to play a significant role in both disorders. Fanconi’s anemia is most frequently associated with the development of acute myelomonocytic leukemia rather than with ALL.4

Lymphoid malignancies, with a predominance of T-ALL, have been reported in patients with ataxia-telangiectasia (AT), an autosomal recessive disorder characterized by increased chromosomal fragility. B-cell and pre–B-cell ALL also have been reported occasionally in AT patients. The gene responsible for AT (ATM) has been cloned, but the mechanism by which this increases patients’ risk for cancer has not yet been uncovered.4

The importance of in utero genetic events has been suspected for many years due to concordance studies on twins with leukemia. The suggestion that leukemogenesis begins in utero also has been explored in studies that have found leukemogenic translocations [i.e., t(4;11) and t(12;21)] and markers of clonality that match that of the later leukemic blasts in heelstick blood samples (Guthrie cards) from newborns who later developed ALL. Although these studies providing tantalizing clues that the process of developing leukemia may begin in utero, the questions of whether these genetic changes are the “accelerating,” permissive, or merely incidental genetic changes in patients who later developed leukemia remain unresolved. Crucial work remains to be done concerning whether the specificity of the leukemogenic mechanism will match the sensitivity of the polymerase chain reaction (PCR) methods used to test for small amounts of presumed leukemic cells. In the neonatal heelstick studies mentioned above, these patients were found to have 1/100 to 1/10,000 of the cells with DNA changes at birth, which contained one genetic alteration found months to years later in their leukemic blasts. It is not clear whether many more “normal” individuals (who never clinically present as leukemics) may show similar chromosomal breakpoints or evidence of clonal rearrangements in their white cells at birth.4

Multiple cases of leukemia within families have been reported, including aggregates among siblings and groups within the same generation or in several generations. The frequency of leukemia is higher than expected in families of leukemia patients. Siblings of children with leukemia, including ALL, have an approximately twofold to fourfold greater risk of developing the disease than do unrelated children in the general population. Although the occurrence of leukemia in identical twins has been used to support the role of genetic factors in the disease, the extent to which this association implicates a genetic susceptibility is ambiguous. The concordance of acute leukemia in monozygotic twins is estimated to be as high as 25%. The risk for concordance among twins (both mono- and dizygotic) is highest in infancy; this risk diminishes with age, and after age 7 years, the risk to the unaffected twin is similar to that for persons within the general population. Although the high concordance rate among younger twins suggests a genetic predisposition or in utero transfer of the leukemic cells, it may also be the result of simultaneous exposure to a common prenatal or postnatal leukemogenic event.4

Pathogenesis

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 is usually adequate to establish a diagnosis, but the other studies are essential for disease classification, which may have a major influence on both the prognosis and the choice of appropriate therapy. In terms of clinical significance, 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. 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 diagnosed with leukemia have a disease characterized by surface markers of both lymphoid and myeloid derivation.3

Chromosomal abnormalities are found in most patients with ALL (Table 2-2). The abnormalities, which may be related to chromosomal number, translocations, or deletions, provide important prognostic information. Specific chromosomal findings, such as the t(9;22) translocation, suggest a need for additional, molecular genetic studies. The polymerase chain reaction and fluorescence in situ hybridization techniques, for example, offer the ability to pinpoint molecular genetic abnormalities and to detect small numbers of malignant cells during follow-up; however, the clinical utility of these findings has yet to be firmly established.3

Classification

Morphologic Classification

There have been several attempts to classify ALL cells morphologically using criteria such as cell size, nuclear to cytoplasmic ratio, nuclear shape, number and prominence of nucleoli, nature and intensity of cytoplasmic staining with a variety of staining agents, presence of cytoplasmic granules, prominence of cytoplasmic vacuoles, and the character of nuclear chromatin (Table 2-3). Most of these efforts were unsuccessful because they were technically difficult to reproduce or lacked meaningful clinical correlations. One system, however, proposed by the French-American-British (FAB) Cooperative Working Group has become generally accepted. The FAB system (Fig. 2-1 and Table 2-3) defines three categories of lymphoblasts. L1 lymphoblasts are usually smaller, with scant cytoplasm and inconspicuous nucleoli. Cells of the L2 variety are larger, and they demonstrate considerable heterogeneity in size, prominent nucleoli, and more abundant cytoplasm. Lymphoblasts of the L3 type, notable for their deep cytoplasmic basophilia, are large, frequently display prominent cytoplasmic vacuolation, and are morphologically identical to Burkitt’s lymphoma cells.4

In 1976, a French-American-British (FAB) cooperative group developed a system for morphologic classification of acute leukemias. The acute lymphoblastic leukemias were divided into three classes:
L1: Lymphoblasts are small, with scant cytoplasm and indistinct nucleoli.
L2: Lymphoblasts are larger, more heterogeneous in size, and have more abundant cytoplasm, prominent nucleoli, and reniform nuclear membranes.
L3: Lymphoblasts are large, with a deep cytoplasmic basophilia, prominent vacuolation, and one or more nucleoli.2

Approximately 85% of children with ALL have predominant L1 morphology, 14% have L2, and 1% have L3. The L2 subtype is more common in adults. Lymphoblasts of the L3 type possess cell surface immunoglobulin and other characteristic B-cell markers. There is, however, no apparent correlation between the FAB L1 and L2 morphologic types and immunologic cell surface markers. Concordance among investigators using the FAB system is relatively high. Since its original description, refinements of the FAB system have been proposed. Although the existence of different approaches to FAB classification can confound interstudy comparisons, a variety of individual studies have demonstrated that the FAB classification has prognostic value.4

L1 morphology has been associated with a higher remission induction rate and better event-free survival (EFS) than L2 morphology, which appears to convey poor prognosis. In early studies, L2 morphology appeared to be an independent prognostic variable indicative of poor outcome. In more recent studies, however, it sometimes loses its predictive value when the patients are stratified for age, sex, and diagnostic white count. Patients with the L3 morphology have the worst overall prognosis. Although the FAB classification system appears to have value as a prognostic indicator, no biologic basis for the morphologic differences delineated by this system has been identified. Generally, the most important morphologic distinctions are those between ALL and AML. Routine Wright’s and cytochemical stains are usually adequate for this task, but fluorescent antibody cell sorting (FACS) and chromosomal analysis can be helpful in equivocal cases.4

An unusual morphologic variant of ALL is the so-called hand mirror–cell variant in which leukemic cells are characterized by a hand mirror shape caused by a handle-shaped uropod. Approximately, 5% to 23% of pediatric ALL cases are said to have this morphology. The data concerning the prognostic implications of hand mirror morphology have been mixed. The suggestion that the hand mirror–cell variant is associated with the development of CNS disease has not been confirmed. In adult ALL the hand mirror morphology has been associated with a subset of female patients whose leukemic blasts display myeloid and lymphoid antigens (i.e., mixed phenotype) and whose clinical course is relatively indolent despite the fact that they rarely enter complete remission.4

Cytochemical stains have been studied with respect to their ability to differentiate between various clinical and immunologic subsets of ALL. The periodic acid–Schiff, acid phosphatase, b-glucuronidase, and acid a-naphthyl acetate esterase reactions have been evaluated. Although some correlations appear strong (e.g., strong focal paranuclear acid phosphatase activity appears to be more common in T-cell disease), the practical use of this type of information is limited and has been supplanted by more sophisticated immunologic techniques, such as immunophenotyping with FACS. In rare cases of acute leukemia that cannot be definitively classified by current immunologic or molecular methods, ultrastructural detection of platelet peroxidase or myeloperoxidase may be helpful in identifying the megakaryocytic or myeloid nature of the disease.4

Diagnostic Approaches

A. Symptoms and Signs

Presenting complaints of patients with ALL include those related to decreased bone marrow production of red cells, white cells, or platelets and to leukemic infiltration of extramedullary (outside bone marrow) sites. Intermittent fevers are common, as a result of either cytokines induced by the leukemia itself or infections secondary to leukopenia. About 25% of patients experience bone pain, especially in the pelvis, vertebral bodies, and legs. Physical examination at diagnosis ranges from virtually normal to highly abnormal. Signs related to bone marrow infiltration by leukemia include pallor, petechiae, and purpura. Hepatomegaly or splenomegaly occurs in over 60% of patients. Lymphadenopathy is common, either localized or generalized to cervical, axillary, and inguinal regions. The testes may be unilaterally or bilaterally enlarged secondary to leukemic infiltration. Superior vena cava syndrome is caused by mediastinal adenopathy compressing the superior vena cava. A prominent venous pattern develops over the upper chest from collateral vein enlargement. The neck may feel full from venous engorgement. The face may appear plethoric, and the periorbital area may be edematous.1

A mediastinal mass can cause tachypnea, orthopnea, and respiratory distress. Leukemic infiltration of cranial nerves may cause cranial nerve palsies with mild nuchal rigidity. The optic fundi may show exudates of leukemic infiltration and hemorrhage from thrombocytopenia. Anemia can cause a flow murmur, tachycardia and, rarely, congestive heart failure. Bone and joint pain may be found on examination, particularly in the pelvis, lower spine, and femurs. There may also be signs of infection.1

B. Laboratory Findings

A complete blood count (CBC) with differential is the most useful initial test because 95% of patients with ALL have a decrease in at least one cell type (single cytopenia): neutropenia, thrombocytopenia, or anemia. Most patients have decreases in at least two blood cell lines. The white count is low or normal (< 10,000/mL) in 50% of patients, but the differential shows neutropenia (absolute neutrophil count < 1000/mL) along with a small percentage of blasts amid normal lymphocytes. In 30% of patients the white count is between 10,000 and 50,000/mL; in 20% of patients it is over 50,000/mL, occasionally higher than 300,000/mL. Blasts are usually readily identifiable on peripheral blood smears from patients with elevated white counts. Peripheral blood smears also show abnormalities in red cells such as tear drops. Most patients’s with ALL have decreased platelet counts (< 150,000/mL) and decreased hemoglobin (< 11 g/dL) at diagnosis. Fewer than 1% of patients diagnosed with ALL have entirely normal CBCs and peripheral blood smears but have bone pain that leads to bone marrow examination. Serum chemistries, particularly uric acid and lactate dehydrogenase (LDH), are often elevated at diagnosis as a result of cell breakdown. Serum phosphorus is occasionally elevated at diagnosis as well.1 The diagnosis of ALL is made by bone marrow examination, which shows a homogeneous infiltration of leukemic blasts replacing normal marrow elements. The morphology of blasts on bone marrow aspirate can usually distinguish ALL from acute myeloid leukemia (AML). Lymphoblasts are typically small, with cell diameters of approximately two erythrocytes. Lymphoblasts have scant cytoplasm, usually without granules. The nucleus typically contains no nucleoli or one small, indistinct nucleolus. Immunophenotyping of ALL blasts helps distinguish precursor B cell ALL from T cell ALL or AML. Histochemical stains specific for myeloblastic and monoblastic leukemias (myeloperoxidase and nonspecific esterase) distinguish ALL from AML. About 5% of patients present with CNS leukemia, which is defined as a cerebrospinal fluid (CSF) white cell count > 5/mL with blasts present on cytocentrifuged specimen.1

C. Imaging

Chest x-ray may show mediastinal widening or an anterior mediastinal mass and tracheal compression secondary to lymphadenopathy or thymic infiltration. Abdominal ultrasound may show kidney enlargement from leukemic infiltration or uric acid nephropathy as well as intra-abdominal adenopathy. Plain x-rays of the long bones and spine may show demineralization, periosteal elevation, or compression of vertebral bodies.1

Differential Diagnose

The differential diagnosis, based on the history and physical examination, includes chronic infections by Epstein-Barr virus (EBV) and cytomegalovirus (CMV), causing lymphadenopathy, hepatosplenomegaly, fevers, and anemia. Prominent petechiae and purpura suggest a diagnosis of immune thrombocytopenic purpura, while significant pallor could be caused by transient erythroblastopenia of childhood, autoimmune hemolytic anemias, or aplastic anemia. Fevers and joint pains, with or without hepatosplenomegaly and lymphadenopathy, suggest juvenile rheumatoid arthritis. The diagnosis of leukemia usually becomes straightforward once the CBC reveals multiple cytopenias and leukemic blasts. Serum LDH levels may help distinguish juvenile rheumatoid arthritis (JRA) from leukemia. LDH is usually normal in JRA but often elevated in ALL patients presenting with bone pain. An elevated white count with lymphocytosis is typical of pertussis; however, in pertussis the lymphocytes are mature, and neutropenia is rarely associated.1

Acute lymphoblastic leukemia must be differentiated from acute myelogenous leukemia (AML); other malignant diseases that may invade the bone marrow and cause marrow failure such as neuroblastoma, rhabdomyosarcoma, Ewing’s sarcoma, and retinoblastoma; and causes of primary bone marrow failure, such as aplastic anemia (either congenital or acquired) and myelofibrosis. Failure of a single cell line, as in transient erythroblastic anemia, immune thrombocytopenia, and congenital or acquired neutropenia, sometimes produces a clinical picture that is difficult to distinguish from ALL and that may 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 and joint swelling. These presentations also may require bone marrow examination.1

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 over the past 40 yr have improved as the results of clinical trials have improved the therapies and outcomes.3

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 blast cells can be cleared from the marrow or peripheral blood). Different study groups use various factors to define risk, but a patient between 1–10 yr of age and with a leukocyte count of less than 50,000/µL is widely used to define average.3

Patients considered to be at higher risk are children who are older than 10 yr of age or who have an initial leukocyte count of more than 50,000/µL. Recent trials have shown that 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 also 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.3

Most children with ALL are treated on 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 and is known as remission induction. During this phase, therapy is usually 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 asparaginase preparation. Intrathecal cytarabine or methotrexate, or both, may also be given. Patients at higher risk also receive daunomycin at weekly intervals. With this approach, 98% of patients are in remission, as defined by less than 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 time of diagnosis and once more during induction.3

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 less than 5%. A small proportion of patients with features that predict a high risk of CNS relapse receive irradiation to the brain and spinal cord. This includes those patients who have lymphoblasts in the CSF and an elevated CSF leukocyte count at the time of diagnosis.3

After remission induction, many regimens provide 14–28 wk of multiagent therapy, with the drugs and schedules used varying depending on the risk group of the patient. 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, principally those with the t(9;22) translocation known as the Philadelphia chromosome, may undergo bone marrow transplantation during the firstremission. In ALL, this chromosome is similar but not identical to the Philadelphia chromosome of chronic myelogenous leukemia (CML).3

The major impediment to a successful outcome is relapse of the disease. Relapse occurs in the bone marrow in 15–20% of patients with ALL and carries the most serious implications, especially if it occurs during or shortly after completion of therapy. Intensive chemotherapy with agents not previously used in the patient followed by allogeneic stem cell transplantation can result in long-term survival for a few patients with bone marrow relapse.

Patients with relapse in the CNS usually present with signs and symptoms of increased intracranial pressure and may present with isolated cranial nerve palsies. The diagnosis is confirmed most readily by demonstrating the presence of leukemic cells in the CSF and, rarely, by imaging studies. The treatment includes intrathecal medication and craniospinal irradiation. Systemic chemotherapy must also be used because these patients are at high risk for subsequent bone marrow relapse. Most patients with leukemic relapse confined to the CNS do well, especially those in whom the CNS relapse occurs after chemotherapy has been completed or during the latter phase of chemotherapy.3

Testicular relapse occurs in 1–2% of boys with ALL, usually after completion of therapy. Such relapse presents as painless swelling of one or both testes. The diagnosis is confirmed by biopsy of the affected testis. Treatment includes systemic chemotherapy and local irradiation. A high proportion of boys with a testicular relapse can be successfully re-treated, and the survival rate of these patients is good.3

A. Specific Therapy

Treatment is determined by prognostic features present at diagnosis. The first month of therapy consists of induction, at the end of which over 95% of patients exhibit remission on bone marrow aspirates. The drugs most commonly used in induction include oral prednisone or dexamethasone, intravenous vincristine and daunorubicin, intramuscular asparaginase, and intrathecal methotrexate. For T cell ALL, intravenous cyclophosphamide may be added during induction.1

Consolidation is the second phase of treatment, during which intrathecal chemotherapy and sometimes cranial radiation therapy are given to kill lymphoblasts in the meninges.1

Maintenance therapy includes daily oral mercaptopurine, weekly oral or intramuscular methotrexate, and, often, monthly pulses of intravenous vincristine and oral prednisone or dexamethasone. Intrathecal chemotherapy, either with methotrexate alone or combined with cytarabine and hydrocortisone, is usually given every 2–3 months. Several months of intensive chemotherapy, termed delayed intensification, is generally interposed within the maintenance chemotherapy phase of treatment.1

These drugs have significant potential side effects. Patients need to be monitored closely to prevent drug toxicities and to ensure early treatment of complications. Most patients receive treatment on protocols designed by the CCG or POG. The duration of treatment is typically 3 years for males and 2 years for females.1

Treatment for ALL is tailored to prognostic groups. A child aged 1–9 years with a white count under 50,000/mL at diagnosis and without t(9;22) or t(4;11) would receive less intensive therapy than a patient who has a white count at diagnosis over 50,000/mL or is over age 10 years. This treatment approach has significantly increased the cure rate among patients with less favorable prognostic features while minimizing treatment-related toxicities in those with favorable features. Bone marrow relapse is usually heralded by an abnormal CBC. After a patient has completed the entire course of chemotherapy, the chance of relapse is about 10% during the subsequent 4 years.1

The CNS and testes are sanctuary sites of extramedullary leukemia. Systemic chemotherapy does not penetrate these tissues as well as it penetrates other organs. Presymptomatic intrathecal chemotherapy is a critical part of ALL treatment because it has reduced relapses in the CNS to only 5–8% of patients. Symptoms suggestive of CNS disease include headache, nausea and vomiting, irritability, nuchal rigidity, photophobia, and cranial nerve palsies. Previously, up to 15% of boys have developed testicular relapse following completion of chemotherapy. The presentation of testicular relapse is usually unilateral painless testicular enlargement. The incidence of testicular relapse has decreased significantly as treatment for ALL has intensified. Routine follow-up of boys both on and off treatment includes physical examination of the testes.1

Bone marrow transplantation (BMT) is rarely used as initial treatment for ALL, because most patients are cured with chemotherapy alone. Patients whose blasts contain certain chromosomal abnormalities, such as t(9;22) and t(4;11), may have a better cure rate with early BMT from an HLA-DR-matched sibling donor than with intensive chemotherapy alone. BMT has cured about 50% of patients who have a relapse of ALL, provided that a second remission was achieved with chemotherapy before transplant. Children who relapse more than 1 year after completion of chemotherapy (late relapse) may be cured with intensive chemotherapy without BMT.1

B. Supportive Care

Tumor lysis syndrome should be anticipated when treatment is started. Alkalinization of urine with intravenous sodium bicarbonate should be undertaken and the patient should be hydrated and given oral allopurinol. If superior vena caval or superior mediastinal syndrome is present, general anesthesia is contraindicated temporarily. If hyperleukocytosis (white count > 100,000/mL) is accompanied by hyperviscosity and mental status changes, leukapheresis may be indicated to rapidly reduce the number of circulating blasts and minimize the potential thrombotic or hemorrhagic CNS complications. Severe anemia at diagnosis can usually be corrected with a number of small red blood cell transfusions and intravenous furosemide. Throughout the course of treatment, all transfused blood and platelet products should be irradiated in order to prevent graft-versus-host disease from the transfused lymphocytes. Whenever possible, blood products should be leukodepleted to minimize CMV transmission, transfusion reactions, and sensitization to platelets.1

During the course of treatment, fever (temperature > 38.3 °C) and neutropenia (absolute neutrophil count < 500/mL) require treatment with empiric broad-spectrum antibiotics. Patients receiving ALL treatment must receive prophylaxis against Pneumocystis carinii. Trimethoprim-sulfamethoxazole given twice each day on 2 or 3 consecutive days per week is the drug of choice. Patients nonimmune to varicella are at risk for very serious – even fatal -infection. Such patients should receive varicella-zoster immune globulin (VZIG) within 72 hours after exposure and treatment with intravenous acyclovir for active infection.1

The management of a patient on chemotherapy for ALL is complex because of the infectious complications and potential toxicities of chemotherapy.1

Close attention to the medical supportive care needs of the patients is essential in successfully administering aggressive chemotherapeutic programs. Patients with a large tumor burden are prone to tumor lysis syndrome as therapy is initiated. Chemotherapy often produces severe myelosuppression, which may require erythrocyte and platelet transfusion and which always requires a high index of suspicion and aggressive empirical antimicrobial therapy for sepsis in febrile children with neutropenia. Patients need to receive prophylactic treatment of Pneumocystis carinii pneumonia during chemotherapy and for several months after completing treatment.3

The success of therapy has changed ALL from an acute disease with a high mortality rate to a chronic disease. However, such chronic treatment can incur substantial academic, developmental, and psychosocial costs for children with ALL and considerable financial costs and stress for their families. Because of the intensity of therapy, long-term and acute toxicity effects may occur. An array of cancer care professionals with training and experience in addressing the myriad of problems that may arise is essential to minimize the complications and achieve an optimal outcome.3

Combination Chemotherapy

Combination chemotherapy is the principal therapeutic modality. The objective of the first phase of treatment is to induce remission (e.g., vincristine, prednisone, L-asparaginase with or without doxorubicin or daunorubicin) and achieve consolidation (i.e., further reduce residual leukemia and minimize the development of cross-resistance; regimens include intensive L-asparaginase treatment or IV methotrexate with 6-mercaptopurine). The second phase of treatment involves presymptomatic CNS prophylaxis (e.g., intrathecal therapy with methotrexate, hydrocortisone, and ara-C). The third phase is maintenance therapy (e.g., weekly methotrexate and daily 6-mercaptopurine). If complete remission is maintained for 2 to 3 years, maintenance therapy is usually discontinued and the patient is monitored closely for evidence of relapse. Approximately 65% of children with ALL achieve complete continuous remission for more than 5 years and remain free of disease. The two most reliable indicators for response to therapy are the patient’s age at diagnosis and the initial leukocyte count (i.e., poor prognosis: <2 or >10 years old, >50,000 cells/µL; good prognosis: 3 to 5 years old, <10,000 cells/µL). Complications of ALL and its therapy include metabolic disturbances (e.g., hyperuricemia, hyperkalemia, hyperphosphatemia, syndrome of inappropriate secretion of antidiuretic hormone, hyponatremia), hemorrhage, hyperleukocytosis (with leukostasis and infarction), infection (agranulocytic: cellulitis, sepsis; lymphopenic: Pneumocystis carinii, herpes simplex virus, cytomegalovirus, varicella), drug-specific side effects (e.g., hypertension with prednisone, mucositis with methotrexate, dysuria with cyclophosphamide), and relapse (e.g., bone marrow, CNS, testis). Relapse is treated with remission reinduction chemotherapy; ablative chemotherapy and allogeneic bone marrow transplantation are considered for refractory cases and high-risk patients in first remission (e.g., Philadelphia chromosome–positive ALL). With prolonged survival, children are monitored for potential late effects of chemotherapy, which include specific organ dysfunction, impaired immunologic mechanisms, delayed sexual maturation, and secondary malignancies. Effective treatment of ALL requires a comprehensive team approach that offers physician and nursing care, psychological and family counseling, nutrition consultation, and occupational and physical therapy.2

Complication

A. Hematologic Complications

The emergency physician should take special care to inform the blood bank that a patient may have acute leukemia. Current blood bank practices for the patient with acute leukemia include 1) initial complete red blood cell (RBC) antigen typing to facilitate future crossmatches if the patient develops anti-RBC antibodies; 2) the use of CMV-negative products for potential bone marrow transplant patients, all patients with myeloid leukemia, and CMV-seronegative patients with lymphoblastic leukemia; 3) the use of in-line leukocyte-depletion filters in many types of acute leukemia; and 4) irradiation to 1500 cGy or greater of all blood products used in oncology patients. Some or all of these practices are followed in major pediatric oncology centers, but transfusion of an acutely ill patient should not be delayed to follow these recommendations.5

Anemia

At the time of diagnosis, most children with leukemia are anemic. If the hemoglobin is less than 8 g/dL, administration of packed blood cells is advisable because the child is unlikely to have the ability to produce erythrocytes for several weeks; however, if the child is not having symptoms or showing signs of severe anemia, transfusion does not need to take place in the ED. If, in the absence of hemorrhage, the child has profound anemia (i.e., hemoglobin, 1 to 4 g/dL), transfusions at the usual rate can precipitate heart failure. Blood should be replaced slowly, at 3 to 5 mL/kg over 4 hours, and supplemental oxygen should be given to enhance oxygen delivery to tissues. Furosemide (1 mg/kg) can help avoid fluid overload or heart failure; however, if the WBC count is greater than 100,000/mm3, diuretics should be withheld because intravascular dehydration encourages sludging and thrombosis. Exchange transfusion has been advocated by some physicians in these exceptional circumstances. When hemorrhage is the cause of a low hemoglobin, transfusion therapy should be carried out quickly to replace losses.5

Hemorrhage

Hemorrhage is the second most common cause of death in leukemia. Spontaneous bleeding can occur at platelet counts less than 10,000 to 20,000/mm3, although spontaneous bruising is seen at higher levels in some patients. Other factors contributing to a bleeding tendency include 1) infection with associated disseminated intravascular coagulation (DIC); 2) consumptive coagulopathy in acute promyelocytic leukemia, monoblastic leukemia, and T-cell ALL; 3) antibiotic therapy, which causes hypoprothrombinemia; and 4) aspirin, which interferes with platelet function.5

In most newly diagnosed leukemic children, bleeding problems can be controlled with local measures alone (i.e., pressure and topical thrombin for epistaxis), or in conjunction with platelet transfusions (0.2 unit/kg platelets). Epistaxis is sometimes a serious problem that may last for hours and may fail to respond to pressure. If local measures and platelets fail, packing is a necessary but uncomfortable therapy. Sedation and analgesia may be helpful in controlling the anxiety associated with severe bleeding.5

In some patients with AML, especially those with hypergranular promyelocytic leukemia and some with monoblastic leukemia, a bleeding diathesis may occur at presentation or upon initiation of therapy. Bleeding is generally refractory to platelet transfusion. Patients show prolonged prothrombin and partial thromboplastin times, elevated fibrin split products, and drastically shortened fibrinogen half-life. The most common form of bleeding in this situation is in the CNS; it may be fatal in the first few days of illness. Fresh-frozen plasma (10 mL/kg) and cryoprecipitate can help maintain levels of fibrinogen and clotting factors. Platelet transfusions (0.2 unit/kg) are given to correct thrombocytopenia. Although no controlled study has been conducted to demonstrate the benefit of prophylactic heparin, heparinization (loading dose, 50 units/kg; then 5 to 10 units/kg per hour to maintain the partial thromboplastin time at approximately 1.5 times normal) is often given to patients who show no improvement with aggressive blood product support.5

Extreme Leukocytosis

Extreme leukocytosis with a WBC count of greater than 200,000/mm3 occurs at diagnosis in about 5% of patients with acute leukemia and in those with chronic myelogenous leukemia (CML). In acute leukemia, extreme leukocytosis predisposes patients to early bleeding and thrombosis in the CNS. It has been suggested that patients with WBC counts greater than 200,000/mm3 should receive prompt cranial irradiation or leukocytopheresis, but these therapies are unproven. Patients with CML may also have the problem of sludging and thrombosis seen in AML when they have a predominance of blasts or when their WBC counts are greater than 200,000/mm3. Hydration and alkalinization often result in a substantially lower WBC count.5

Leukopenia

Leukopenia is defined as a WBC count of less than 3000/mm3 and neutropenia, in children, as less than 500 neutrophils/mm3. Leukopenia per se is not life-threatening, but it can predispose patients to life-threatening infections.5

B. Infectious Complications

Infection remains the leading cause of death in acute leukemia. The patient with acute leukemia has quantitative and qualitative cellular immune dysfunction. Leukopenia and neutropenia are common at diagnosis. Even if the absolute neutrophil count is more than 500/mm3, as may be the case in a patient with a WBC count of 50,000/mm3 and 1% neutrophils, defective chemoattraction and killing have been documented in patients with acute leukemia. Therefore, any patient with newly diagnosed leukemia, especially those with AML, should be considered at increased risk for infection. In the ED, handwashing by staff, strict asepsis for drawing blood and performing other procedures, and protection of the patient from airborne infections (e.g., measles and varicella) must be enforced.5

Although fever is a symptom of leukemia in 25% of patients, more often it indicates infection. In the leukemic patient, significant fever is defined by three temperature elevations of 38.0°C (100.4°F) or higher over 4 hours or a single temperature higher than 38.4°C (101.1°F). There are exceptions to the association between fever and infection. A leukemic patient in septic shock may have no fever or may be hypothermic.5

Management of fever begins with a thorough physical examination to search for localizing signs of infection. Even an apparently minor swelling or a tear in the skin or a mucosal surface can be a source of disseminated infection. Blood and urine cultures should be obtained. All leukemic patients should have baseline chest radiograph films taken. Thereafter, chest radiograph is needed only if the child has respiratory symptoms or signs. Bacterial meningitis is rare in leukemia, but if symptoms of meningitis are found, spinal fluid should be sent for bacterial, fungal, and viral culture and for cytology to rule out CNS leukemia.

After the appropriate cultures are obtained, intravenous broad-spectrum antibiotics should be started in a patient with leukemia and fever. Most patients do not have invasive fungal disease. However, oral candidiasis sometimes occurs in a patient who has been treated with antibiotics before the diagnosis of leukemia. Thrush should be treated with oral Mycostatin, fluconazole, or clotrimazole troches.5

Infection can cause septic shock in a patient with leukemia. Treatment consists of aggressive measures to maintain intravascular volume and blood pressure and broad-spectrum antibiotics. Because the patient with leukemia is commonly anemic at diagnosis, bolus infusions of packed RBCs can be useful when treating shock.5

C. Metabolic Complications

Uric Acid Nephropathy

Some patients with acute leukemia have an elevated serum uric acid caused by spontaneous breakdown of leukemic cells. The excess uric acid precipitates in the renal tubules. Antileukemic therapy accelerates breakdown of leukemic cells; more urates are formed and renal failure can occur. To prevent urate nephropathy, all children with leukemia should receive the xanthine oxidase inhibitor allopurinol (150 mg/d orally in three daily doses for those 6 years old or younger; 300 mg/d orally in three daily doses for those older than 6 years) for at least 24 hours before starting therapy. Hydration at the rate of twice maintenance and alkalinization of urine to pH between 6.5 and 7.5 with sodium bicarbonate (40 mEq/L) facilitates dissolution of uric acid crystals. Once the serum uric acid level is normal and the child is adequately hydrated and producing a dilute urine, specific antileukemic therapy may begin. Bicarbonate is stopped at this time to avoid development of hypoxanthine nephropathy.5

Hypercalcemia

Hypercalcemia occurs in about 2% of patients with acute leukemia. Hypercalcemia is caused by destruction of bone by malignant cells, by ectopic production of parathormone by the leukemic cells themselves, or by elevated levels of peripheral plasma prostaglandin E2, vitamin D–like substances, or osteoclast-activating factors. The serum calcium can reach levels high enough to cause anorexia, nausea, vomiting, constipation, lethargy, confusion, coma, tachycardia or bradycardia, and renal failure. The ultimate therapy of leukemic hypercalcemia is treatment of the leukemia. Interim supportive management consists of hydration with normal saline (200 mL/m2 per hour), followed by diuresis with furosemide (1 to 2 mg/kg intravenously every 4 to 6 hours). Monitoring of the cardiovascular status is essential. For indications for corticosteroids, calcitonin, gallium nitrate, or dialysis in symptomatic hypercalcemia (usually greater than 12 to 15 mg/dL), see Chapter 86. Phosphorus has no role in the emergency treatment of the patient who has leukemia and an acute elevation of serum calcium. Malignant hypercalcemia may require management in an intensive care setting.5

Tumor Lysis Syndrome

In a patient with a large tumor burden, especially patients with leukemia and massive organomegaly or with high WBC counts, or in patients with non-Hodgkin’s lymphoma, antineoplastic therapy can cause a potentially fatal tumor lysis syndrome that consists of a rapid rise in serum potassium and phosphorus, a precipitous fall in serum calcium, and elevations of the serum uric acid, blood urea nitrogen (BUN), and creatinine. These abnormalities may occur despite appropriate hydration and allopurinol therapy. Hyperkalemia, the most dangerous abnormality, demands prompt treatment with Kayexalate, insulin and glucose infusion, or dialysis.5

D. Other Complications

Spinal Cord Compression

Spinal cord compression occurs in leukemia because of epidural or subarachnoid collections of leukemic cells. Symptoms include radicular pain, back pain, difficulty with urination, paresis, and paralysis. Physical examination can be unremarkable or may show percussion tenderness over spinous processes, weakness, hyperactive (or later, absent) deep tendon reflexes, absent superficial reflexes, inability to walk on the toes or heels, and a sensory level. Radiographs may show a collapsed vertebral body, but they are often normal. Magnetic resonance imaging (MRI) with and without gadolinium confirms the diagnosis; therapy consists of immediate corticosteroid administration (dexamethasone 0.25 to 0.5 mg/kg every 6 hours), prompt irradiation, or both. Leukemia and lymphoma of the spinal cord respond to steroids or radiation therapy and do not require laminectomy.5

Central Nervous System Leukemia

Leukemia can present or relapse in the CNS as diffuse subarachnoid disease or as localized deposits of cells. Symptoms include headache, stiff neck, malaise, cranial nerve palsy, and rarely, fever. Diagnosis is made by finding greater than 5 leukemic blasts/mm3 in the spinal fluid. Spinal fluid should be examined by cytospin preparation. Treatment consists of intrathecal chemotherapy and craniospinal irradiation, as well as reinstitution of systemic chemotherapy in the case of CNS relapse.5

Testicular Leukemia

Clinically apparent testicular disease is rarely present at diagnosis, but the first site of relapse may be the testes. A painless, hard swelling is seen in one or both testes. Treatment consists of reinduction therapy and irradiation. Testicular relapse may be a harbinger of marrow relapse.5

Prognosis

Cure rates depend on specific prognostic features present at diagnosis. The two most important features are white count and age. Children aged 2–9 years whose diagnostic white count is less than 50,000/mL have a higher rate of cure than other patients. Certain chromosomal abnormalities present in the leukemic blasts at diagnosis influence prognosis. Patients with t(9;22) generally have a very poor chance of cure even with intensive chemotherapy. Likewise, infants with t(4;11) have a poor chance of cure with conventional chemotherapy. In contrast, patients whose blasts are hyperdiploid (containing over 50 chromosomes instead of the normal 46) have a greater chance of cure than do children without hyperdiploidy, particularly if trisomy of chromosome 10 is present. About 25% of children with ALL have blasts that contain a gene rearrangement of chromosomes 12 and 21 called TEL-AML1 detected by molecular but not by cytogenetic techniques. Children with the TEL-AML1 rearrangement appear to have an excellent prognosis. Techniques have been developed to detect residual lymphoblasts of one per 104 or greater cells in bone marrow during remission. Investigators are studying whether detection of residual blasts has prognostic significance.1

Most children with ALL can now be expected to have long-term survival, with the rate greater than 80% after 5 yr. The most important prognostic factor is the choice of appropriate risk-directed therapy, with the type of treatment chosen according to the type of ALL, the stage of disease, the age of the patient, and the rate of response to initial therapy. Characteristics generally believed to adversely affect outcome include an age younger than 1 yr or older than 10 yr at diagnosis, a leukocyte count of more than 100,000/µL at diagnosis, or a slow response to initial therapy. Chromosomal abnormalities, including hypodiploidy, the Philadelphia chromosome, and t(4;l1), portend a poorer outcome. More favorable characteristics include a rapid response to therapy, hyperdiploidy, and rearrangements of the TEL/AML1 genes.3

REFERENCES

1. Albano EA, Neoplastic Disease. In: Hay WW, Hayward AR, Levin MJ, editors. Current Pediatric Treatment and Diagnosis.16th ed. McGraw-Hill Education Europe: 2002. p. 36
2. Mahoney DH. Acute Lymphoblastic Leukemia. In: McMillan JA, Deangelis CD, editors. Oski’s Pediatrics Principles and Practice. Lippincott Williams and Wilkins Publishers: 1999. p. 327
3. Tubergen DG, Bleyer A. The Leukemias. In: Behrman RE, Kliegman RM, editors. Nelson Textbook of Pediatric. 17th ed. Saunders: 2003. p. 622
4. Margolin JF, Steuber CP, Poplack DG. Acute Lymphoblastic Leukemia. In: .Pizzo PA, Poplack DG. Principles and Practice of Pediatric Oncology. 4th ed. Lippincott Williams and Wilkins Publishers: 2001. p. 489-526
5. Hogarty MD, Lange B. Oncologic Emergencies. In: Fleisher GR, Ludwig S, editors. Textbook of Pediatric Emergency Medicine. 4th ed. Lippincott Williams and Wilkins Publisher: 2000. P. 108

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