Many environmental factors (eg, exposure to ionizing radiation and electromagnetic fields and parental use of alcohol and tobacco) have been investigated as potential risk factors, but none have been shown to definitively cause lymphoblastic leukemia. Improvements in diagnosis and treatment have produced cure rates that now exceed 70%.

Further refinements in therapy, including the use of risk-adapted treatment protocols, now attempt to improve cure rates for high-risk patients while limiting the toxicity of therapy for low-risk patients. This chapter summarizes the advances made in the diagnosis and treatment of childhood ALL.

Pathophysiology: In ALL, a lymphoid progenitor cell becomes genetically altered and subsequently undergoes dysregulated proliferation and clonal expansion. In most cases, the pathophysiology of transformed lymphoid cells reflects the altered expression of genes whose products contribute to the normal development of B cells and T cells. It has been long thought that leukemic blasts represent the clonal expansion of hematopoietic progenitors blocked in differentiation at discrete stages of development. Recent data challenge this theory and suggest that leukemia arises from the stem cell that acquires features of differentiated cells. While this may appear to be a subtle difference, it is important because it implies the need to eradicate the leukemic stem cell, and not just the differentiated blasts, to achieve a cure. Nevertheless, leukemic blasts provide large uniform populations for molecular and functional analyses.

ALL generally is thought to arise in the bone marrow, but leukemic blasts may be present systemically at the time of presentation, including in the bone marrow, thymus, liver, spleen, lymph nodes, testes, and the central nervous system (CNS).

Frequency:

• In the US: Each year, 2000-2500 new cases of childhood ALL are diagnosed.

• Internationally: Incidence is thought to be similar throughout the world.

Mortality/Morbidity: Despite overall improvements in outcome, the prognosis for patients whose leukemic blast cells carry the BCR-ABL fusion (created by the t[9;22]) or MLL gene rearrangements (created by translocations involving 11q23) is poor, with event-free survival (EFS) estimates of only about 30%. In fact, until recently, allogeneic hematopoietic stem cell transplantation (HSCT) during first remission was believed to be the only curative treatment option for these 2 groups of patients.

Recent data, however, indicate that heterogeneity exists within each group. For example, the outcomes of patients whose leukemic blast cells are positive for the BCR-ABL fusion and whose disease has a good initial response to prednisone may be quite good. In one study, the 4-year EFS estimate for patients with a good response to prednisone was 55%, whereas that for patients with a poor response was 10% (Schrappe et al). Similarly, the 4-year EFS estimate for infants with MLL rearrangements and a good prednisone response was 41%, whereas for those with a poor prednisone response, it was only 9%.

Race: ALL occurs more frequently in whites than in blacks. The annual incidence of ALL in children younger than 15 years in the white population is 33 per million, compared to 15 per million children younger than 15 years in the black population.

Sex: ALL occurs slightly more frequently in males than in females. This difference is most pronounced for T-cell ALL.

History: Children with ALL generally present with signs and symptoms that reflect bone marrow infiltration and extramedullary disease. Because the bone marrow is replaced with leukemic blasts, patients present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia. Clinically, the manifestations include fatigue and pallor, petechiae and bleeding, and fever. In addition, leukemic spread may be seen as lymphadenopathy and hepatosplenomegaly. Other signs and symptoms of leukemia include weight loss, bone pain, and dyspnea.

Physical: The physical examination of children with ALL reflects bone marrow infiltration and extramedullary disease. Patients present with pallor as a result of anemia, petechiae, and bruising secondary to thrombocytopenia, and signs of infection because of neutropenia. In addition, leukemic spread may be seen as lymphadenopathy and hepatosplenomegaly.

Lab Studies:

• Basic labs

• Upon initial evaluation, obtain a CBC. The peripheral smear needs to be evaluated by a hematologist or hematopathologist for the presence and morphology of lymphoblasts. Hemoglobin and platelet count may be low, and patients may require transfusions.

• Although not universally performed, coagulation studies can be helpful, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimers to assess the presence of disseminated intravascular coagulation (particularly important in an acutely toxic child).

• Immunophenotyping

• A complete morphologic, immunologic, and genetic examination of the bone marrow is necessary to establish a diagnosis of ALL.

• An important advance in the classification of ALL was the observation that malignant lymphoblasts share many of the features of normal lymphoid progenitors. ALL cells rearrange their immunoglobulin and T-cell receptor genes and express antigen receptor molecules in ways that correspond to such processes in normal developing B and T lymphocytes. However, lymphoblasts also can show aberrant gene expression, which can result in phenotypes that differ from those of normal lymphocyte progenitors. Nevertheless, ALL cases still can be classified broadly as either B- or T-lineage.

• The diagnosis of B-cell leukemia, which accounts for only about 3% of ALL cases, depends on the detection of surface immunoglobulin on leukemic blasts. Lymphoblasts with this phenotype have a distinctive morphology, with deeply basophilic cytoplasm containing prominent vacuoles; this morphologic pattern is designated L3 in the French-American-British (FAB) system. Prominent clinical features include extramedullary lymphomatous masses in the abdomen or head and neck and frequent involvement of the
  CNS.

• Approximately 80% of childhood ALL cases have lymphoblasts with phenotypes that correspond to those of B-cell progenitors. These cases can be identified on the basis of cell surface expression of 2 or more B lineage-associated antigens, which are CD19, CD20, CD24, CD22, CD21, or CD79. Of these, only CD79 is specific for B-lineage ALL. In addition, about one fourth of B-precursor cases express cytoplasmic immunoglobulin µ heavy-chain proteins and are designated pre–B-cell ALL. B-precursor cases can be further subclassified as early pre-B, pre-B, or transitional pre-B. Although it is essential to distinguish mature B-cell ALL from B-precursor cases, distinguishing the subtypes of B-precursor ALL probably is not clinically relevant.

• T-cell ALL is identified by the expression of T-cell-associated surface antigens, of which cytoplasmic CD3 is specific. T-cell ALL cases can be classified as early-, mid-, or late-thymocyte. The clinical features most closely associated with T-cell ALL are high blood leukocyte counts and CNS involvement; a mediastinal mass will be present in about half of the cases at the time of diagnosis. Historically, the prognosis of patients with T-cell ALL has been worse than that of patients with B-lineage ALL. With the use of intensive chemotherapy, however, the outlook for patients with T-cell leukemia appears improved.

• Cytogenetic and molecular diagnosis

• In more than 90% of ALL cases, specific genetic alterations can be found in the leukemic blasts. These alterations include changes in chromosome number (ploidy) and structure; about half of all childhood ALL cases have recurrent translocations. Standard cytogenetic analysis is an essential tool in the workup of all patients with leukemia, because the karyotype of the leukemic cells has important diagnostic and therapeutic implications. In addition, molecular techniques, including reverse-transcriptase polymerase chain reaction (RT-PCR), Southern blot analysis, and fluorescence in situ hybridization (FISH), have helped improve diagnostic accuracy. Molecular analysis can identify translocations that are not detected by routine analysis of karyotype and can distinguish lesions that appear identical cytogenetically but differ at the molecular level.

• Clinically important genetic alterations in B-precursor ALL include chromosomal translocations (BCR-ABL, E2A-PBX1, TEL-AML1 gene fusions), a variety of MLL gene rearrangements, and hyperdiploidy. Hyperdiploidy, defined as a DNA index (DI) 1.16 or higher, occurs in about 20% of B-precursor cases and is a favorable prognostic factor. The good outcome of patients with hyperdiploid blasts probably is due to a combination of factors, including increases in the accumulation of methotrexate polyglutamates by leukemic blast cells, sensitivity to antimetabolites, and propensity for apoptosis. Heterogeneity within the hyperdiploid group is demonstrated by the fact that the outcomes of patients with hyperdiploidy and trisomies of chromosomes 4 and 10 are much better than those of patients with hyperdiploidy but without both trisomies.

• Molecular techniques have demonstrated that the TEL-AML1 fusion gene, created by the t(12;21), is the most common genetic abnormality thus far observed in childhood ALL, occurring in approximately 20% of patients and mainly in children aged 3-5 years. The TEL-AML1 fusion occurs only in B-precursor ALL, and 50% of these cases express myeloid-associated antigens (CD13, CD33, or both). Many studies have suggested that the TEL-AML1 fusion is associated with an excellent prognosis. The favorable prognosis of patients with TEL-AML1-positive ALL has been questioned in 2 studies of relapsed cases, which revealed an approximately 20% incidence of TEL-AML1. Each of 3 recent studies has reported less than a 10% incidence of TEL-AML1 in relapsed cases; a finding consistent with a favorable prognosis for TEL-AML1-positive ALL.

  Therefore, the TEL-AML1 fusion appears to identify a large subset of patients with B-precursor ALL who have a favorable prognosis. Additional studies are needed to determine whether these patients can be treated successfully with less intensive, antimetabolite-based therapy.

• Minimal residual disease

• Although still experimental, molecular analysis promises to not only play a role in the diagnosis and treatment of ALL, but also to allow us to monitor patients' responses to therapy. Minimal residual disease (MRD) studies may rely on the detection of chimeric transcripts generated by fusion genes, the detection of clonal T-cell receptor (TCR) or immunoglobulin heavy chain (IgH) gene rearrangements, or the identification of a phenotype specific to the leukemic blasts.

• Recent studies have demonstrated that both the presence and the level of MRD correlate with outcome. A prerequisite for using MRD detection in protocol treatment is the ability to apply detection methods to all patients. Our recent study indicated that immunologic and molecular techniques are equally reliable in detecting clinically significant levels of MRD, and that they achieve concordant results. They can be applied in tandem for universal monitoring of MRD in childhood ALL.

• Risk classification

• With the recognition of distinct prognostic subgroups, contemporary protocols stratify children with B-precursor ALL according to the risk of relapse; low-risk, standard-risk, and high-risk groups generally are recognized. Risk classification is based, in part, on clinical features, the most important of which are age and leukocyte count at the time of diagnosis. Participants at a workshop sponsored by the National Cancer Institute defined the standard-risk group as consisting of children aged 1-10 years with an initial leukocyte count of less than 50 x 10e9/L; all other patients were considered to have high-risk ALL. When these criteria are used, 4-year event-free survival (EFS) estimates are 80% for the standard-risk group and 65% for the high-risk group. However, the EFS estimates for hyperdiploid patients within both risk groups are approximately 89%. This finding suggests that genetic factors may be more accurate predictors of outcome than age and leukocyte count.

• Further evidence that genetic features of leukemic blasts may be the best factors on which to base risk classification schemes comes from patients with TEL-AM1 expression, who generally have excellent outcomes regardless of age or leukocyte count. Similarly, infants younger than 1 year once were considered a very high-risk group, whereas now only those infants with MLL rearrangements fall into this classification. The outcomes of the 20% of infants without this genetic feature may be similar to those of children older than 1 year. Therefore, a risk classification scheme based on a combination of clinical features, genetic features, and response to therapy is used.

  According to this scheme, the low-risk group comprises patients with B-lineage ALL and hyperdiploidy or the TEL-AM1 fusion, whereas the high-risk group comprises infants with MLL gene rearrangements and patients with BCR-ABL expression. All other patients with B-lineage leukemia and all patients with T-cell leukemia are placed into the standard-risk group. However, as discussed above, even specific genetic features are not perfect predictors of outcome. Therefore, additional clinical and biologic information, including rate of cytoreduction, helps refine this classification system and improves the ability to direct treatment.

Imaging Studies:

• Chest x-ray: Evaluate for the presence of a mediastinal mass. In general, no other imaging studies are required. However, if the physical examination reveals enlarged testes, obtain an ultrasound to diagnose testicular infiltration.

• Testicular ultrasound: Obtain testicular ultrasound if testes are enlarged on physical examination.

• Renal ultrasound: Some clinicians prefer to evaluate for leukemic kidney involvement to assess the risk of tumor lysis syndrome.

• Obtain echocardiogram and ECG prior to the administration of anthracyclines.

Procedures:

• Bone marrow aspirate: this confirms the diagnosis of ALL. In addition, special stains (immunohistochemistry), immunophenotyping, cytogenetic analysis, and molecular analysis all help classify each case.

• Lumbar puncture with cytospin morphologic analysis: This is performed before systemic chemotherapy is administered to assess the presence of CNS involvement and to administer intrathecal chemotherapy.

Medical Care: Because leukemia is a systemic disease, therapy is primarily chemotherapy-based. Different forms of ALL require different approaches for optimal results. For example, B-cell ALL does not respond well to the chemotherapy traditionally used for childhood ALL. However, outstanding results, with EFS estimates of nearly 90%, have been obtained with treatments designed for Burkitt lymphoma, which emphasize cyclophosphamide and the rapid rotation of antimetabolites in high dosages. Thus, B-cell ALL was the first form of ALL to be recognized as a distinct clinical entity on the basis of immunophenotypic and cytogenetic features and the first to be treated by separate protocols designed specifically for this leukemia's unique features.

• Tumor lysis syndrome

• Prior to and during the initial induction phase of chemotherapy, patients may develop tumor lysis syndrome. This syndrome refers to the metabolic derangements caused by the systemic and rapid release of intracellular contents as the leukemic blasts are destroyed by chemotherapy. Because some cells can die prior to therapy, such derangements can occur even before therapy begins.

• Primary features of tumor lysis syndrome include hyperuricemia (due to metabolism of purines), hyperphosphatemia, hypocalcemia, and hyperkalemia. The hyperuricemia can lead to crystal formation with tubular obstruction and, possibly, acute renal failure, requiring dialysis. Therefore, electrolytes and uric acid should be monitored closely throughout initial therapy.

• To prevent complications of tumor lysis syndrome, all patients initially should receive IV fluids at twice maintenance rates, usually without potassium. Sodium bicarbonate is added to the IV fluid to achieve moderate alkalinization of the urine (pH 7.5-8) to enhance the excretion of phosphate and uric acid. Avoid a higher urine pH to prevent crystallization of hypoxanthine or calcium phosphate. Administer allopurinol to prevent or correct hyperuricemia.

• Phases of therapy
  • With the exception of B-cell ALL, the treatment of childhood ALL has 4 components, including remission induction, consolidation, continuation, and treatment of subclinical CNS leukemia. Induction therapy generally consists of 3-4 drugs, which may include a glucocorticoid, vincristine, asparaginase, and an anthracycline. This type of therapy induces complete remission in more than 95% of patients.
  • Consolidation (ie, intensification) therapy is given soon after remission has been achieved in an attempt to further reduce the leukemic cell burden before the emergence of drug resistance. In this phase of therapy, the drugs are used at higher doses than during induction, or different drugs are used, such as high-dose methotrexate and 6-mercaptopurine, epipodophyllotoxins with cytarabine, or multiagent combination therapy. Consolidation therapy, first used successfully in the treatment of patients with high-risk disease, also appears to improve the long-term survival of patients with standard-risk disease. Similarly, the addition of intensive reinduction therapy (administered soon after remission has been achieved) is beneficial for patients in both risk groups.

• Duration of therapy: Whereas B-cell ALL is treated with a 2- to 8-month course of intensive therapy, achieving acceptable cure rates for patients with B-precursor and T-cell ALL requires approximately 2-2.5 years of continuation therapy. Attempts to reduce this time frame resulted in high relapse rates after therapy was stopped. Most contemporary protocols include a continuation phase based on weekly parenterally administered methotrexate given with daily, orally administered 6-mercaptopurine, interrupted by monthly pulses of vincristine and a glucocorticoid. Although these pulses have improved outcome, they are associated with avascular necrosis of the bone. Patients with high-risk ALL also may benefit from intensified continuation therapy that includes the rotational use of drug pairs. The improvements in relapse-free survival gained by intensification with anthracyclines or epipodophyllotoxins must be weighed against the late sequelae of these agents, which include cardiotoxicity and treatment-related acute myeloid leukemia.
• CNS disease: Treatment of subclinical CNS leukemia also is an essential component of ALL therapy. Although cranial irradiation effectively prevents overt CNS relapse, concern about subsequent neurotoxicity and brain tumors has led many investigators to replace irradiation with intensive intrathecal and systemic chemotherapy for most patients. This strategy has produced excellent results, with CNS relapse rates of less than 2% in some studies. It is uncertain whether cranial irradiation is necessary for patients with very high-risk ALL.
• High-risk patients: The optimal treatment for patients with very high-risk ALL (those with BCR-ABL or MLL gene rearrangements) has not yet been found. Many institutions treat these patients with allogeneic bone marrow transplantation soon after first remission is achieved. For patients without a matched family donor, transplantation of marrow from an unrelated donor is a reasonable treatment option. Results of stem cell transplantation, often reported from single institutions, have been inconsistent and sometimes disappointing. Large, multi-institutional controlled trials clearly are needed to determine the effectiveness of this therapy for patients without a matched donor.
• Impact of genetic studies: More than two thirds of children with ALL now can be cured. Because of the diverse nature of the disease, use of risk-directed therapy for all patients based on the molecular characterization of the leukemic cells at the time of diagnosis is favored. Future goals include the identification of new genetic subgroups of ALL and the development of new therapies to directly target the oncogenic products of ALL translocations.

Surgical Care: Surgical care generally is not required in the treatment of ALL, except for the placement of a central venous catheter. Such catheters are used for the administration of chemotherapy, blood products, and antibiotics, and for drawing blood samples.

Consultations: A number of consultations should be obtained, depending on the clinical circumstance of patients newly diagnosed with ALL.

• Pediatric oncologist: Refer all patients to a subspecialist to direct their care.

• Pediatric surgeon: Patients require placement of a central venous catheter.

• Psychosocial team: Involve psychologists and social workers in the care of patients with ALL to aid them and their families in navigating all of the difficult issues surrounding their care.

• Radiation oncologist: Depending on their risk group, some patients require craniospinal radiation as part of the treatment plan.

• Other subspecialists: Other consultations may be appropriate depending on the clinical circumstances (eg, infectious disease, nephrology).

Drugs commonly used during remission induction therapy include dexamethasone or prednisone, vincristine, asparaginase, and daunorubicin. Consolidation therapy often includes methotrexate and 6-mercaptopurine. Drugs used for intensification or continuation include cytarabine, cyclophosphamide, etoposide, dexamethasone, asparaginase, doxorubicin, methotrexate, 6-mercaptopurine, and vincristine. Intrathecal chemotherapy includes methotrexate, hydrocortisone, and cytarabine. Refer to specific protocol for duration of therapy with each drug and timing of administration within each treatment cycle.
Drug Category: Antineoplastics agents -- Cancer chemotherapy is based on an understanding of tumor cell growth, and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy, and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) also is a potential mechanism of many antineoplastic agents.

Drug Category: Antiemetics -- To prevent chemotherapy-induced nausea and vomiting. Antineoplastic induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ or acetylcholine in VC appears to be a major mediator for inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3-receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Drug Category: Prophylactic antimicrobials -- To prevent infection in patients receiving chemotherapy.

Further Inpatient Care:

• Frequent hospitalizations may be required to deal with complications of therapy, including the need for blood or platelet transfusions or antibiotics. Admit any patient who is neutropenic and develops chills or fever without delay for intravenous broad-spectrum antibiotics.

Further Outpatient Care:

• Frequent clinic visits will be required for administration of outpatient chemotherapy, to monitor blood counts, and to evaluate new symptoms.

In/Out Patient Meds:

• Pneumocystis prophylaxis: All patients should be on trimethoprim/sulfisoxazole to prevent Pneumocystis carinii pneumonia (PCP) infection.

• Fungal prophylaxis: Patients should be on oral nystatin or Mycelex troches to prevent candidiasis. High-risk patients should also be on daily itraconazole.

• Mouth cares: Patients need swish and spit antimicrobial mouth care, such as Peridex or Biotene, 4 times daily.

Transfer:

• Initially transfer patients to the care of a pediatric oncologist, preferably at a center that participates in multi-institutional clinical trials.

Deterrence/Prevention:

• Because the cause of ALL is unknown, no preventions are known.

Complications:

• Complications of leukemia and its therapy include the following:

• Tumor lysis syndrome

• Renal failure

• Sepsis

• Bleeding

• Thrombosis

• Typhlitis

• Neuropathy

• Encephalopathy

• Seizures
• Secondary malignancy
• Short stature (if craniospinal radiation)
• Growth hormone deficiency
• Cognitive defects

Prognosis:

• Overall, the cure rate for childhood ALL is nearly 80%. However, the prognosis depends on clinical and laboratory features described above. In general, the prognosis is best for children aged 1-10 years. Adolescents have intermediate outcome, whereas infants younger than 1 year have a poor outcome, with cure rates of about 30%.

Patient Education:

• Ensure that parents/guardians have a reasonable understanding of the expected adverse effects of each medication. In addition, it is essential that parents/guardians understand signs and symptoms that require medical attention, such as signs and symptoms of anemia, thrombocytopenia, and especially infection. Parents must know how to quickly access medical help from the oncology team.