Acute leukemia is the most common cancer in children, representing about 31% of all childhood cancers.1,2 Because early diagnosis and treatment have been shown to greatly improve outcomes, primary care providers should know how to recognize the manifestations of leukemia and understand the process of diagnosis, treatment, and prognosis for their patients. This article reviews the pathophysiology and management of the most common forms of childhood leukemia.
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Leukemia is classified based on the type of white blood cell affected. Children most often are affected by one of three of the nearly dozen types of leukemia: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). The majority of leukemias are pre-B cell phenotype, or lymphoid, as opposed to the T-cell lineage.1,2
The most common form of childhood leukemia, ALL, accounts for almost 80% of cases.1,3 This fast-growing cancer affects lymphoblasts. The four main subtypes of ALL are based on the immunophenotype, or the type of lymphocyte affected, and the maturity of the leukemia cells. The three subtypes of B-cell ALL account for 85% of ALL in children, with early pre-B cell being the most common subtype.3 T-cellALL accounts for about 15% of ALL in children and has been shown to have a greater prevalence among boys and older children.1,3,4
AML, the second most common form of childhood leukemia, accounts for 15% to 20% of cases. This fast-growing cancer affects the myeloid lineage that develops neutrophils, macrophages, red blood cells, and platelets. AML is classified into subtypes based on the appearance of the cells under a microscope, the proteins on the surface of cells, the changes in chromosome number and structure, and mutations in certain genes. Seven major subtypes are recognized, and the subtype directs treatment options.5,6
CML is uncommon in children but does occur. A slower-growing cancer of immature myeloid bone marrow cells, specifically the myeloblasts, CML is classified into 3 phases based mainly on the number of leukemia cells present. The earliest phase, the chronic phase, is defined as less than 10% myeloblasts in blood and bone marrow samples. Most patients in this phase have few symptoms. The second phase, the accelerated phase, is defined as 10% to 20% myeloblasts in blood and bone marrow samples. Often B-cell symptoms, such as fever, night sweats, and weight loss, become apparent during this phase. The third phase, the blast/acute phase, is defined as more than 20% blasts, often spreading to tissues and organs beyond bone marrow. During this phase, the leukemia often acts more like an aggressive leukemia, much like AML or ALL. CML is associated with a translocation of chromosome 9 onto chromosome 22, known as the Philadelphia chromosome, which results in the uncontrolled cell growth of myeloblasts.
Childhood leukemia has few known causes, although research has identified lifestyle, environmental, and genetic factors that may contribute to an increased risk of leukemia development. Lifestyle factors such as poor diet, limited physical activity, and environmental exposure to tobacco, radiation, and chemicals may play a role in leukemia risk; however, these factors have not been proven to cause the development of cancer in children.1,2 Genetic mutations and some genetic disorders that have been linked to an increased risk of childhood leukemia include trisomy 21, Klinefelter syndrome, and Li-Fraumeni cancer syndrome.2
Fever, petechiae, lethargy, and pallor caused by bone marrow suppression by leukemic cells are a common clinical presentation. More than a third of children with leukemia present with limping, bone pain, arthralgia, or other complaints referable to the extremities or spine. About 40% of children presenting with acute leukemia have at least one radiographic skeletal abnormality including transverse lucent metaphyseal bands, diffuse demineralization, subperiosteal cortical bone erosion, periosteal reaction, lytic bone lesions, osteosclerosis, and pathologic fractures.7,8
Most signs and symptoms of childhood leukemia are systemic and nonspecific, leading to a delay in identification of acute disease. Patients will typically present with systemic symptoms that are the result of leukemic infiltration of bone marrow and resulting cytopenias. These symptoms include fever, hemorrhage, and frequent infections.5,9 With the body's immune system lacking its normal ability to fight off diseases due to the increase in leukemic cells and decrease in mature white blood cells, children with leukemia have higher rates of office visits and treatment for repeat infections. Some patients present with osteoarticular manifestations, such as limb pain, nighttime pain, arthritis without evidence of inflammation, and skeletal radiologic manifestations, which include osteopenia, periosteal new bone formation, osteosclerosis, permeative destruction, and fractures.5,9,10 Other important manifestations include anemia, pallor, fatigue, hepatosplenomegaly, and development of metabolic abnormalities.5,9 These symptoms result from leukemic cells overcrowding the bone marrow space and decreasing other cell lines.
Leukemic cells have a tendency to collect in lymph nodes, especially those in the axilla, groin, chest, and neck, causing lymphadenopathy. Unexplained persistence of these manifestations should prompt practitioners to consider malignancy in their differential diagnoses.
Because of the variability in presentation of leukemia in the pediatric population, practitioners must be mindful of the potential diagnosis when patients present with unexplainable symptoms. The evaluation and workup for a patient with suspected leukemia includes a variety of laboratory tests and imaging studies. The initial step in diagnosing leukemia involves a complete blood cell (CBC) count with differential. If abnormal levels of blood cell types are present, further workup by the provider is warranted.
Diagnosis of leukemia comes from the results of a bone marrow biopsy or aspiration, taken most often from the pelvic bones, and analyzed to determine what form of leukemia is present. These studies also are used to follow the patient's course through the duration of treatment. Lumbar punctures are used to determine the extent of disease and if metastasis to the central nervous system (CNS) has occurred.
A definitive diagnosis of leukemia is usually made by bone marrow aspiration or biopsy revealing malignant cells of myeloid or lymphoid lineage. Definitive diagnosis can also be established by biopsy of an extramedullary mass of leukemic cells.
Imaging is another important component in the workup for leukemia. Chest radiographs can detect enlargement of the thymus or lymphadenopathy in the chest and are a diagnostic tool for detecting lung infections, which are common in children with weakened immune systems due to leukemia. Computed tomography (CT) scans and magnetic resonance imaging (MRI) are other forms of imaging that detect metastasis throughout the body. Gallium scans and bone scans are not often used diagnostically; however they may be used if a child has unexplained bone pain.
New developments in treatment and management of childhood leukemia have increased the rate of survival. The goal of treatment is to induce remission, decrease the number of blasts in bone marrow to below 5%, and prevent disease relapse. Most often, combination therapies including radiation, chemotherapy, and bone marrow transplants are the preferred method of induction therapy. Hematopoietic stem cell transplantation (HSCT, also called bone marrow transplant) may be pursued for certain high-risk patients with ALL and those with relapse. Bone marrow transplant may not be necessary in patients with complete remission and a favorable prognosis.11
The chemotherapy regimen is typically anthracyclines, cytarabine, and etoposide (the regimen also may include methotrexate) given as a minimum of four cycles of therapy.6 The treatment regimen given is based on the diagnosed classification of leukemia and is tailored to the patient's risk of relapsing.
Treatment usually is performed in three phases: induction, intensification, and maintenance. Induction is done to bring about remission so that the leukemic cells are no longer found in the bone marrow. Intensification is intended to remove any cancerous cells that may remain. The schedule and timing of the intensification affects effectiveness, as the Children's Cancer group reports that it was more advantageous to have the second cycle delivered 10 days after the first cycle.6
Finally, maintenance is performed after the prior two phases are complete. In patients who experience relapse of the disease, treatment is often marrow-ablative, using high-dose cytotoxic treatments followed by hematopoietic stem cell transplantation. Future studies are aimed at further increasing the rate of survival by exploring new medications and techniques to improve these rates.
Chemotherapy causes many acute adverse reactions that the healthcare provider must be aware of and monitor. Common adverse reactions include pancytopenias, alopecia, mouth sores and ulcers, mucositis, nausea, vomiting, constipation, organomegaly, infertility, increased risk of infection, and easy fatigability. Closely monitor the patient's electrolytes to prevent liver and kidney damage. The best way to counter common adverse reactions is to closely monitor the patient's CBC, metabolic profile, liver function tests, urinalysis, and other laboratory tests. Blood transfusions and antibiotics are usually provided to prevent anemia and infections. The use of granulocyte colony stimulating factor (GCS-F) has become part of the post-cycle protocol to combat the duration of immunosuppression and reduce the risk of infection.12
Providers have a responsibility to understand the possible chronic long-term effects of childhood leukemia and its treatment. Treatment has been shown to increase patients' risk of developing long-term neurocognitive, physical, and psychosocial complications. Patients may have resulting muscle weakness and motor and sensory dysfunction, making activities of daily life difficult and challenging. Bone toxicities and increased risk of fracture may occur, indicating the need for medical and surgical intervention at relatively young ages. Avoiding the development of obesity is essential to minimizing the risk of developing other chronic conditions.
One of the most serious consequences of therapy, although the overall risk is low, is secondary malignant neoplasms. Secondary neoplasms usually occur within 2 to 5 years of cancer therapy, but have been reported to develop 10 to 15 years later.13 Educate families on how to cope with these changes, provide information on special education services, and recommend interventions.
New research is aimed at minimizing the long-term toxicities of treatment while maintaining or increasing remission rates. New protocol designs, some based on the treatment of pediatric T-cell ALL, include intrathecal chemotherapy for CNS-directed therapy to improve the chances of complete remission without the use of prophylactic cranial irradiation.14 However, due to the current potential chronicity of chemotherapy adverse reaction, survivors of childhood leukemia should have annual physical examinations, be screened early for adult malignancies, and be encouraged to partake in preventive health measures.
Life-threatening complications can manifest in children with acute leukemia before, during, and after treatment. Understanding oncologic emergencies increases the ability of practitioners to identify these emergencies in patients, implement lifesaving treatment, and improve prognosis and treatment outcome.
Infection An oncologic emergency, infection is especially critical when the patient is neutropenic, defined as a dramatic decline in absolute neutrophil count. Closely monitor neutropenic patients for fever, which may indicate infection. Febrile neutropenia is defined as an absolute neutrophil count less than 500/mm3 and a single oral temperature of 101° F (38.3° C) or more than one temperature of 100.4° F (38° C) one hour apart.15 To prevent sepsis, hospitalization is indicated for high-risk patients with febrile neutropenia (defined as patients who are hemodynamically unstable, have medical comorbidities, or have prolonged neutropenia). Impaired immunity after chemotherapy increases the patient's risk of infection and requires broad-spectrum IV antibiotic treatment, with a third- or fourth-generation cephalosporin or vancomycin.6
Initiating GCS-F after therapy completion is indicated to prevent febrile neutropenia or shorten the duration of neutropenia.7,16 Factors that increase risk of febrile neutropenia in children include a previous episode of febrile neutropenia, advanced disease, serious comorbidities, poor performance/nutritional status, female gender, decreased hemoglobin level, combined chemotherapy, open wounds or active infections, and a chemotherapy regimen with curative intention. Practitioners should be aware of the patient's risk for developing febrile neutropenia and implement preventive measures to avoid septic infections.16
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If a patient has febrile neutropenia and complains of abdominal pain, evaluate for neutropenic enterocolitis or typhlitis. The cytotoxic property of chemotherapy causes damage to the mucosal lining of the gastrointestinal tract, eliminating protection and increasing microbial infiltration. The resulting inflammatory response causes abdominal discomfort, tenderness, and distension; nausea; vomiting; diarrhea; and disseminated signs of sepsis. Diagnosis should be based on presentation, and the indicated treatment is supportive therapy combined with IV antibiotics. Appropriate broad-spectrum antibiotic regimens include piperacillin-tazobactam as monotherapy or combined with an aminoglycoside, or the use of a third- or fourth-generation cephalosporin plus metronidazole.
Supportive therapy with bowel rest, fluids, and GCS-F should be implemented as well. To decrease mortality, appropriate treatment should be started promptly, and based on a high index of clinical suspicion.17 Assess patients' risk of febrile neutropenia on an individual basis, taking into account the regimen, patient- and disease-related factors, and treatment intent. Predictive tools that help clinicians identify which patients are most likely to benefit from GCS-F prophylaxis are now starting to become available.
Leukostasis (hyperleukocytosis) Associated with respiratory failure, intracranial hemorrhage, and early death, leukostasis involves WBC counts greater than 100,000/mm3 with thrombocytopenia, and poses a high risk of death. Leukostasis is the result of leukemic blast cells collecting in high concentrations in the microvasculature; unfortunately why it occurs is not completely understood. Manifestations include headache, dizziness, visual changes, tinnitus, and a range of respiratory symptoms and mental status changes. Physical examination may reveal papilledema, retinal vein bulging, retinal hemorrhage, focal neurologic deficits, and diffuse infiltrates on chest radiograph. Rapid treatment is essential to prevent morbidity and mortality. Leukapheresis and hydroxyurea are widely accepted as effective ways of decreasing blood viscosity and preventing death. Supportive treatment with fluid resuscitation and electrolyte normalization helps to promote filtration and prevent organ damage.15
Tumor lysis syndrome Another concern for practitioners is the development of tumor lysis syndrome, or life-threatening electrolyte abnormalities. The development of tumor lysis syndrome can arise during cytotoxic treatment as cellular contents infiltrate the bloodstream at toxic levels. Laboratory and clinical findings consistent with hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia can progress quickly, causing toxic effects and leading to multiorgan failure if not assessed and treated properly and promptly. Seizures, cardiac rhythm disturbances, neuromuscular irritability, and renal insufficiency may result, warranting emergent treatment. Necessary measures to minimize these risks and decrease their severity should they occur include hydration, urine alkalinization, and changing therapy as needed to correct the specific electrolyte imbalance.18
Due to the diligence of research, the number of children who achieve complete remission has increased significantly, the relapse rate is between 30% and 40%, and the event-free survival rate of pediatric leukemia is 50%.19 AML treatment has greatly improved the prognosis; however the 5-year survival rate is about 60%.19 Remission rates for children with ALL have exceeded 90%, with an overall survival rate of about 80%. The frequency of relapse of ALL is about 25% and is highly dependent on immunophenotypic and genetic subtype. Patients at high risk for relapse will do so in the first 3 to 5 years, with a very small percentage relapsing 5 years from diagnosis.
Important features that influence survival and prognosis include age, gender, ethnicity, body mass index (BMI), time of treatment initiation, and genetic mutations.6,20 Karyotypes have been evaluated to determine specific genetic mutations that favor certain treatment regimens.6 Patients with Philadelphia chromosome ALL have an extremely poor prognosis due to the failure of induction therapy of the relapsed leukemia cell type.
Cytogenetic evaluation of the initial and relapsed leukemia can direct possible treatment options. Intensifying the treatment approach and adding other treatment modalities is an effective method for increasing the response to therapy, especially when the treatment is tailored to the cell type.3 Atypical chemotherapy regimens (those used in lymphoma) can be considered in the instance of relapse to combat cell resistance.21
Primary care providers should be aware that the bone marrow is the most common site of relapses for patients with ALL, with the CNS and testes being the next most common sites. Isolated marrow involvement occurs in 48% of cases of relapsed ALL in children at a median time of 26 months.22 The incidence of isolated CNS relapse is less than 5%, and the incidence of isolated testicular relapse is less than 2%.23 Outcome of ALL is poorer with early relapse and with isolated bone marrow relapse than with later relapse and combined marrow and testicular or CNS relapse.22
Most AML relapses occur in the marrow, with CNS relapse being uncommon. Survival is substantially lower in patients with shorter remissions, and relapsed leukemia is still the primary cause of death in patients with AML.23
Continued research into the molecular mechanism of leukemic cells and use of gene-expression profiling will help identify prognostic factors. More intensive and novel therapy options for childhood leukemia must consider the multifactorial mechanism of the development of malignant leukemic cancer cells and multifactorial phenomenon of cellular drug resistance.
Acute leukemia may be challenging for primary care providers to identify in children because of the lack of specific findings. The key is to recognize unexplained symptoms and consider leukemia as a differential. Although specific causes of childhood leukemia may still be unknown, future studies may help to decrease the incidence of leukemia by identifying and decreasing these factors. Survival rates have been improving, but future studies must better-identify diagnostic and treatment options to increase survival. The responsibility of understanding prognosis and potential relapse also falls on the primary care provider. Being aware of childhood leukemia and understanding its causes and complications can help PAs support their patients and families throughout therapy.
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© 2013 American Academy of Physician Assistants.