Pediatric Leukemia

Although pediatric leukemia is the most common malignancy of childhood, many of the presenting signs and symptoms of leukemia, such as fever, limp, back pain, and bone pain, can be also seen in common and benign pediatric illnesses. To avoid delays in diagnosis and treatment, it is crucial to consider leukemia in the differential diagnosis in children with persistent symptoms. With advances in treatment over recent decades, the prognosis for pediatric leukemia has improved, and we are seeing more long-term survivors of this disease. Along with increased survivorship, increases in long-term potential adverse effects of treatment unfortunately are also observed. Critical roles of the primary care clinician are to recognize the signs and symptoms of pediatric leukemia to prompt initial examination and referral to pediatric oncology and caring for patients after completion of treatment when they may develop long-term adverse effects from treatment.After completing this article, readers should be able to: Discuss the epidemiology and risk factors of pediatric leukemia.Describe the clinical and laboratory features of pediatric leukemia.Recognize the presentation of oncologic emergencies in pediatric leukemia.Describe supportive care needs in pediatric leukemia.List the potential long-term complications of pediatric leukemia treatment.Leukemia is the most common malignancy diagnosed in childhood, with acute leukemia accounting for approximately one-third of all childhood cancers. Acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) are the main types of pediatric leukemias. Various factors contribute to prognosis and treatment within each group. Modifications to treatment through collaborative studies and risk stratification have led to marked improvements in outcomes. Improved outcomes have led to a growing population of long-term survivors of childhood leukemia who must be monitored for potential late effects of treatment that may occur even years following its completion. Many symptoms of acute leukemia can mimic symptoms of benign pediatric illnesses. By recognizing signs and symptoms of childhood leukemia, the pediatrician plays a crucial role both in expediting the complete diagnostic examination and initiation of treatment and monitoring for late effects in the expanding population of long-term survivors.Cancer is the leading cause of mortality owing to disease among children and adolescents in the United States, with approximately 15 000 children and adolescents diagnosed in the United States annually.1,2 Pediatric leukemia is the most commonly diagnosed malignancy of childhood, representing approximately 28% and 13% of cancers in children and adolescents, respectively.1,2 The rate of new cases of childhood leukemia is approximately 5 per 100 000 children per year, and age-adjusted rates for new childhood leukemia cases have been rising over the most recent decades (on average 0.7% each year from 2012–2021).3,4 ALL represents approximately 80% of pediatric leukemias, and among those with ALL, precursor B-cell ALL (B-ALL) is the most common subtype, representing 80% of ALL cases. However, the incidence of specific types of childhood leukemia and their respective survival rates vary among ethnic groups.5Cancers occurring in childhood and adolescence have few established risk factors. Some external factors implicated include exposure to radiation therapy and to certain chemotherapeutic agents. A high concordance rate for AML and ALL in identical twins (≤25%) has been noted, most commonly at younger age and rarely documented as adults.6–11 A fraternal twin of a patient with leukemia has an increased risk (2–4 fold) of developing leukemia up until 6 years of age.12,13 The risk of childhood leukemia also increases in patients with certain genetic syndromes, including Fanconi anemia, Li-Fraumeni syndrome, and Down syndrome.14–16 Children with Down syndrome are at increased risk of developing AML (>100 fold increased risk) and ALL (20–30 fold increased risk) relative to the general population.17–19 Of note, up to 10% of newborns with Down syndrome may develop transient myeloproliferative disorder (TMD)/transient abnormal myelopoiesis (TAM), which is a megakaryocytic leukemia that may be deadly in some infants but can self-resolve without treatment in others.20 Every infant with Down syndrome should have a complete blood cell count (CBC) drawn within the first few days of life to screen for TMD/TAM.21In acute leukemia, leukemic blast cells rapidly proliferate and replace the typical bone marrow (BM). This atypical proliferation expands the BM cavity and can cause pain, which may manifest as bone pain, limp, refusal to walk, or back pain. If performed, a magnetic resonance imaging (MRI) scan may show increased BM signal intensity or vertebral compression deformities or fractures (Figure 1). Because the BM normally serves as the “factory” where white blood cells (WBC), platelets, and red blood cells (RBC) are produced, the rapid clonal proliferation of leukemic blasts affects typical BM production, leading to varying degrees of neutropenia, anemia, and thrombocytopenia. The clinical presentation of acute leukemia typically reflects symptoms of cytopenias. Specifically, patients with anemia may present with pallor, dizziness, near-syncope, lethargy, headache, and/or dyspnea with exertion. Those with thrombocytopenia may present with increased bruising, petechiae, and bleeding (which is not typically serious despite severely reduced platelet counts).Although patients may have severe neutropenia at diagnosis, newly diagnosed acute leukemia rarely presents with severe infection or sepsis. Nevertheless, fever and neutropenia in this setting should prompt examination for infection including blood cultures and treatment with empirical antibiotics. Patients with acute leukemia may also present with leukocytosis, characterized by circulating WBC that are not functionally typical. Fevers are commonly noted in patients with acute leukemia. Leukemia cells can infiltrate other areas of the body, including the central nervous system (CNS), lymph nodes, spleen, testes, liver, and kidneys, resulting in hepatosplenomegaly and enlarged lymph nodes. With testicular involvement, enlargement of the testicles or a single hard enlarged testicle may be noted. CNS leukemia may occur in either ALL or AML but is more common in the former, specifically more common in the subtype, T-cell ALL (T-ALL). CNS leukemia may manifest with headaches, seizures, mental status changes, cranial nerve palsies, and/or vision changes or may be completely asymptomatic. In addition, leukemia cells can infiltrate the skin (leukemia cutis), which can have a variable appearance and mimic other dermatologic conditions. One example of leukemia cutis is shown in Figure 2.22 It is important to note that the type and degree of symptoms can vary substantially among patients.Notable differences in presentation of specific leukemia types or patient populations include CML, which can present with significant splenomegaly and mild anemia with significant leukocytosis and thrombocytosis rather than thrombocytopenia; AML in patients with Down syndrome, which may present with isolated thrombocytopenia; and T-ALL with an anterior mediastinal mass (Figure 3), resulting in respiratory distress, especially notable while supine. Chloromas, which are seen more commonly in AML, are collections of leukemic blasts outside the BM and can be found anywhere on the body, most commonly in the CNS and soft tissue. Acute promyelocytic leukemia (APL) is significantly associated with disseminated intravascular coagulation (DIC), bleeding, and CNS hemorrhage.Pediatricians are often the first to examine patients with signs and symptoms of leukemia and to determine the need for further testing and referral. The CBC with differential is often obtained as an initial evaluation of these symptoms because the CBC reflects BM function. Low neutrophil counts, low or high total WBC counts, low hemoglobin, and low platelet counts can be seen with varying degrees of severity in patients with acute leukemia. In general, patients with acute leukemia typically present with aberrations in more than 1 cell line at diagnosis; therefore, isolated cytopenias should be first evaluated as appropriate for the specific cytopenia, reserving consideration of leukemia when more than 1 cytopenia is present. Of note, cytopenias owing to other pediatric conditions (such as viral suppression, autoimmune disorders, splenic sequestration, and aplastic anemia) can be mistaken for leukemia. Blasts noted in the peripheral blood should be immediately discussed with a pediatric oncologist. If there is suspicion for leukemia based on clinical and laboratory findings, immediate discussion with a pediatric hematologist/oncologist is warranted to avoid delays in diagnosis and treatment.The diagnosis of acute leukemia typically involves a BM aspirate but in some cases may be made on peripheral blood if a sufficient number of leukemic blasts are present. A morphologic review of smears along with flow cytometric analysis provides diagnostic information, distinguishing between ALL vs AML and allowing classification of B-ALL and T-ALL.23 Analysis of cerebrospinal fluid (CSF) in acute leukemia can help to determine the presence of CNS involvement. A brain MRI scan may be needed in patients who present with cranial nerve palsies, severe headaches, or other neurologic symptoms. In addition, an examination of the testes in male patients with leukemia is necessary to evaluate for testicular involvement. CML can be diagnosed based on morphology and review of the peripheral blood smear, which contain typical progenitor hematopoietic cells that are normally confined to the BM. CML is also associated with an elevated WBC count, increased metamyelocytes and myelocytes, neutrophilia, basophilia, eosinophilia, and thrombocytosis, along with the presence of the pathognomonic Philadelphia (Ph) chromosomal translocation t(9;22). Figure 4 shows the morphology of ALL (Figure 4a), AML (Figure 4b), CML (Figure 4c), and a subtype of AML, APL (Figure 4d).Approximately 3100 people under 20 years of age are diagnosed with ALL in the United States each year. ALL occurs across all age groups but is most common in children 2 to 5 years of age.24,25 Between 1975 and 2020, the 5-year survival rate for children with ALL increased from 60% to approximately 90% and from 28% to 75% in children under 15 years of age and adolescents 15 to 19 years of age, respectively.2,26,27The first report of successful remission in a small group of patients with ALL using folate antagonist monotherapy was published by Farber, et al.28 in 1948. At that time, pediatric ALL remissions were brief with few long-term survivors. Because of the collaborative studies in pediatric oncology that better-classified patients with ALL and investigated treatment regimens, overall survival (OS) improved dramatically. The overall long-term survival of children with ALL has increased from about 10% in the 1960s to well over 90% today. Multiagent chemotherapy regimens have been tailored to risk stratification based on various features, including biological factors, patient characteristics, and response to treatment.29–31 Risk-based stratification allows for patients with predicted positive outcomes to be spared more aggressive and toxic treatments.32 The Children’s Oncology Group (COG) ALL study group, for example, considers several factors at diagnosis, such as immunophenotype, National Cancer Institute (NCI) risk group stratification, extramedullary disease, the presence of Down syndrome, and steroid pretreatment to determine intensity of first cycle of chemotherapy (induction). NCI risk group classifies standard risk (SR) as age 1 year to less than 10 years of age and WBC count less than 50 at diagnosis, and disease at 10 years of age and and/or WBC count 50 or 1 some of the and to pediatric patients with patient and genetic have been to and the most important in pediatric leukemia is treatment has been disease testing allows for of small of leukemic blasts and is a of prognosis across leukemia can be using such as flow or and years of have outcomes but significantly when with pediatric rather than leukemia treatment of ALL of therapy cycle is a over the of 2 to with varying based on the type of ALL and risk of chemotherapy are to the and the of by a 2 shows some of the potential effects of in ALL treatment are to the standard of care chemotherapy in clinical patients they often to and to many of their The of treatment and to the has for patients with ALL for with if from the should be The evaluation of fever should include blood cultures and initiation of for empirical of and blood are as needed chemotherapy is standard treatment of CNS CNS is typically for CNS disease as and positive for blasts in a or clinical signs of CNS of chemotherapy the treatment significantly the rate of CNS With improved outcomes with the of hematopoietic cell has in newly diagnosed of risk for T-ALL is to that of with the that patients with T-ALL more therapy because of the of T-ALL blasts as well as the with other features, such as rates of CNS disease, and WBC The of to the treatment of T-ALL was and has led to a 5-year survival and CNS outcomes for pediatric ALL have significantly improved, the prognosis for ALL is can occur in the BM and/or in extramedullary from is associated with outcomes and 5-year for BM and isolated extramedullary ALL has as low as and at 5 years and 10 In general, the prognosis for B-ALL is than therapy and are the of B-ALL The treatment of ALL has seen significant with and agents. The and T-cell with in pediatric in for positive B-ALL at year of and T-cell based therapy for pediatric leukemia in have improved the outcomes of patients with and the treatment of pediatric NCI B-ALL of average of risk of significantly improved patients be with a of chemotherapy and is the of in patients with newly diagnosed B-ALL T-cell therapy cells to cells with and can or both in is an that led to an overall remission rate of with at 1 year in pediatric or and patients with A 1 study of in patients to are in patients with a ALL, and studies are the in patients with newly diagnosed ALL by initial diagnosis in patients year of for less than of pediatric ALL, and these patients outcomes. ALL to be by more aggressive associated with to and high rates of and long-term adverse of pediatric are of with the as AML is typically by the presence of than leukemic blasts in the BM or a blast when an genetic is AML may extramedullary such as testes, skin (leukemia cutis), and brain AML is more common in infants with extramedullary of leukemia a is noted in approximately of patients with AML along with BM disease at diagnosis vs less than presenting with of flow to of AML is an important diagnostic chromosomal are found in the leukemic blasts of approximately 75% of children with AML and are of and The of AML treatment is The CNS is with The of CNS radiation has been owing to of and the potential for long-term adverse BM and disease must be for treatment, which typically involves of chemotherapy to remission by several or to the risk of chemotherapy is in AML treatment because was noted when after chemotherapy However, of such as chemotherapy and as a in AML has improved in supportive care have the rates of toxic in supportive care and have led to increased survival in childhood treatment may include a of (such as therapy (such as and supportive may be for such as those in the disease in first or chemotherapy is and can to significant and mortality owing to including infection and and has the rates of and even each until neutrophil or has has reduced neutropenia in pediatric AML should be evaluated and and for infection should be with despite antibiotics. and in AML is the 5-year survival rate for AML has increased from less than to about to remission rates are to 90% and survival from initial diagnosis is to be to However, there is a of outcomes based on specific features of In addition, the count is to with WBC associated with of CNS and complications and younger than 1 year of age with AML have 60% to 5-year survival to children on standard AML treatment regimens but with more CNS in childhood AML, which has been noted in up to one-third of cases and is associated with younger age, and certain is associated with response to therapy and the of after the first cycle of are for outcomes in pediatric and in AML include in the of and AML with or Various have been noted in AML, including positive with an than with with with and risk stratification in pediatric AML a of diagnostic and as well as response to treatment status at the of the first cycle of in pediatric AML occur within 4 years of to 60% of in AML occur within 1 year of cases of AML occur in the BM. CNS are AML treatment may include or associated with survival in disease include of first remission children with a first remission of year have rates of a at of a response to in first and in patients with Down syndrome to be more to is for children with Down syndrome diagnosed with AML to age 4 this age group the of cases of pediatric AML in children with Down children with Down syndrome and AML have outcomes to those without Down The outcomes in patients with Down syndrome can be despite therapy and less chemotherapy regimens, which is their increased risk of a subtype of AML, occurs in approximately of pediatric patients with The translocation is the chromosomal associated with APL leading to of the have improved with the of and bleeding risk for patients with APL and is as as APL is based on both clinical and morphologic APL is also in that the at the of not have because of the in leukemia for less than 10% of all in patients between 15 and 19 years of age, and it is even more in younger accounting for to of all in children under 15 years of Although it has been in most patients who have CML diagnosed are at 6 years of CML for up to of and is characterized by the which from the translocation between and leading to the of the the of as treatment of CML, was the main treatment for pediatric CML, with documented survival rates to 80% for patients who in chronic are the treatment of chronic is and in pediatric and are that are for the treatment of pediatric for include treatment for to 5 years and response for at 2 A response is as a significant in the a low disease is most common within the first 6 of a treatment of on in pediatric CML owing to the small pediatric patient population and because children with CML to the less Children to their treatment to have outcomes to their a WBC count than 100 can be seen in patient with newly diagnosed leukemia but is more commonly seen in patients with AML, and infant leukemia. The complications of are most commonly seen with WBC counts of than in AML and than to in The number of blast cells outside of the BM increases blood and can to which in of occur with a WBC in AML because AML blasts are and and can present as neurologic or respiratory emergencies associated with to include respiratory and acute respiratory syndrome, and on CNS include headache, dizziness, lethargy, and and may be seen in to by and and the WBC count is an important for to to avoid further increases in blood with acute leukemia and WBC counts are also at risk for a of as syndrome occurs because of the of of cells and of the blood If they these most often occur within the first few days of treatment but can occur and be noted at initial The of these in can the and the to and which can to and of even treatment is and for of are in serious emergencies include bleeding in APL and presence of an anterior mediastinal mass with its complications in Because of the many complications that can be seen in leukemia, initial laboratory evaluation in cases of leukemia should include a time, type and and along with a The signs and along with the to several of these are in in treatment have ALL from a to with a 5-year survival rate of over 90% and AML to a disease with a rate than to from clinical and improvements in the population of pediatric leukemia survivors to However, with increased patients may on to adverse including both acute and long-term to years after completion of The of at 1 chronic by years after initial diagnosis in of ALL survivors and most AML the of the need to rates by therapy with the late effects of treatment through patient stratification based on risk factors. example, among AML survivors who and primary are seen at a with survivors of AML with chemotherapy a of and The adverse effects of chemotherapy treatment of pediatric ALL to develop within 10 years of completing of childhood ALL are more to have or chronic with the seen for or neurologic acute and adverse effects of treatment therapy are by or in with the pediatric long-term effects are often first evaluated by the primary care diagnosis the of many late complications of leukemia treatment, such as syndrome, and in of treatment, characteristics, and all contribute to the risk for and the types of potential long-term adverse In the type of leukemia risk stratification the and the of radiation therapy or all are important factors. example, patients with ALL have late (such as age, and along with (such as and also may contribute to these late a role in the risk of long-term complications of leukemia example, when with other survivors of leukemia, patients with Down syndrome have of bone and of chemotherapy is associated with including with and and testing are important for pediatric leukemia especially if are noted, or if in of increased is is the main long-term of the of is a common potential of ALL most commonly with an incidence of up to in adolescents who ALL often can in treatment from to and is diagnosed or within a few of of in leukemia treatment to long-term in a patients with ALL who of have a risk of AML of and the of in with of has been shown to therapy in these can develop many years after exposure and is a disease that an can this in the and should be 2 to 5 years after late including and and syndrome, and have been documented in patients for leukemia. effects are more commonly seen in patients who total with or cranial is also in patients with ALL or AML without monitoring of blood mass along with and should be in the for treatment is also may cause in and in bone are long-term effects to the of and T-cell (such as which are more in the treatment of pediatric Although the specific adverse effects and outcomes for each patient may care is by a and at diagnosis, treatment, and for years after completion of leukemia may present with signs and symptoms of anemia, bone pain, refusal to walk, limp, and Patients may also present with and symptoms to CNS involvement. on in the of clinical and clinical can be an oncologic and should be with immediate appropriate supportive and treatment of is can often be on in the of clinical studies and clinical in children has an With treatment, T-ALL has outcomes to Pediatric patients with leukemia are based on various factors when stratification is based on several factors, including leukemia and response to treatment with on in the of clinical for ALL have improved with the of to standard on in the of clinical care is crucial in the treatment of as well as prompt examination and treatment of with empirical is crucial to on in the of clinical and clinical such as and therapy have in the setting of has shown and is evaluated as of treatment in of newly diagnosed pediatric on in the of clinical (Figure 1 and