Acute Lymphoblastic Leukemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has acute lymphoblastic leukemia? What are the typical findings for this disease?

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer and one of the major success stories in cancer treatment. Before the early 1960s, this was a nearly uniformly fatal diagnosis. With carefully organized collaborative treatment trials conducted through cooperative groups, the overall cure rate for this disease is in excess of 85%, and there are some subsets of patients who have a greater than 95% cure rate. Although the diagnosis is devastating to families, and the treatments can be demanding, the chance for an excellent outcome for patients is extremely high.

The majority of children with acute lymphoblastic leukemia (ALL) present with a constellation of symptoms which are attributable to bone marrow infiltration with leukemic blasts. Additional symptoms can be caused by infiltration of other tissues. Many symptoms are general and relatively nonspecific. Not all patients will have all symptoms but the following are typical:

Fever, fatigue, and/or bone pain are observed in the majority of patients.

Bone pain, arthralgia, and/or arthritis may manifest as decreased activity, general fussiness, irritability, or refusal to walk. Long bones, in which the marrow cavities are being replaced with lymphoblasts, are more often affected; however, generalized bony pain and discomfort are common.

Weight loss, if present, is usually relatively mild, but anorexia is frequent.

Bleeding manifestations from thrombocytopenia are common. Bruising and petechiae are frequent. Often caregivers will note a "rash" or "red spots," which are actually petechiae. Central nervous system (CNS) bleeding or hemorrhagic stroke are rare but life-threatening complications.

Anemia may manifest as pallor, headache, fatigue, dizziness, decreased energy or exercise tolerance, and sometimes syncope.

Hepatomegaly and/or splenomegaly due to leukemic infiltration are present in many patients at diagnosis but are often overlooked. Massive splenomegaly is more common in chronic myeloid leukemia (CML), which is relatively rare in children, representing only about 3% of leukemias diagnosed in persons younger than 18 years.

Lymphadenopathy is more common in ALL than in acute myeloid leukemia (AML), although it may occur in either. Mediastinal adenopathy is sometimes severe enough to lead to obstruction of the superior vena cava, leading to facial swelling, plethora, respiratory distress, and potentially airway obstruction. This is known as superior vena cava syndrome, or SVC syndrome, and is much more common in T cell ALL than in precursor B-ALL.

SVC syndrome is a medical emergency and particular care should be used in managing these patients. Take special note of the patient's position of comfort and do not disturb or attempt to alter that position. Much like a patient with peritonsillar abscess, often the patient is the best judge of how to protect his or her airway. Coughing or needing to lean forward to breathe or to sleep upright are particularly ominous signs.

Patients should not be set in the supine position, and sedation could lead to fatal cardiorespiratory collapse. Intubation is not advised, as the obstruction may be distal to the tip of the endotracheal tube, and the patient may not be able to be resuscitated in this event. Patients with SVC syndrome often require emergent radiation therapy to reduce the mass burden on the airway, after which diagnostic procedures can be completed in a more controlled and safe manner.

CNS involvement occurs in about 5% of patients with ALL, with higher rates occurring in those with T cell ALL and in infants less than 1 year of age at diagnosis. In most cases, CNS involvement is asymptomatic, but sometimes patients present with headaches, meningismus, or cranial nerve palsies.

Boys may present with unilateral or bilateral testicular enlargement or a testicular mass caused by leukemic infiltration. The testes typically feel "rock hard" and "bumpy" or irregular in contour, but there is usually no pain or tenderness.

Not all patients with ALL have high white blood cell counts. Even subtle abnormalities on the complete blood count (CBC) may suggest leukemia. These may include a mild increase or decrease in white blood cell count or some suppression in any or all lineages of red cells, white cells, and platelets. Pancytopenia may be subtle or more profound. Almost all patients with ALL have one or more abnormalities of the CBC.

Leukemic blasts may not be present on the peripheral blood smear, and only a bone marrow aspirate and/or biopsy can confirm the diagnosis in this situation. Light microscopy is not sufficient for specific diagnostic information, although it can distinguish ALL from AML most of the time. In many circumstances, special stains and laboratory techniques are required to confirm the diagnosis and phenotype. Additional analyses with flow cytometry and cytogenetic techniques (both conventional and molecular) are required to further categorize different subsets of ALL and to appropriately plan treatment.

Some children with a new diagnosis of ALL present with tumor lysis syndrome, a metabolic derangement caused by the release of intracellular contents in the face of cell death caused by rapid cell turnover. The most common findings can be seen on routine chemistry panels and include elevations in potassium, phosphorus, and uric acid levels, which can lead to secondary hypocalcemia and renal injury with an elevated blood urea nitrogen and creatinine levels.

Transaminase levels may be elevated.

Epidemiology of Childhood Acute Lymphoblastic Leukemia

ALL is the most common childhood malignancy, accounting for approximately 25% of cancers in children under the age of 15 years.

Leukemia occurs in approximately 50/1,000,000 person-years, with ALL accounting for approximately 80% of childhood leukemias that occur before age 15 years and 50% of those among adolescents 15-20 years old.

Approximately 85% of children with ALL have precursor B cell ALL and 10%-15% have T cell ALL. This is not evident under the microscope, and flow cytometric analysis is most useful to delineate phenotype.

The majority of children diagnosed with ALL have no predisposing factors, although detailed genetic analyses are elucidating more potential causal relationships. See sections entitled, "What caused this disease to develop at this time?" and "What causes childhood acute lymphoblastic leukemia and how frequent is it?" below for additional information about causes of childhood ALL.

The incidence of ALL is higher in boys than in girls, and there is a greater predominance of T cell-lineage ALL in boys. Despite this, there is no known hormonal link to the development of ALL.

What other disease/condition shares some of these symptoms?

Many children who are eventually diagnosed with ALL have been evaluated for other causes of their symptoms. Commonly, patients may have been evaluated for recurrent fevers, fatigue, adenopathy, splenomegaly, hepatomegaly, weight loss, and bone pain.

Most commonly, infectious diseases and rheumatologic conditions are considered in the differential diagnosis.

Infections, particularly viral disease, not only mimic the physical symptoms and findings but also may share an elevated white blood cell count or some element of pancytopenia, as well as elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).

Concerns for autoimmune or collagen vascular disease far outnumber the actual incidence of these conditions, and ALL in childhood masquerades as many other conditions. In reality, ALL is more common than all childhood collagen vascular and autoimmune diseases combined. However, there is a small subset of childhood ALL cases that presents with symptoms closely resembling those associated with juvenile idiopathic arthritis (JIA). In such cases, bone marrow aspiration should be done before undertaking treatment for JIA.

A smaller percentage of patients see orthopedic specialists because of recurrent fever and bone pain, and a subset of patients is actually treated for osteomyelitis because of these symptoms when radiologic imaging shows bony abnormalities, which are mistaken for infection but actually represent bone marrow or bone involvement with leukemic infiltration.

Patients may also have other malignancies. The subtype of leukemia cannot be diagnosed based on signs and symptoms, because those of ALL are quite similar to those of AML and CML. Sometimes the signs and symptoms of other "small round blue-cell tumors" of childhood - including Ewing sarcoma, lymphoma, rhabdomyosarcoma, or neuroblastoma - can mimic those of ALL. Each of these tumors shares a similar appearance under the microscope, and only further testing coupled with imaging and clinical information can distinguish them from each other.

Aplastic anemia or other conditions of bone marrow failure may present with similar symptoms, physical findings, and blood counts, such as pancytopenia, anemia, headaches, infections, petechiae, or bleeding manifestations.

What caused this disease to develop at this time?

The incidence of childhood ALL peaks between the ages of 2-5 at approximately 80 cases/million. Historical analysis suggests that a dramatic increase in the incidence of childhood ALL in the population developed in concert with industrial development. The peak incidence of ALL in the preschool years is thought to be related to changes in exposure to early childhood infections, but this link has not been definitively proved.

In many and perhaps the majority of cases, the initial genetic changes involved in leukemogenesis occur in utero. It is possible that childhood infections may lead to proliferation of this premalignant clone, and the acquisition of additional mutations is required for full-blown leukemia to develop.

ALL is not one of the typical cancers that occur in familial cancer syndromes; however, there is an increased incidence in some genetic syndromes (see section entitled "What causes childhood acute lymphoblastic leukemia and how frequent is it?" for additional details).

The only dietary link to childhood ALL has been examined by Greaves et al., who found an increased incidence of ALL in babies born to mothers who had high intake of dietary phytates (antioxidant compounds found in whole grains, legumes, nuts, and seeds) during their pregnancies.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

CBC and differential of the white blood cell count is abnormal in the overwhelming majority of children with ALL and may show cytopenias of one, two, or three lineages. In approximately one third of children with ALL, the peripheral smear does not show blasts; however, subtle changes may suggest an infiltrative process, including presence of "teardrop" red cells, relative thrombocytopenia (platelet count <100,000/mm3), or lack of an appropriate reticulocyte count for the degree of anemia.

Lactate dehydrogenase levels are frequently elevated, as this enzyme is contained within white blood cells, and "spills" out when these cells turn over.

Uric acid levels are often elevated because of rapid cell turnover and breakdown of intracellular contents, including DNA.

Serum chemistry panels may reflect mild to moderate renal insufficiency with an elevated creatinine level, hyperphosphatemia, hypocalcemia, and other metabolic markers of tumor lysis syndrome.

The ESR and the CRP level are usually elevated and are not particularly helpful because they do not help distinguish ALL from other inflammatory or infectious processes. The converse is also true - a normal ESR or CRP level would not rule out ALL.

Would imaging studies be helpful? If so, which ones?

In general, imaging for pediatric ALL is fairly limited. A plain chest radiograph should be obtained in all patients before any sedation or anesthesia to determine whether or not a mediastinal mass is present, which is more common with T cell ALL. Most other forms of ALL do not have classic imaging findings, with the exception of lymphadenopathy and hepatosplenomegaly.

Occasionally plain radiographs will show a "moth-eaten" appearance to long bones from marrow infiltration. Signs of growth arrest, including growth arrest lines, may also be present. Some patients with childhood leukemia are actually seen by orthopedic services and diagnosed with osteopenia, avascular necrosis, or osteomyelitis before coming to definitive diagnosis, as the bony changes on plain radiograph or magnetic resonance imaging may masquerade as any of these diagnoses.

Ultrasonography or computed tomography may show enlargement or diffuse infiltration of the liver or spleen but are not diagnostic for ALL and should not be considered appropriate testing for this diagnosis.

Positron emission tomography or nuclear medicine imaging obtained in a search for a diagnosis will often show diffuse enhancement of the bone marrow spaces, but neither of these tests is indicated to make the diagnosis of ALL and are not helpful in differentiating ALL from other conditions.

What testing modalities are required to make the definitive diagnosis of ALL?

Once suspected based on a CBC, clinical history, and physical examination, the definitive diagnosis of ALL is made by bone marrow aspiration and/or biopsy. When the white blood cell count is high and there are peripheral blood blast cells, flow cytometry can be performed on the peripheral blood. Although this can give an accurate diagnostic picture, bone marrow aspiration and biopsy are still the gold standard and should be pursued unless the procedure is medically contraindicated.

A lumbar puncture is performed to assess the presence or absence of leukemic involvement in the CNS. Cytologic analysis is the only means to assess this appropriately. This should be done by a practitioner who has extensive experience in treating pediatric oncology patients and should not be performed at a local office or emergency department. Imaging is not indicated unless there are focal CNS signs that suggest imaging would be indicated.

Studies have shown that a traumatic lumbar puncture at diagnosis can compromise survival for patients because of the potential seeding of leukemic blasts into the CNS, and as a result special precautions should be taken with the initial lumbar puncture. These precautions include having the procedure performed by a highly experienced practitioner, transfusing platelets as needed to maintain a platelet count of at least 50,000-100,000/mm3, and the use of deep sedation or anesthesia. It is generally preferable to administer intrathecal chemotherapy at the time of the initial lumbar puncture, so this procedure may need to be delayed until it is certain that the patient has leukemia.

The presence of cranial nerve findings or focal neurologic deficits should raise the suspicion of CNS infiltration until proven otherwise. CNS imaging should be undertaken when it is appropriate to the symptoms and complaint noted.

A chest radiograph must be obtained before any sedation to evaluate for mediastinal compromise.

Additional radiographic studies are not likely to be helpful in making the diagnosis but may help delineate symptoms or complaints in a given patient.

Confirming the diagnosis

If you are able to confirm that the patient has acute lymphoblastic leukemia, what treatment should be initiated?

Patients suspected of having ALL should be stabilized and transferred to the care of trained pediatric oncologists in a setting that can support intensive care of children. Expertise in pediatric surgery and anesthesia are helpful, as is a strong transfusion medicine service.

Initially, patients should be hydrated with 1.5-2 times maintenance intravenous fluids that are alkalinized (often 5% dextrose and 0.45% normal saline without potassium and with sodium bicarbonate titrated to try to maintain urine pH of approximately 6.5-7). This is done to maintain good flow through the kidneys to prevent renal damage from tumor lysis and to increase the solubility of uric acid that is excreted in the urine. It is critical not to add potassium to the intravenous fluids given to a patient with newly diagnosed ALL, because hyperkalemia is a risk secondary to tumor lysis.

Patients should not be given any steroid medication if leukemia is suspected, as steroids can mask a complete diagnosis by temporarily decreasing the leukemic burden.

In emergent circumstances, any blood product that is transfused should be leukofiltered (to prevent transmission of cytomegalovirus [CMV]) and irradiated. It is wise to discuss any potential transfusions with the receiving pediatric oncologist to determine the best transfusion plan and product selection in advance.

Patients should be given medication to prevent and/or treat acute tumor lysis syndrome. In most cases, allopurinol, a xanthine oxidase inhibitor that decreases production of uric acid, is used at doses of 150-300 mg per dose, given once to three times daily, and adjusted according to serum uric acid levels. For patients with significant hyperphosphatemia, a phosphate binder such as aluminium hydroxide is used. Rasburicase, a recombinant form of uric oxidase that directly cleaves and breaks down uric acid, is indicated for patients with clinical manifestations of tumor lysis or those at high risk because of a very elevated white blood cell count (>50,000-100,000/mm3) or substantial extramedullary tumor burden.

Because rasburicase is quite expensive, it is usually not given to patients with low risk for tumor lysis, as the cost-benefit ratio is not favorable. Conversely, in patients at high risk for tumor lysis, the cost of sometimes a single dose of rasburicase and the clinical benefit manifested far outweigh the risk and cost for renal dialysis that may be required in these patients.

Once the definitive diagnosis is made, treatment can begin.

Treatment of Childhood ALL

The major improvements in cure rates for pediatric ALL that have occurred have been facilitated by the fact that most children with ALL are enrolled into large, collaborative, multi-institutional, and multi-national randomized clinical trials. In North America, the Children's Oncology Group (COG) conducts such trials. In Europe, the International BFM Study Group conducts similar trials. In 2014, 75-95% of all cases of childhood ALL in the United States were enrolled in COG clinical trials.

Studies have consistently shown substantially higher cure rates for older adolescents and young adults (AYA) aged 16-21 years who enroll in pediatric compared with adult cooperative group clinical trials. Across the globe, the difference in survival is approximately twice that for patients treated in pediatric centers compared with those treated in adult centers. More recent studies have demonstrated similar efficacy of pediatric regimens over adult regimens in AYA patients up to the age of 40 years, and many adult ALL treatment regimens are now much more closely modeled after pediatric protocols. For this reason, it is critical that patients with ALL in this age group be referred to a pediatric cancer center or an adult cancer center with extensive experience with pediatric treatment regimens.

Treatment for ALL is relatively standardized, and the majority of children are treated in or according to a clinical trial. For newly diagnosed patients, standard of care includes combination chemotherapy. In North America, the COG has protocols for ALL and subcategorizes treatment on the basis of a number of risk factors, including age, white blood cell count at diagnosis, and the phenotype of the leukemic blasts (precursor B or T cell lineages).

These factors are used to determine the intensity for the first 4 weeks of treatment, called "induction," which includes either three (a corticosteroid-dexamethasone or prednisone, vincristine, and an asparaginase preparation) or four (addition of an anthracycline) systemic agents along with several doses of intrathecal chemotherapy. More than 95% of patients will enter complete remission at the end of induction, with failures being due to refractory leukemia and/or death from toxicity or complications such as fatal infection.

After induction therapy is completed, the clinical and leukemia genetic risk factors are integrated with measures of early treatment response to determine the intensity of post-induction therapy. Today, sensitive measures of end-induction minimal residual disease (MRD) that can detect a 0.01% or lower burden of remaining leukemia cells are used to measure treatment response and have been shown to be predictive of ultimate prognosis.

Various forms of multi-agent chemotherapy are given for 6-8 months after induction to "consolidate" the remission. This is followed by a prolonged (18-30 months) period of low-intensity "maintenance" chemotherapy. Most children feel quite well during maintenance therapy and are able to return to their usual activities.

Treatment differs and is typically more intensive for certain smaller high-risk subsets of childhood ALL, such as infants less than 1 year of age at diagnosis.

Another critical part of ALL therapy is pre-symptomatic CNS-directed treatment. In the past this consisted of cranial or craniospinal irradiation plus intrathecal chemotherapy. Because of improved systemic treatment, fewer and fewer patients now receive radiation therapy for ALL, and some researchers believe that this treatment modality can be eliminated for all patients.

Bone marrow or hematopoietic stem cell transplantation is used infrequently (about 5% of cases) in first remission for childhood ALL but is used much more commonly during retrieval therapy after bone marrow relapse.

Targeted therapies directed at the genetic lesions that cause leukemia are now being developed and tested. The prototypes are inhibitors of the BCR-ABL tyrosine kinase that have revolutionized the treatment of Philadelphia chromosome-positive ALL, a rare subset of childhood ALL that was previously frequently treated with bone marrow or stem cell transplantation.

What are the adverse effects associated with each treatment option?

Side effects depend on the particular drugs used and in which phase of treatment the patient is. Some routine, expected acute side effects are listed by drug below. See below for discussion concerning long-term toxicity and late effects.

Corticosteroids (dexamethasone, prednisone): These agents can cause weight gain, Cushingoid appearance, fluid retention, muscle weakness (especially proximal muscle groups), steroid-induced acne, headache, gastritis/esophagitis, mood changes that can be extreme, and hyperglycemia (5%-10% of patients can require insulin therapy during induction). Corticosteroids play an important role in the pathogenesis of avascular necrosis, which occurs in up to 20% of patients and almost always develops acutely during therapy.

Vincristine: Neuropathy and constipation can result from vincristine therapy. Adolescents and young adults are particularly susceptible to vincristine-induced neuropathy, which may be reversible but can be disabling.

L-Asparaginase: Hyperglycemia, pancreatitis, coagulopathy, and/or hypersensitivity reactions can result. Allergic or hypersensitivity reactions may be associated with the development of neutralizing antibodies that inactivate the drug. Paradoxically, asparaginase use is associated with both bleeding and thrombotic complications, which most commonly occur during the induction phase of chemotherapy.

Anthracyclines (doxorubicin, daunorubicin): Myelosuppression and mucositis are the most common and problematic effects.

What are the possible outcomes of childhood acute lymphoblastic leukemia?

One of the modern success stories in oncology is the dramatic improvement in outcomes for children with ALL. With proper treatment, the vast majority of children diagnosed with ALL today will be cured. Overall, more than 85% of children diagnosed with ALL will be long-term survivors, with some subsets having a more than 95% chance for cure. Other patient subsets have a much poorer prognosis.

Recent work has focused on identifying prognostic factors at diagnosis, including molecular and gene abnormalities and early response to therapy, which help define prognosis; the use of combination chemotherapy to maximize response; and the careful and selected use of therapy to minimize long-term side effects for survivors.

Without treatment, ALL is fatal. Families should be told gently that with modern treatment, cure is highly likely but cannot be guaranteed. The vast majority of individuals treated for ALL in childhood can expect to have an excellent quality of life after treatment, but long-term side effects and late complications are not unheard of. Most children treated will attain an academic, employment, and social status in adulthood that is similar to their siblings or age- and socioeconomically matched peers.

Because survival is very common with childhood ALL, more attention is now turning to the reduction of therapy burden in current treatment protocols. Some of the late effects and complications are addressed in the next section.

What causes this disease and how frequent is it?

There are myriad investigations into the cause of childhood ALL. To date, there are few conclusive relationships, although large-scale genomic research is helping to uncover low-penetrance genetic risk factors. Detailed epidemiology of childhood ALL is as follows:

Approximately 3250 cases of ALL are diagnosed in children younger than 19 years of age in the United States each year. Over time, the case rate has been relatively stable at approximately 50/1,000,000 person-years.

The peak age for ALL occurs between ages 2-5 years, with decreasing incidence with each decade of life. This contrasts sharply with AML, in which the median age at diagnosis is 65 years, and the incidence increases with each decade of life.

There appears to be a slight rise in new diagnoses after seasons in which there are large numbers of viral infections, particularly with respiratory illnesses, which some argue supports the hypothesis that an infectious exposure predisposes to the development of childhood ALL, and seasonal incidence is relatively consistent throughout the year.

Leukemias in children do not have an acute contagious or infectious exposure transmission. Children do not "catch" leukemia from others.

Identical twins have a high concordance rate for ALL in the first 5 years of life, particularly in the first year, with a higher concordance in monochorionic twins than in dichorionic twins. Other than this, there is little or no increased risk among family members, except those with rare familial cancer syndromes.

Advanced maternal age appears to confer a slight increase in risk for the development of ALL.

Predisposing factors are myriad and the genetics of ALL are complex and can be broken down into children with and without known predisposing factors.

Genetic predisposing factors for the development of ALL include genetic syndromes such as Down syndrome, Klinefelter syndrome, neurofibromatosis, Shwachman syndrome, Li-Fraumeni syndrome, and chromosome fragility or breakage syndromes such as Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia.

By far, the most common of these is Down syndrome, and about 3% of ALL cases occur in children with Down syndrome. Emerging data show that the genetics of Down syndrome ALL differs significantly from non-Down syndrome ALL. There are also unique issues regarding toxicity and a significantly increased risk of treatment-related mortality in children with Down syndrome and ALL.

Environmental factors contributing to childhood ALL are relatively few but include maternal exposure to pesticides, insecticides, or DNA-damaging agents and paternal exposure to pesticides and fungicides. Benzene exposure is more frequently associated with AML and myelodysplastic syndromes (MDS), although it has been reported in ALL. Similarly, exposure to environmental radiation has been studied, although no clear-cut linkage has been established to childhood ALL.

Despite intense media interest, there is no evidence that electric power lines or cell phone use contribute to the risk of ALL developing.

Few studies have confirmed protective factors for childhood ALL. One study found that babies who were breast-fed for at least 6 months appeared to have a decreased risk of ALL, although the inciting reason was not defined. Other studies have shown that genetic polymorphisms that protect against DNA damage may be protective. The most well-known example of this is in the methyltetrahydrofolate reductase gene.

Risk factors for the development of childhood ALL include advanced maternal age and higher birth weight in the neonate.

Paternal risk factors for the development of childhood ALL include pesticide and fungicide exposure.

The concept of "cancer clusters" - the observation of what seems to be a higher than expected incidence of cancer in a particular community - is not borne out when placed under careful epidemiologic scrutiny.

How do these pathogens/genes/exposures cause the disease?

Recently there have been major new insights into the genomic landscape of childhood ALL. Like other cancers, ALL is caused by an accumulation of mutations, almost all of which are somatic and not present in the germline. The mechanisms of mutation include chromosomal translocations (the exchange of genetic material between chromosomes), point mutations, and deletions of genes.

Interestingly, a high percentage of patients with ALL have mutations in genes that normally regulate B or T cell differentiation. Some of these mutations are prognostic of outcome and can be used to stratify patients into high- and low-risk groups. This allows the appropriate intensity of therapy for patients who need it, while attempting to minimize side effects, both short- and long-term, for patients who do not warrant such aggressive treatment. Other mutations create targets for therapy, the most well-known of which is the Philadelphia chromosome that produces a BCR-ABL1 fusion that can be targeted by tyrosine kinase inhibitors.

Good-risk cytogenetic features are present in a high percentage of children with ALL. Trisomies of chromosomes 4 and 10, or a translocation between the ETV6 and RUNX1 genes, also known as t(12;21), are associated with a particularly good prognosis.

Translocations involving the MLL gene are a harbinger of a more aggressive form of leukemia, particularly in infants less than 1 year of age at diagnosis.

What complications might you expect from the disease or treatment of the disease?

There are a number of potential long-term toxicities associated with ALL therapy, but it is important to emphasize that the overwhelming majority of patients who are cured will lead productive lives (see above for a discussion of acute toxicities). Long-term complications are more common in patients who relapse and receive intensive retrieval therapy and/or stem cell transplantation.

It is likely that there are host genetic factors that contribute to the relative tolerance or intolerance to therapy. Some patients have essentially no significant toxicities, whereas others seem to have tremendous difficulty tolerating therapy. In the near future, knowledge of such variation may allow more "personalized" treatment to increase cure rates and decrease toxicities. Careful follow-up by specialists trained in childhood cancer survival is available at many major pediatric medical centers and should be encouraged.

It is helpful to divide possible side effects into acute and chronic complications of treatment.

Acute Complications

During induction therapy, electrolyte abnormalities from tumor lysis, bleeding from thrombocytopenia, and infection due to neutropenia are the most common acute and potentially serious problems encountered. Thrombocytopenia is usually easily managed with platelet transfusion support.

Any transfused blood product given to an oncology patient should be irradiated to prevent the development of transfusion-associated graft-versus-host disease. Prophylactic antibiotic support is indicated in the presence of fever or other signs of infection and should be continued through the period of recovery through induction chemotherapy until healthy marrow neutrophil recovery is evident.

Infections, including those from opportunistic organisms, remain problematic throughout therapy. Risk of infection is greatest during induction and the intensification phases of treatment, when patients are usually more neutropenic for more prolonged periods. Both neutropenia and leukopenia/lymphopenia are problematic, although the risk of serious bacterial infection is more commonly due to neutropenia, whereas lymphopenia is more concerning for viral and fungal processes.

Patients receiving multi-agent chemotherapy are relatively T cell immunodeficient as a result of the therapy. As such, prophylaxis for Pneumocystis carinii (now often called P. jiroveci) pneumonia is indicated in all patients. Additional prophylaxis may be important for patients based on underlying conditions or susceptibilities, including viral or fungal prophylaxis, based on a patient's inherent flora or chronic colonization. For example, patients who have recurrent herpes virus infections are often managed with prophylactic acyclovir or later-generation antiviral medications.

A small minority of patients with newly diagnosed leukemia will present with signs and symptoms of disseminated intravascular coagulation, although this is more common with AML and acute promyelocytic leukemia, specifically. Blood product and factor support, including cryoprecipitate and fresh frozen plasma, should be administered as clinically indicated. Activated factor VIIa may be used in special circumstances, based on institutional standards.

Late complications of therapy and long-term side effects

These complications and side effects may be separated by organ system as follows:

Cardiac: Decreased myocardial contractility is seen in patients who are treated with higher doses of anthracycline chemotherapy (doxorubicin, daunomycin, idarubicin, mitoxantrone are the most common, although the latter two agents are also used more frequently in therapy for AML). There is a sharp rise in the incidence of decreased ejection fraction and subsequent cardiac compromise in patients who receive more than 450 mg/m2 cumulative lifetime exposure to anthracyclines. Fortunately, the majority of children with ALL do not require doses in this range, and generally have no increased cardiac risk.

For children treated with anthracyclines during childhood, special attention should be paid to those who become endurance athletes or participate in sports that require Valsalva maneuvers (wrestling is a common example) or to young women who become pregnant. Consultation with and active involvement by an experienced cardiologist is recommended in these circumstances so that proper monitoring can be undertaken in a proactive manner. Similarly, any patient who demonstrates a decline in cardiac function should be referred to a pediatric cardiologist for further evaluation and possibly ongoing follow up and/or management.

Endocrine: Disturbances of growth and hormonal axes are seen in patients with ALL, particularly those who require radiation therapy to the CNS. Growth hormone or thyroid hormone therapy may be indicated. Infertility is relatively uncommon in patients with standard-risk ALL. However, those patients who require higher doses of alkylating agents or those who need high-dose chemotherapy and stem cell transplantation, with or without total body irradiation, are at a substantially high risk for growth failure, thyroid disturbances, delayed or premature puberty, and/or infertility.

Consultation with pediatric and/or reproductive endocrinologists is appropriate for peri- or post-pubertal patients as early in treatment as possible. For pre-pubertal patients, such consultation may help provide accurate information to the family and can assist in understanding potential long-term issues for the child and his or her future fertility potential.

Sperm banking is a well-established procedure that can be offered to many adolescents and young men who are undergoing cancer treatment and should be done as soon as possible after the diagnosis. Options for preserving fertility for young women are less well established, although newer techniques in egg storage and protection are starting to become more common and consultation with reproductive medicine specialists should be offered.

The ultimate success of these procedures is more variable, but most major pediatric oncology centers can provide education about various patient options. Again, the sooner after diagnosis reproductive endocrinology consultation is undertaken, the more planning for fertility preservation can take place in patients at the highest risk.

Orthopedic: Treatment for childhood ALL may cause avascular necrosis (AVN) (also termed osteonecrosis), particularly in patients treated during adolescence and young adulthood. Girls seem to be at a substantially higher risk than boys, and teenagers older than 15 years of age of both sexes are at greater risk. Any patient who is experiencing significant bone pain after entering remission should be considered for evaluation of possible AVN. Referral to an experienced pediatric orthopedic service is warranted, although some pediatric oncologists begin imaging evaluations prior to the primary referral.

Early imaging assessments and intervention are increasingly common, and consultation with orthopedic surgeons is encouraged to maximize functional outcomes for these patients. There appears to be a substantial risk of "silent" AVN based on imaging evaluation, and current studies are evaluating scheduled scans and the potential effectiveness of early identification of bony changes to allow for early intervention.

Neuropsychological and educational: Patients who undergo radiation therapy as part of their ALL treatment, particularly those who require CNS irradiation or those who are treated when younger than 3 years of age, are at risk for learning and cognitive and sensory processing difficulties. More recent data suggests that these risks are present even in children who received only chemotherapy as treatment for their ALL. Consultation with a pediatric neuropsychologist is recommended as soon as possible to identify areas that require attention and to develop individualized educational programs to facilitate interaction and coordination with school programs.

Psychosocial: The majority of children with ALL are able to return to school during therapy except during periods of extreme neutropenia and can interact with peers and participate in activities normally. Most children adapt well to the treatment environment and are able to attain their pre-diagnosis potential with regard to educational and career goals. The Childhood Cancer Survivor Study has followed patients treated for a variety of childhood malignancies and shown that most patients treated for ALL match siblings and age- and socioeconomic-matched controls in education level, employment level, and income potential attained.

Second malignant neoplasms/secondary malignancies: A second malignancy may develop in approximately 1%-2% of patients treated for ALL without cranial or craniospinal irradiation. This rate is increased for patients who do receive cranial or craniospinal irradiation and is manifested primarily as tumors of the CNS. Secondary brain tumors can range in histologic type from meningiomas to highly aggressive anaplastic astrocytomas/glioblastoma multiforme. Secondary leukemias or myelodysplastic syndromes (MDS) may arise in patients treated with higher doses of epipodophyllotoxins (etoposide being the most common) or alkylating agents (such as cyclophosphamide or ifosfamide) in retrieval regimens.

The risk for secondary leukemias and MDS appears to be most related to the cumulative exposure of drug, although individual pharmacogenomic host factors are known to contribute substantially. The risk for secondary leukemias typically occurs between 2 and 7 years after primary therapy, whereas there is no "plateau" as yet defined for the risk of CNS tumors.

Overall, the risk of second cancers in children diagnosed with ALL is small, and usually smaller than for those with other pediatric cancers (e.g., the risk of breast cancer in survivors of Hodgkin lymphoma, particularly in patients who receive mantle irradiation, continues to rise with each year of survival after the primary disease). Although not negligible, the risk of second cancers in childhood ALL survivors is small.

Are additional laboratory studies available; even some that are not widely available?

Perhaps the greatest advancement in the treatment of childhood ALL in the past 10 years has been the discovery that minimal residual disease (MRD) - which is molecular evidence of disease in patients for whom no morphologic evidence of disease can be found - is prognostic of relapse and overall survival. It is now standard of care for pediatric ALL patients to evaluate for the presence of MRD during ALL therapy, using molecular genetics and flow cytometry both at diagnosis and at various intervals during therapy. These techniques require sophisticated laboratory equipment and highly trained personnel to validate and continuously monitor quality control of methodologies.

Molecular cytogenetic changes in leukemia cells have been shown to confer independent prognosis for patients, and the early identification of these abnormalities allows patients to be stratified into risk groups to maximize their treatment outcomes. Patients with adverse cytogenetic findings, such as severe hypodiploidy (<45 chromosomes), the t(9;22) Philadelphia chromosome, or rearrangements of the MLL gene are typically "upstaged" to more aggressive treatment regimens. Conversely, patients with "good risk" cytogenetic features, such as trisomies of chromosomes 4 and 10 or the t(12;21) ETV-RUNX1 fusion can be given relatively modest therapy and maintain excellent disease-free survival.

Newer prognostic features based on molecular characterization include alterations in gene copy number, presence of intra-chromosomal amplification of chromosome 21, and Ikaros or CRLF2 gene mutations. Even more recently, the discovery of “Philadelphia-like mutations”, through the use of molecular screening methodologies, has also identified a subset of patients whose previously poor prognoses can be altered through the use of small molecule inhibitors that target defined molecular aberrations.

Sensitive multicolor flow cytometry analyses allow for monitoring of disease burden as soon as 8 days after beginning therapy for ALL and have been shown in large multicenter trials to be predictive of ultimate disease outcome.

How can childhood acute lymphoblastic leukemia be prevented?

To date, there are no proven interventions for prevention of ALL in the vast majority of children. Greaves et al in the United Kingdom have examined the relationship of prenatal maternal exposure to dietary phytochemicals in high amounts and their possible contribution to infant ALL (with rearrangements of the MLL gene) in particular. Larger prospective multinational studies are needed to confirm these findings.

Unlike MDS and some types of AML, ALL does not have frequently identified environmental causes such as radiation exposure, benzene exposure, or exposure to other toxins, although parental pesticide exposure has been linked to the development of ALL in the children of exposed fathers.

A compelling link was identified in the United Kingdom among young children cared for in the home compared with children who participated in day care programs, with a reported increased incidence of ALL in children who were not exposed to a larger number of contacts outside the home before starting primary school. One hypothesis suggested that children exposed to day care environments experienced a significantly larger number of minor acute illnesses, which "tested" their immune response to challenges. It was theorized that when children were exposed to such challenges, the immune response was able to more accurately develop a fuller immune repertoire, thus potentially "surveying" and making appropriate immune response to the development of leukemic cells. This theory has not been proven in large multinational studies, although it is compelling in its implications for the cause of pediatric leukemia, immune surveillance, and disease resistance.

What is the evidence?

The tremendous advances in curing childhood ALL have been reached through the careful conduct of collaborative clinical trials over the past 40-50 years. Current standard of care for childhood ALL should be treatment in a clinical trial conducted by one of the large pediatric cooperative cancer groups or similar protocols. The COG, the International BFM Study Group consortium in Europe, the United Kingdom's Medical Research Council, St. Jude Children's Research Hospital, and the Dana Farber Cancer Institute Consortium are all examples of these types of collaborative efforts.

A landmark study conducted jointly by COG and the Cancer and Leukemia Group B showed that when matched for known risk factors, patients aged 16-21 years who were treated in pediatric centers had twice the survival as those patients treated in an adult cancer center (64% versus 32% 5-year event-free survival). There are myriad hypotheses for this outcome, but it has been replicated in studies throughout the world, suggesting that this was not an isolated finding. As such, the current recommendation worldwide is for adolescents and young adults to be treated in a pediatric cancer center whenever possible.

Armstrong, GT, Chen, Y, Yasui, Y. "Reduction in late mortality among 5-year survivors of childhood cancer". NEJM. vol. 374. 2016. pp. 833-842.

Bailey, HD, Infante-Rivard, C, Metayer, C. "Home pesticide exposures and risk of childhood leukemia: findings from the Childhood Leukemia International Consortium". Int J Cancer. vol. 137. 2015. pp. 2644-2663.

Borowitz, MJ, Wood, BL, Devidas, M. "Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232". Blood. vol. 126. 2015. pp. 964-971.

Curran, E, Stock, W. "How I treat acute lymphoblastic leukemia in older adolescents and young adults". Blood. vol. 125. 2015. pp. 3702-3710.

Essig, S, Li, Q, Chen, Y. "Risk of late effects of treatment in children newly diagnosed with standard-risk acute lymphoblastic leukaemia: a report from the Childhood Cancer Survivor Study cohort". Lancet Oncol. vol. 15. 2014. pp. 841-851.

Hoffman, LM, Gore, L. "Blinatumomab, a bi-specific anti-CD19/CD3 BiTE antibody for the treatment of acute lymphoblastic leukemia: perspectives and current pediatric applications". Frontiers in Oncology. vol. 4. 2014. pp. 1-5.

Hunger, SP, Mullighan, CG. "Acute lymphoblastic leukemia in children". NEJM. vol. 373. 2015. pp. 1541-1552.

Iyer, NS, Balsamo, LM, Bracken, MB. "Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis". Blood. vol. 126. 2015. pp. 346-353.

Lee, DW, Kochenderfer, JN, Stetler-Stevenson, M. "T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial". Lancet. vol. 385. 2015. pp. 517-528.

Maude, SL, Frey, N, Shaw, PA. "Chimeric antigen receptor T cells for sustained remissions in leukemia". NEJM. vol. 371. 2014. pp. 1507-1517.

Roberts, KG, Mullighan, CG. "Genomics in acute lymphoblastic leukaemia: insights and treatment implications". Nat Rev Clin Oncol. vol. 12. 2015. pp. 344-357.

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Gore, L, Hunger, SP, Carroll, WI, Finlay, JL. "Molecular oncology and translational therapy". Cancer in children and adolescents. Jones and Bartlett Publishers. 2010. pp. 23-32.

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Ongoing controversies regarding etiology, diagnosis, treatment

One of the major efforts in recent years has been to reduce the burden of toxicity of treatment for childhood ALL without compromising the current excellent outcomes. Evidence from clinical trials suggest that low-risk patients (those 1-10 years of age without hyperleukocytosis or frank CNS disease, with favorable cytogenetics, and with good initial response to therapy) can receive reductions in the dose frequency of cytotoxic chemotherapy without any adverse effect on survival.

Additional studies are examining whether or not the chronic complications induced by current therapy can be reduced or eliminated in at least a proportion of patients. The incidence of neuropathy increases with increasing age in patients treated for ALL. Very young children have an extremely low incidence, whereas the occurrence increases with each decade of life so that patients who are in their teens have a marked increase compared with children younger than 10 years and adults have a substantially higher risk than teenagers. One current research question is whether or not acute and/or chronic neuropathy can be reduced by decreasing the amount of vincristine that is used in maintenance therapy without compromising outcomes for patients with good prognosis.

Another great burden of treatment is the current high frequency of avascular necrosis and osteoporosis/osteopenia from high doses of corticosteroids that develops in higher percentages of teenagers and female patients. Altering both the schedule (continuous steroids versus discontinuous/alternating weeks of treatment) and the medication itself (prednisone versus dexamethasone) has been shown to potentially alter the incidence of osteopenia/osteoporosis and their consequences.

Newer work is studying the effects of bisphosphonates as both a preventive and therapeutic intervention. Randomized studies evaluating reduced vincristine use and altered steroid dose and schedule are designed to evaluate these questions more completely and will contribute importantly to the questions of reducing treatment burdens without compromising disease outcome.

Another burgeoning area of investigation is the use of immune-stimulating agents as adjuncts to therapy. In this context, ALL is at the forefront of research endeavors. Blinatumomab, which is a bi-specific (CD3/CD19) T cell engaging antibody that recruits cytotoxic T cells to CD19-expressing leukemia cells, has been shown to have good efficacy in cases of relapsed/refractory pre-B ALL.

Similarly, chimeric antigen receptor T cells (CAR-T) have had remarkable efficacy in some patients who have relapsed after multiple courses of chemotherapy and even post-bone marrow transplant. CAR-T cells are T cells harvested from the patient and genetically engineered in culture to express a chimeric T cell receptor. Binding of this receptor to a specific protein (in most cases, CD19) automatically leads to T cell activation and destruction of the cell which expresses that antigen. CD19 CAR-T cell treatment is currently reserved for pre-B ALL patients who have failed multiple lines of chemotherapy and in most cases is considered a bridge to bone marrow transplant.

Patients receiving this therapy must be closely monitored for acute toxicities, the most common of which is cytokine release syndrome (CRS). This is a transient immune activation syndrome whose symptoms closely resemble systemic inflammation or sepsis (hypotension, pulmonary edema and respiratory failure, high fevers, neurologic changes). If severe, it can be treated with anti-IL6 targeted agents or systemic corticosteroids. Long-term side effects include B cell aplasia due to on-target off-tumor destruction of normal CD19-expressing B cells, which requires long-term IVIg replacement. Relapses can occur post-CAR-T therapy, and are usually due either to short lifespan of the CAR-T cells in the patient or selection for CD19-negative leukemia cells.

With an ever-increasing number of individuals who survive childhood ALL, the challenges in the coming decades are to refine the treatment so that more survivors have fewer complications. Through the conduct of carefully constructed collaborative clinical trials, as well as the development of a better molecular understanding of disease, this is a realistic goal, and both patients and their families as well as physicians and scientists have great reason to be optimistic about the outcomes for these patients.

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