US Pharm. 2016;41(5)(Specialty & Oncology suppl):3-7.
ABSTRACT: Leukemia is the most common form of cancer affecting pediatric patients, and the majority of cases are diagnosed as acute lymphoblastic leukemia (ALL). This type of cancer, which occurs when the bone marrow makes too many immature lymphocytes, originates in the T and B lymphoblasts in the bone marrow. Great strides have been made in developing treatments for ALL, which was considered fatal almost 5 decades ago. Patients with ALL may present with symptoms that are initially nonspecific, such as fever, bruising, bone pain, and lymphadenopathy. The treatment of ALL requires a team approach involving collaborative efforts among members of the healthcare team. Pharmacists are in a pivotal position to ensure that patients with ALL will be provided efficacious treatment and supportive care to achieve optimal therapeutic results and increase incidence of remission.
According to the American Cancer Society, leukemia is the most prevalent form of cancer affecting the pediatric patient population, accounting for an estimated one out of three cases of cancer in children.1 The majority of pediatric leukemia cases are diagnosed as acute lymphoblastic leukemia (ALL), and this type of cancer represents approximately 25% of all cancer diagnoses among children <15 years of age.1-4
ALL, which occurs when the bone marrow makes too many immature lymphocytes, originates in the T and B lymphoblasts in the bone marrow.1 An estimated three out of four cases of leukemia among children and teens are diagnosed as ALL, with the remaining cases being acute myelogenous leukemia (AML).1 Annually in the United States, ALL accounts for an estimated 3,500 new cases of cancer in patients aged 1 to 19 years, with a peak incidence in early childhood between the ages of 2 and 5 years.5,6
Over the past 25 years, there has been a steady escalation in the overall incidence of pediatric ALL.2 The incidence of pediatric ALL appears to be greatest among Hispanic children in the U.S., who also have the lowest survival rates.2,6 In addition, the incidence is considerably greater in Caucasian children when compared to African-American children, with a nearly threefold higher incidence of ALL from ages 2 to 3 years.2-4,7 Although African-American children are least likely to develop ALL, they tend to experience more adverse effects associated with ALL therapy and fare much worse when compared to European Americans and Asian Americans.6
Almost 50 years ago, pediatric ALL was universally considered to be fatal; however, within the past few decades, there have been noteworthy advances in treatment.7 In the U.S., statistics reveal that long-term survival rates have been reported to be an estimated 85% to 90% with current therapy regimens.8-10
With improvements in diagnosis and treatment, overall cure rates for children with ALL continue to be encouraging. Improved cure rates have been chiefly attributed to the recognition of the critical importance of central nervous system (CNS)–directed anti-leukemia therapy, implementation of multiagent chemotherapy cycles with a prolonged maintenance phase, and improved supportive care measures.10,11 Furthermore, the use of risk-adapted treatment protocols has improved cure rates while limiting the risks of toxicity and adverse effects associated with therapy.11 Unfortunately, despite remarkable survival rates for the majority of pediatric patients diagnosed with ALL, relapse rates tend to occur in an estimated 15% to 20% of children and remain a substantial cause of morbidity and mortality in pediatric cancer.10,12
Research efforts have enabled health-care professionals to gain a deeper insight into pediatric ALL. Various epidemiologic studies have repeatedly documented racial and ethnic differences in the incidence and outcome of pediatric ALL, and a few cases are associated with inherited genetic syndromes. However, the underlying causes of ALL are still not fully understood.6 In ALL, a lymphoid progenitor cell becomes genetically transformed and consequently undergoes dysregulated proliferation, with clonal expansion.11 The transformed lymphoid cells reflect the altered expression of genes usually involved in the normal development of T and B cells.11 Several studies have also indicated that leukemic stem cells are present in certain types of pediatric ALL.11
Risk Factors for Developing ALL
Research has identified several factors that may increase one’s risk for developing ALL. The primary accepted risk factors for ALL can be found in TABLE 1.2,11,13,14
Signs and Symptoms of ALL
In many cases, the most frequently occurring symptoms associated with pediatric ALL are normally nonspecific and may include fever, bruising, bleeding, pallor, bone pain, and lymphadenopathy.15,16 Unexplained persistence of any of these common signs or symptoms should prompt healthcare providers to ascertain or rule out the presence of possible malignancy. At the time of diagnosis, leukemic infiltration of the liver, spleen, lymph nodes, and mediastinum is also very common. In addition, pediatric patients with ALL often present with signs and symptoms that reflect bone marrow infiltration and/or extramedullary disease. When leukemic blasts replace the bone marrow, patients may also present with signs of bone marrow failure, including anemia, thrombocytopenia, and neutropenia.15,16
Other presenting signs and symptoms of pediatric ALL are based on the particular subtype and may include the following signs and symptoms11:
- B-precursor ALL: Bone pain, arthritis, limping; fevers (low or high); neutropenia; fatigue, pallor, petechiae, and bleeding; lymphadenopathy and hepatosplenomegaly
- Mature B-cell ALL: Extramedullary masses in the abdomen or head/neck; CNS involvement (i.e., headache, vomiting, lethargy, nuchal rigidity)
- T-lineage ALL: Respiratory distress/stridor due to a mediastinal mass.
While symptoms suggestive of CNS involvement are infrequently noted at the time of the initial diagnosis, these symptoms are more common in T-lineage and mature B-cell ALL.11,17 Testicular involvement at the time of diagnosis is also rare; however, if present, it appears as unilateral painless testicular enlargement.11,17
An evaluation of a patient suspected of having pediatric ALL typically involves a thorough clinical examination, including blood work. Bone marrow aspiration and biopsy aid the clinician in diagnosing ALL and help ascertain the leukemia phenotype as well as the presence or absence of cytogenetic abnormalities.11,18
Prognosis for Pediatric ALL
Guidelines from the National Cancer Institute (NCI) for the management and treatment of pediatric ALL state that the likelihood of long-term cure in pediatric ALL is dependent upon clinical and laboratory features and the treatment options.2 Moreover, prognostic risk assessment typically includes clinical features such as age and white blood cell (WBC) value at time of diagnosis, biologic characteristics of the leukemic blasts, response to the induction chemotherapy, and minimal residual disease (MRD) burden, which is the value of leukemic cells that remain in the patient during treatment or after treatment when the patient is in remission.2,11 Factors that may affect the prognosis and selection of treatment options for pediatric ALL are listed in TABLE 2.2,11
Cases of pediatric ALL are typically classified according to two risk groups2:
1. Standard (low) risk: Includes children aged 1 to <10 years who have a WBC count of <50,000/mcL at diagnosis
2. High risk: Includes children >10 years and/or children who have a WBC count of >50,000/mcL at diagnosis.
The NCI provides healthcare professionals with comprehensive, peer-reviewed, evidence-based clinical information to inform and assist clinicians who treat patients with ALL. In addition, the American Academy of Pediatrics (AAP) has issued guidelines for cancer centers and healthcare providers that address their role in the treatment of pediatric cancer patients.2,19
Treatment of pediatric ALL typically involves chemo-therapy given over a duration of 2 to 3 years.2 Since myelosuppression and generalized immunosuppression are projected consequences of leukemia and chemotherapy treatment, it is imperative that patients be closely monitored throughout therapy.2 According to the NCI, the central treatment for children with ALL is the use of chemotherapy.2 Other therapy may include radiation and blood and marrow transplantation.2 In the past few decades, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL.20
Different forms of ALL require varying approaches for optimal results; however, ALL treatment typically consists of a remission-induction phase, intensification (consolidation) phase, and continuation therapy targeted at eliminating residual disease, with an overall duration of therapy of 2 to 3 years.2,11,21 Examples of the major drugs used during treatment phases include glucocorticoids (prednisone or dexamethasone), anthracyclines (e.g., doxorubicin or daunorubicin), vincristine, and L-asparaginase (L-ASP), which has been used for a long time in the treatment of pediatric ALL.2,11,21,22 Furthermore, CNS-directed therapy is critical for improved survival rates, and the addition of the use of cyclophosphamide and asparaginase is also beneficial in the treatment of T-cell ALL.2,11,21,22
Treatment guidelines state that ALL is treated with a combination of chemotherapy drugs over the course of several years, with an overall survival of approximately 80% to 85% for all newly diagnosed patients.2,23 Those patients with a higher risk of relapse obtain more aggressive treatment, while those with more favorable features can be spared the more toxic effects.2,23 Treatment is progressively less intensive as the duration of therapy progresses, and must include CNS-directed therapy regardless of involvement of the CNS at diagnosis.2 Multicenter, randomized clinical trials through international cooperative groups have assisted in efforts to promote and improve survival through the investigation of novel therapeutic approaches.2
Treatment of Newly Diagnosed ALL
The remission-induction phase is the first block of chemo-therapy, which typically lasts 4 to 6 weeks.2,11,23 During this phase, the child is generally admitted to the hospital for the initial treatment and workup, but once any complications have stabilized, the patient may be discharged before the completion of this phase with close follow-up on an outpatient basis.2,11,23 The goal of this phase of therapy is to induce a complete remission by the end of the phase, and studies reveal that an estimated 95% of ALL patients meet this goal.23 Of those who do not achieve complete remission by the end of the induction phase, an estimated 50% experience induction failure and the remainder succumbs to treatment-related mortality.2,11.23 For those with induction failure, an allogeneic bone marrow transplant is usually pursued, although there is no consensus standard of care regarding the chemotherapy used to achieve remission before transplant.23,24
The agents used during the induction phase include vincristine, corticosteroids, and asparaginase, with most regimens adding an anthracycline (generally doxorubicin or daunorubicin).2,11,23 Both anthracyclines have been shown to have similar efficacy and toxicity in randomized trials, and certain groups spare the addition of anthracyclines to those lower-risk groups in an effort to decrease toxicity.23,25 The corticosteroid used in therapy is typically prednisone or dexamethasone, with dexamethasone demonstrating improved CNS penetration and decreased risk of relapse, but with increased incidence of adverse effects such as avascular necrosis, infection, and reduction in linear growth.23,26
Several different agents for asparagine depletion exist as well, including polyethylene glycol (PEG)-asparaginase and Erwinia asparaginase.23 PEG-asparaginase has been modified by covalently attaching PEG to asparaginase, which has been demonstrated to result in a longer half-life and decreased immunogenicity in comparison with native Escherichia coli L-asparaginase.23 Randomized trials have also shown superior efficacy of the pegylated formulation.2,11,23,27 Erwinia asparaginase is usually given to those patients who have experienced an allergic reaction to PEG-asparaginase, and it requires a more frequent administration schedule.23
The remission-induction phase is followed by the consolidation phase. Its major goal is to eradicate the submicroscopic residual disease that remains after a complete remission is obtained.2,11,23 The phase typically lasts an estimated 6 to 9 months, but may vary in duration and intensity due to various protocols and the patient’s status, with those patients with higher-risk disease receiving longer and more intensive consolidation regimens.23,28 The consolidation phase is generally administered on an outpatient basis, although there are protocols with more aggressive regimens that require inpatient care.23 This phase of chemotherapy involves combinations of different chemotherapeutic agents to maximize synergy and minimize drug resistance, and it often utilizes medications not used in the initial remission induction, such as mercaptopurine, thioguanine, methotrexate, cyclophosphamide, etoposide, and cytarabine.2,11,23
The maintenance chemotherapy phase is the final and longest stage of treatment in pediatric ALL.2,11,23 This phase is considered to be a much less intensive regimen than the prior chemotherapy, and the prolonged maintenance phase has been proven to decrease the risk of relapse once remission has been established.23 This phase typically lasts at least 2 years (extended to 3 years for boys in some protocols), is administered on an outpatient basis, and classically is associated with fewer adverse effects.2,11,23 The foundation of maintenance therapy is the implementation of anti-metabolite therapy with methotrexate and mercaptopurine, both available in oral formulations, making strict adherence vital.23,29 Furthermore, emerging evidence regarding the pharmacogenomics of these drugs underscores the importance of differences in metabolism.23 Understanding these metabolic differences is particularly important because studies have shown that the degree of myelosuppression correlates with relapse risk.23,30-32 Consequently, many protocols include guidelines for dose adjustments to assist in achieving the goal of balancing the risks of inadequate myelosuppression with the risks of severe pancytopenia, which may result in infection, bleeding, and other complications.23 Some regimens also incorporate the use of monthly vincristine and corticosteroids, although the evidence for additional benefit is uncertain.23,33
Therapy Directed Against the CNS
Another part of pediatric ALL treatment is therapy directed against the CNS. This stage of therapy involves both treatment of patients with clinical CNS disease at diagnosis and prophylaxis for patients with subclinical disease.2,23 Its significance was clearly demonstrated before the 1970s, when this type of treatment did not exist.23 Although bone marrow remission can be achieved using systemic chemotherapy, the majority of pediatric patients eventually experience relapse in the absence of specific therapy directed toward this sanctuary site.23,34 Sanctuary sites are defined as anatomical spaces that are poorly penetrated by many of the systemically administered chemotherapy agents typically used to treat ALL.2 The two most essential sanctuary sites in childhood ALL are the CNS and the testes.2
Treatment that may be implemented to achieve the goal of eradication of disease from the CNS may include direct intrathecal administration of chemotherapy, systemic administration of chemotherapy able to penetrate the blood-brain barrier, and cranial radiation.2,23 All treatment plans include the use of intrathecal administration of chemotherapy beginning during the remission-induction phase, and some protocols include intrathecal treatment throughout therapy, whereas others do not include it in the maintenance phase.2,23 Options for intrathecal chemotherapy include intrathecal methotrexate or a combination of intrathecal methotrexate, cytarabine, and hydrocortisone, which is known as triple intrathecal therapy.2,23 Studies have shown no conclusive variance in overall or event-free survival between the two protocols, although some evidence points to decreased frequency of CNS relapse with the use of triple intrathecal therapy.2,23 Systemically administered chemotherapy with CNS effects typically consists of dexamethasone, high-dose methotrexate, cytarabine, and asparaginase.2,23
Treatment of Relapsed ALL
Despite significant advances in treatment, an estimated 15% to 20% of patients with pediatric ALL experience relapsed disease, which is considered to be the most common cause of treatment failure.23 Intensive therapy may include the use of hematopoietic stem cell transplantation (HSCT), and the overall survival from relapsed ALL is estimated to be at 40%.23,35,36 Patients with relapsed disease can be categorized according to risk; the length of first complete remission and site of relapse have progressively shown that these are the two most critical prognostic factors in these cases.23
Adverse Effects Associated With Therapy
Patients should be monitored throughout therapy because some children with ALL may experience substantial adverse effects during induction chemotherapy. Toxicity may result from the use of chemotherapeutic agents or from the rapid elimination of a large tumor burden.37 Life-threatening adverse effects of induction therapy include tumor lysis syndrome, thrombosis, bleeding, and infection. Other acute adverse effects include mucositis, pancreatitis, and hyperglycemia.37 In addition, patients may experience cardiomyopathy as well as neuropathy, and ALL patients are at risk of a deficiency of growth hormone and associated metabolic disorders.38
According to the NCI, there are a host of clinical trials being conducted to learn more about pediatric ALL and its possible causes and optimal treatment protocols.2 These trials are usually available for children with ALL, with specific protocols designed for children at standard or higher risk of treatment failure.2 Clinical trials for children with ALL are generally designed to compare therapy that is currently accepted as standard for a particular risk group with a potentially better treatment approach that may improve survival outcome and/or diminish toxicities associated with the standard treatment regimen.2 Advances in various therapies have resulted in major enhancements in survival since ALL was first treated decades ago, and many of these advancements in treating ALL clearly demonstrated the critical nature of clinical trials via cooperative multicenter groups.23
Remarkable progress has been made in the treatment of pediatric ALL. Pharmacists can be instrumental in the management and treatment of pediatric ALL by making clinical interventions when warranted and educating patients and their caregivers on the various treatment options available for ALL. Pharmacists can also inform patients about the numerous patient education resources that are available (TABLE 3). The treatment of ALL requires a team approach involving collaborative efforts among various healthcare providers to ensure that patients will obtain efficacious treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life. Optimal use of existing antileukemic agents and improved supportive care in clinical trials have enriched the 5-year survival rate of pediatric ALL above an estimated 85% in developed countries.39,40 Further advances in survival and quality of life will require an improved understanding of the pathobiology of pediatric ALL as well as the expansion and development of novel pharmacologic agents to combat this disease.39
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37. Horton TM, Steuber CP. Overview of the treatment of acute lymphoblastic leukemia in children and adolescents. UpToDate. www.uptodate.com/contents/overview-of-the-treatment-of-acute-lymphoblastic-leukemia-in-children-and-adolescents. Accessed March 31, 2016.
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40. Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia from 1990-2005: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(14):1663-1669.
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