Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

111. Acute Leukemias

Betsy Bickert Poon and Amy Hatfield Seung


KEY CONCEPTS

 Images Acute leukemias are the most common malignancies in children and the leading cause of cancer-related death in patients younger than age 35 years.

 Images To establish a definitive diagnosis of acute leukemia, the following diagnostic components are required: bone marrow biopsy and aspirate (with >20% blasts), cytogenetics, and immunophenotyping.

 Images Several risk factors correlate with prognosis for acute lymphoblastic leukemia (ALL). Poor prognostic factors include high white blood cell count at presentation, very young or very old age at diagnosis, delayed remission induction and presence of certain cytogenetic abnormalities (e.g., Philadelphia chromosome positive [Ph+]).

 Images For children with ALL, remission induction therapy includes vincristine, a corticosteroid, and asparaginase, with or without an anthracycline. For adults with ALL, vincristine, prednisone, and an anthracycline are given, and asparaginase is sometimes added.

 Images All patients with ALL require prophylactic therapy to prevent CNS disease because of the high risk of central nervous system relapse. The choice for therapy includes a combination of the following: cranial irradiation, intrathecal chemotherapy, or high-dose systemic chemotherapy with drugs that cross the blood–brain barrier.

 Images Long-term maintenance therapy for 2 to 3 years is essential to eradicate residual leukemia cells and prolong the duration of remission. Maintenance therapy consists of oral methotrexate and mercaptopurine, with or without monthly pulses of vincristine and a corticosteroid.

 Images Disease-free survival is lower in adults with ALL and has been attributed to greater drug resistance, poor side effect tolerance with subsequent nonadherence, and possibly less-effective therapy. This population is also more likely to have Ph+ ALL, which is associated with a worse outcome, but the use of tyrosine kinase inhibitors has improved treatment results.

 Images There are several poor prognostic factors for adult acute myeloid leukemia (AML): older age, organ impairment, presence of extramedullary disease, and presence of certain cytogenetic and molecular abnormalities.

 Images Therapy of AML usually includes induction therapy with an anthracycline and cytarabine. Postremission therapy is required in all patients and can include either consolidation chemotherapy with or without maintenance therapy, or hematopoietic stem cell transplantation.

 Images It is estimated that up to 108 to 109 malignant cells remain following attainment of a complete remission. Postremission therapy with either chemotherapy or hematopoietic stem cell transplantation is essential in AML.

 Images Treatment of acute promyelocytic leukemia consists of induction therapy, followed by consolidation and maintenance therapy. Induction includes tretinoin and an anthracycline; consolidation therapy consists of two to three cycles of anthracycline-based therapy; maintenance consists of pulse doses of tretinoin, mercaptopurine, and methotrexate for 2 years.

 Images Hematopoietic growth factors can be safely and effectively used with myelosuppressive chemotherapy for acute leukemias. The benefits may include reduced incidence of serious infections, reduced hospital stays, and fewer treatment delays, but do not include prolonged disease-free survival or overall survival.


The leukemias are heterogeneous hematologic malignancies characterized by unregulated proliferation of the blood-forming cells in the bone marrow. These immature proliferating leukemia cells (blasts) physically “crowd out” or inhibit normal cellular maturation in bone marrow, resulting in anemia, neutropenia, and thrombocytopenia. Leukemic blasts may also infiltrate a variety of tissues such as lymph nodes, skin, liver, spleen, kidney, testes, and the central nervous system.

Historically, leukemia has been classified based on the cell of origin and cell line maturation, and as acute or chronic based on differences in clinical presentation, rapidity of progression of the untreated disease, and response to therapy. The four major leukemias are acute lymphoblastic (or lymphocytic) leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia, and chronic myeloid leukemia. Undifferentiated immature cells that proliferate autonomously characterize acute leukemias. Chronic leukemias also proliferate autonomously, but the cells are more differentiated and mature. Untreated, acute leukemia is fatal within weeks to months.

EPIDEMIOLOGY

It is estimated that 20,660 new cases of acute leukemia—14,590 cases of AML and 6,070 cases of ALL—will be diagnosed in the United States in 2013, accounting for 1.2% of the total cancer incidence.1The incidence has been relatively stable for two decades. An estimated 11,800 deaths per year, representing about 2% of all cancer deaths, are caused by acute leukemias.1 Images Leukemia is the leading cause of cancer-related deaths in persons younger than age 20 years, but an uncommon cause of cancer-related death after age 40 years.1 Among adults, acute and chronic leukemias occur at equal rates. More than 90% of the cases of acute and chronic leukemia occur in adults. AML accounts for most cases of acute leukemia in adults, and occurs with increasing frequency in elderly patients. There are about 3.6 cases of AML and 1.4 cases of ALL per 100,000 individuals.2 The median age at diagnosis of patients with AML is about 67 years, whereas the peak age for ALL patients is 2 to 3 years.1,2 The incidence of AML increases with age from 1.8 per 100,000 in individuals younger than age 65 years to 16 per 100,000 in those 65 years or older.2,3 Acute leukemia is about 30% more common in males than in females. In the United States, acute leukemia is more common among whites than among African Americans, American Indians, and Hispanic ethnicities.2

Despite the low incidence, the acute leukemias are the most common malignancy in persons younger than 20 years of age, accounting for 26% of all childhood malignancies.2 About 80% of children with leukemia have ALL and 15% AML.2 Childhood ALL is about 30% more common in males than in females, peaks at 2 to 4 years of age, and is almost twice as likely to affect white children as African American children.2 The incidence of childhood AML is highest in the Hispanic population and occurs throughout childhood without any peak age period. Acute leukemia during the first year of life (infant leukemia) slightly favors ALL over AML.2,4

Chemotherapy has dramatically improved the outlook of patients with acute leukemia. More than 85% of children and young adults with acute leukemia achieve an initial complete remission (CR) of their disease. Overall, 65% to 85% of adults achieve an initial CR.3 For persons younger than 19 years of age, the 5-year survival rate is nearly 90% for ALL and 70% for AML.2,5 The prognosis of adult acute leukemia is generally worse than that of childhood leukemia, with only 30% to 40% of patients becoming long-term survivors. When all ages are included, the 5-year relative survival rate in 2008 for ALL was 66% and 25% for AML.2

ETIOLOGY

The exact cause of the acute leukemias is unknown. A multifactorial process involving genetics, environmental and socioeconomic factors, toxins, immunologic status, and viral exposures is likely. Table 111-1 summarizes the major factors that have been linked to acute leukemias. Infectious and genetic factors have the strongest associations to date.6 In pediatric ALL, a number of environmental factors are inconsistently linked to the disease: exposure to ionizing radiation, toxic chemicals, herbicides and pesticides; maternal use of contraceptives, diethylstilbestrol, or cigarettes; parental exposure to drugs (amphetamines, diet pills, and mind-altering medications), diagnostic radiographs, alcohol consumption, or chemicals before and during pregnancy; and chemical contamination of groundwater.7,8 A growing body of evidence indicates that high birthweight is a risk for ALL.6,9 Ionizing radiation and benzene exposure are the only environmental risk factors strongly associated with ALL or AML.8 A few studies have reported a possible link between electromagnetic fields of high-voltage power lines and the development of leukemia, but larger studies could not confirm this association. In most patients who develop leukemia, a cause cannot be identified.

TABLE 111-1 Risk Factors for Acute Leukemia

Images

Childhood AML is associated with Hispanic ethnicity, prior exposure to alkylating agents or epipodophyllotoxins, and in utero exposure to ionizing radiation.8 Maternal alcohol consumption, parental and child organophosphate pesticide exposure, and parental benzene exposure are also associated with childhood AML. AML has been associated with both low and high birth weight.9 Adult AML has been associated with prior anthracycline exposure in addition to prior exposure to alkylating agents or epipodophyllotoxins.

PATHOPHYSIOLOGY

A basic understanding of normal hematopoiesis is needed before one can understand the pathogenesis of leukemia. eChapter 20 has a detailed discussion of hematopoiesis. Normal hematopoiesis consists of multiple well-orchestrated steps of cellular development. A pool of pluripotent stem cells undergoes differentiation, proliferation, and maturation, to form the mature blood cells seen in the peripheral circulation. These pluripotent stem cells initially differentiate to form two distinct stem cell pools. The myeloid stem cell gives rise to six types of blood cells (erythrocytes, platelets, monocytes, basophils, neutrophils, and eosinophils). Lymphoid stem cells differentiate to form natural killer cells, B lymphocytes, and T lymphocytes. Leukemia may develop at any stage and within any cell line.

Two features are common to both AML and ALL: First, both arise from a single leukemic cell that expands and acquires additional mutations, culminating in a monoclonal population of leukemia cells. Second, there is a failure to maintain a relative balance between proliferation and differentiation, so that the cells do not differentiate past a particular stage of hematopoiesis. Cells (lymphoblasts or myeloblasts) then proliferate uncontrollably. Proliferation, differentiation, and apoptosis are under genetic control, and leukemia can occur when the balance between these processes is altered.

AML probably arises from a defect in the pluripotent stem cell or a more committed myeloid precursor, resulting in partial differentiation and proliferation of immature precursors of the myeloid blood-forming cells. In older patients, trilineage leukemia occurs suggesting that the cell of origin is probably a stem or very early progenitor cell. In younger patients, a more differentiated progenitor becomes malignant, allowing maturation of some granulocytic and erythroid populations. These two forms of AML exhibit different patterns of resistance to chemotherapy, with resistance more evident in the older adults with AML. ALL is a disease characterized by proliferation of immature lymphoblasts. In this type of acute leukemia, the defect is probably at the level of the lymphopoietic stem cell or a very early lymphoid precursor.

Leukemic cells have growth and/or survival advantages over normal cells, leading to a “crowding out” phenomenon in the bone marrow. This growth advantage is not caused by more rapid proliferation as compared with normal cells. Some studies suggest that it is caused by factors produced by leukemic cells that either inhibit normal cellular proliferation and differentiation, or reduce apoptosis as compared with normal blood cells.

The types of genetic alterations that lead to leukemia have only recently become evident. The genetic defects may include (a) activation of a normally suppressed gene (protooncogene) to create an oncogene that produces a protein product that signals increased proliferation; (b) loss of signals for the blood cell to differentiate; (c) loss of tumor suppressor genes that control normal proliferation; and (d) loss of signals for apoptosis. Most normal cells are programmed to die eventually through apoptosis, but the appropriate programmed signal is often interrupted in cancer cells, leading to continued survival, replication, and drug resistance. Signal transduction, RNA transcription, cell-cycle control factors, cell differentiation, and programmed cell death may all be affected.

LEUKEMIA CLASSIFICATION

In 2001, the World Health Organization (WHO), in collaboration with the Society for Hematopathology and the European Association of Haematopathology, proposed a new classification system for myeloid neoplasms. This new classification system incorporates not only morphologic findings, but also genetic, immunophenotypic, cytochemical, and clinical features. About 40% to 50% of adult patients with AML have no detectable chromosomal abnormality on standard cytogenetic analysis, but the percent increases with age.10 The WHO classification attempts to formally incorporate the relationship between AML and myelodysplastic syndrome (MDS). In 2008, this classification was revised (Table 111-2) and is being used routinely for children and adults.11 The WHO classification defines acute leukemias as more than 19% blasts in the marrow or blood.

TABLE 111-2 World Health Organization Classification of Acute Myeloid Leukemia

Images

Lymphoblast analysis is used to classify ALL. Immunophenotype is determined by flow cytometry that analyzes specific antigens, known as clusters of differentiation (often abbreviated “CD”), present on the surface of hematopoietic cells. Although no leukemia-specific antigens have been identified, the pattern of cell-surface antigen expression reliably distinguishes between lymphoid and myeloid leukemia. The immunophenotype defines the cell of origin. The major phenotypes are mature B-cell, precursor B-cell, and T-cell disease; however, the WHO classifies ALL as either B lymphoblastic or T lymphoblastic. About 80% of childhood ALL derives from precursor B cells and about 15% from T cells; the remainder is either mixed lineage or from mature B cells. T-cell ALL is more common in teenage males.

Leukemias may also be described by cytogenetic abnormalities. Chromosome alterations include numerical (hyperdiploidy and hypodiploidy), and structural abnormalities due to exchanges of genetic information within (inversion) or between (translocation) chromosomes. Unique translocations can identify specific subtypes of acute leukemia. Twenty-five percent of children with precursor B-cell ALL have the ETV6-RUNX1 (formerly TEL-AML1) fusion gene generated by the t(12;21) (p13;q22) chromosomal translocation.6,12 This translocation appears to endow the preleukemia cell with altered self-renewal and survival properties. The most common translocation in adult ALL, occurring in 25% of patients, is the t(9;22) or Philadelphia chromosome positive (Ph+), which causes fusion of the BCR signaling protein to the ABL nonreceptor tyrosine kinase, resulting in constitutive tyrosine kinase activity. More than 50% of childhood T-cell ALL have activating mutations of the NOTCH1 gene that encodes for a transmembrane receptor implicated in regulation of T cell development.6,12 Acute promyelocytic leukemia (APL) is characterized by a specific translocation between chromosomes 15 and 17: t(15;17). Molecular tests may be used to identify products of specific translocations, such as promyelocytic leukemia (PML) retinoic acid receptor-α (RARα) in APL and AML1-ETO and CBFβ/MYH 11 in other subtypes of AML.

A number of factors may affect the cytogenetics of AML in adults. First, in about 5% of patients, simultaneous blood and marrow samples demonstrate normal cytogenetics versus abnormal cytogenetics, respectively.10 Second, central cytogenetic analysis is done in multicenter trials because of variability in specimen examination. A small number of patients may have a normal karyotype on standard review, but carry fusion genes, which are identical to those of translocations or inversions. These insertions of very small chromosome segments do not alter chromosome morphology but may affect outcome.

CLINICAL PRESENTATION AND DIAGNOSIS

Common signs and symptoms at presentation result from malignant cells that replace and suppress normal hematopoietic progenitor cells and infiltrate into extramedullary spaces. Many of the signs and symptoms result from low blood cells. Thrombocytopenia can result in bruising, petechiae, and bleeding; low red blood cells can result in fatigue and loss of energy; and low white blood cells can result in signs and symptoms of infection such as fever, chills, and rigors. Patients with ALL may rarely present with small blue-green collections of leukemia cells under the skin called chloromas.

Images In addition to clinical presentation, laboratory and pathology evaluations are required for a definitive diagnosis of leukemia. An abnormal complete blood count is usually the diagnostic test that initiates a leukemia workup. The most important test is a bone marrow biopsy and aspirate, which is submitted to hematopathology for numerous evaluations. A lumbar puncture is performed to determine if there are blasts in the central nervous system (CNS). A chest radiograph is performed to screen for a mediastinal mass (most common in T-cell disease).


CLINICAL PRESENTATION

General

    • Recent history of vague symptoms such as tiredness, lack of exercise tolerance, weight loss, and “feeling unwell,” but in no obvious distress.

Signs and Symptoms

    • Common: Patients with anemia present with pallor, malaise, palpitations, and fatigue. Patients with low platelet counts present with bruising, ecchymoses, and petechiae. Temperature is often elevated and may be caused by disease or infection. Patients may have bone pain from a hyperactive bone marrow.

    • Other possible symptoms include epistaxis, dyspnea on exertion, seizures, or headache. Splenomegaly, hepatomegaly, and/or lymphadenopathy are common in patients presenting with acute lymphoblastic leukemia (ALL), but may also have painless testicular enlargement and rarely, small, blue-green collections of leukemia cells under the skin (chloromas). Patients with acute myeloid leukemia (AML) may present with gum hypertrophy and bleeding.

Laboratory Tests

    • Complete blood count with differential. Anemia (43% <7 g/dL [4.34 mmol/L]) is normochromic and normocytic (without a compensatory increase in reticulocytes). Thrombocytopenia (severe, <20,000 cells/mm3 [20 × 109/L]) is present in 28% of ALL and 50% of AML cases. Patients can present with leukopenia or leukocytosis; about 20% of patients will present with a white blood cell (WBC) count ≥50,000 cells/mm3 (50 × 109/L) and 53% of ALL and 20% of AML cases with a WBC <10,000 cells/mm3 (10 × 109/L). Even patients with elevated counts can be considered functionally neutropenic.

    • Uric acid may be elevated because of rapid cellular turnover and is more common in patients presenting with elevated WBC count and with ALL.

    • Electrolytes: potassium and phosphate may be elevated with a compensatory decrease in calcium, more common with ALL.

    • Coagulation (more common with AML): elevated prothrombin time, partial thromboplastin time, D-dimers; hypofibrinogenemia.

Other Diagnostic Tests

    • Bone marrow aspirate and biopsy: send for morphologic examination, cytochemical staining, immunophenotyping, and cytogenetic (chromosome) analysis. Molecular testing for FMS-like tyrosine kinase 3 (FLT3), nucleophosmin (NPM1), and CCAAT/enhancer binding-protein α (CEBPA) mutations is warranted for suspected AML.

    • All children and adults with ALL should have a screening lumbar puncture performed to assess CNS involvement.

ACUTE LYMPHOBLASTIC LEUKEMIA

Risk Classification

Many clinical and biologic features at diagnosis are associated with response to treatment, as measured by the CR rate, duration of remission, and long-term survival. The patient’s response to initial therapy is also strongly associated with response to treatment. Identification of these risk factors allows the clinician to better understand the disease and to tailor treatment according to risk of disease recurrence (i.e., risk-adapted therapy). For example, if a patient has many clinical and laboratory features that are associated with a good response to chemotherapy (“standard risk”), then the clinician may choose to give less-intensive therapy to reduce the risk of long-term adverse effects. Conversely, if a patient is unlikely to respond well to standard therapy (high-risk or very-high-risk disease), then the clinician may choose to give more intensive chemotherapy. The factors can be grouped as follows: patient characteristics at diagnosis, leukemic cell features at diagnosis, and patient response to initial therapy.

Patient Characteristics

Images The National Cancer Institute (NCI) developed an ALL risk stratification to create a standard for comparison in children.13 Induction therapy is initially selected based on this classification, which divides children into standard- or high-risk categories based on age and initial white blood cell (WBC) count (Table 111-3a). Age remains an independent predictor of outcome with children aged 1 to 9 years having the best event-free survival (EFS). This is mostly explained by the more frequent occurrence of the ETV6-RUNX1 translocation and hyperdiploidy (>51 chromosomes) in addition to increased drug sensitivity in this age group.14 Presence of CNS disease at diagnosis is associated with a higher relapse rate. About 2% of males have testicular disease at diagnosis, but cooperative groups vary in whether this is an adverse prognostic factor. Patients with Down syndrome tend to have lower EFS, but this is mostly attributed to higher treatment-related morbidity and mortality.

TABLE 111-3a National Cancer Institute (NCI) Risk Classification (Smith 1996)

Images

Race is controversial, with older studies indicating worse outcomes for minorities. Male race and obesity have been associated with worse outcome in cooperative group studies, but not single-institution studies.6Hepatosplenomegaly and mediastinal mass are both associated with worse outcomes.

Leukemic Cell Characteristics

With current therapy, the cell of origin no longer has a prognostic significance as therapy is tailored to account for this historical difference. Several chromosomal (cytogenetic) abnormalities are associated with prognosis. Children with ALL have an average of six DNA copy number alterations.12 Favorable outcomes are associated with three copies of chromosomes 4 and 10, high hyperdiploidy (51-65 chromosomes), and the ETV6-RUNX1 cryptic translocation, t(12;21).12 NOTCH1 and FBXW7 mutations confer a favorable prognosis for patients with T-cell disease.12 The Philadelphia chromosome is present in 3% to 5% of children and 25% of adults and is historically associated with a poor prognosis.15 The mixed lineage leukemia (MLL) gene rearrangement (11q23), intrachromosomal amplification of chromosome 21 (iAMLP21), and hypodiploidy (<44 chromosomes) are associated with a poorer prognosis.16

Initial Response to Therapy

The strongest prognostic factor for outcome for ALL is response to therapy. Both the rapidity of response and the level of residual disease at the end of induction therapy are associated with long-term outcome. Children with a reduction of bone marrow lymphoblasts within 14 days of initiating chemotherapy (rapid early responders) have a more favorable prognosis. Molecular measurement of sub-clinical minimal residual disease (MRD) by either flow cytometry or polymerase chain reaction has enabled detection of leukemic cells not visible on morphologic examination to assess treatment response and detect relapse in children and adults.17 This technique allows detection of 1 leukemia cell in 10,000 normal cells, which is about 100-fold more sensitive than morphologic examination.17 If MRD is detected at the end of induction therapy, the clinician may decide to give more intensive therapy to decrease the risk of relapse.

The Children’s Oncology Group uses a risk- and response-based classification of childhood ALL (Fig. 111-1).18 This classification system uses the NCI risk assignment to initially categorize patients into standard- or high-risk groups (Table 111-3a). Following induction therapy, risk is reclassified based on the rapidity and completeness of response to therapy, the presence or absence of cytogenetic abnormalities or CNS involvement (Table 111-3b). Patients are then reclassified as low risk, standard risk, high risk, or very-high risk (Fig. 111-1). Patients who are initially high risk do not have therapy reduced, but may have it intensified to very-high risk as discussed below.

Images

FIGURE 111-1 Pediatric precursor B-cell acute lymphoblastic leukemia risk classification. (NCI, National Cancer Institute.)

TABLE 111-3b Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia Risk Classification

Images

Children are classified as low risk and will have therapy reduced if they have trisomy 4 and 10 or the ETV6-RUNX1 cryptic translocation with less than 0.01% MRD on day 8 peripheral blood and day 29 bone marrow samples. Children with testicular disease, >5% blasts in the bone marrow by day 15, MRD ≥0.01% at day 29, or who received steroids prior to diagnosis have postinduction therapy intensified and are classified as high risk. Childhood precursor B-ALL with more than five WBCs and blasts present in the cerebrospinal fluid (CSF), Ph+ disease, hypodiploidy, iAMLP21, induction failure, or MLL gene rearrangement have therapy intensified and are considered very-high risk. Infant ALL, trisomy 21, or childhood T-cell ALL have unique risk classification schemas. Children with T-cell leukemia historically have an inferior response to standard-risk therapy and are automatically categorized as high risk to receive augmented therapy and T cell targeted therapy. T-cell and mature B-cell disease are favorable phenotypes in adults.6 Age is inversely associated with prognosis in patients with Ph+ ALL.6

TREATMENT

Acute Lymphoblastic Leukemia

Desired Outcomes

The short-term goal for ALL treatment is to rapidly achieve a complete clinical and hematologic remission. A CR is defined as the disappearance of all physical and bone marrow evidence (normal cellularity with <5% blasts) of leukemia, with restoration of normal hematopoiesis. After a CR is achieved, the goal is to maintain the patient in continuous CR. In general, a child is considered to be “cured” after being in continuous CR for 5 to 10 years.

Successful treatment of ALL was first developed in children. Current regimens induce clinical remission in 96% to 99% of children with ALL.6 MRD is a strong predictor of relapse in ALL. Children with MRD in the bone marrow at the end of induction have a 5-year EFS of 59% versus 88% in children without.19 Children with low-risk disease have a 5-year EFS of more than 95%.21 The 5-year EFS for average-risk disease is 90 to 95%.21 The 5-year EFS is nearly 90% for high-risk childhood B-precursor and T-cell ALL including rapid and slow responders. Children with very-high-risk disease have a 5-year EFS of less than 80%.21 Response to treatment is determined by intrinsic drug sensitivity and the patient’s pharmacogenomics and pharmacodynamics, treatment received, and treatment adherence. Cure rates in children have risen from less than 5% with treatments used in the 1960s to about 90% by 2005.22 The reason for this improvement lies largely in improved scheduling of existing drugs, as relatively few new drugs have come to the market since the 1960s.

Although treatment results with adult ALL are worse than those with childhood ALL, recent use of aggressive chemotherapy in adult ALL has increased the CR rate from 60% to 85%. Long-term EFS in this population, however, remains low (between 30% and 40%) because a higher proportion of adults present with poor-risk disease. CR rates and EFS vary according to a number of poor prognostic factors and certain types of ALL are associated with a very poor outcome.

Treatment Phases

Therapy for childhood ALL is divided into five phases: (a) induction, (b) consolidation therapy, (c) interim maintenance, (d) delayed intensification, and (e) maintenance therapy (Fig. 111-2). CNS prophylaxis is a mandatory component of ALL treatment regimens and is administered longitudinally during all phases of treatment. The total duration of treatment is 2 to 3 years.

Images

FIGURE 111-2 Treatment algorithm for (A) acute lymphoblastic leukemia and (B) acute myeloid leukemia.

Induction

The goal of induction is to rapidly induce a complete clinical and hematologic remission. Images The CR rate is 98% for standard-risk children treated with vincristine, a glucocorticoid (dexamethasone or prednisone), and asparaginase or pegaspargase.22 Most treatment protocols add daunorubicin to induction (four-drug induction) for high-risk or very-high-risk ALL, while others add cyclophosphamide, methotrexate, or cytarabine. Most children achieve a CR in 4 weeks, which classifies them as rapid early responders. Those who have a M2 (5% to 25% blasts) or M3 (>25% blasts) marrow on day 15 of induction or have positive MRD at day 29 are classified as slow early responders and receive intensified therapy. Only 2% to 3% of children fail induction therapy, but the therapy results in a 10-year survival rate of 32%.23

Prednisone has historically been the primary glucocorticoid used in pediatric ALL regimens.24 Dexamethasone is now being used in most standard-risk protocols because of its longer duration of action and higher CSF penetration compared to prednisone.6,22,24 When dexamethasone is used in place of prednisone, absolute EFS improves by 5% to 9% and the risk of CNS relapse decreases by 2% to 4%.14,24,25However, dexamethasone increases the risk of side effects such as osteonecrosis, mood alteration, steroid myopathy, hyperglycemia, and infections.2426 Patients older than 10 years of age are particularly prone to osteonecrosis and receive prednisone instead of dexamethasone to minimize this side effect. Low serum albumin prolongs dexamethasone exposure and may contribute to increased toxicity.14 Since patients with Down’s syndrome have increased infections and mortality with dexamethasone, these patients receive prednisone.


Clinical Controversy…

Which corticosteroid is superior for the treatment of ALL? Prednisone or prednisolone have been the steroids of choice for many years. Dexamethasone was recently shown to have better CNS penetration than prednisone with a consequent decrease in CNS relapse rate. However, the incidence of debilitating side effects, such as osteonecrosis, is higher with dexamethasone. Many investigators have difficulty weighing the quality-of-life decrease from the side effects against the small increase in survival.

The incidence of transient hyperglycemia during pediatric ALL induction therapy has increased. In a recent study, 20% of children had transient hyperglycemia, defined as at least two random serum glucose levels greater than or equal to 200 mg/dL (11.1 mmol/L).27 The incidence was higher (42%) in children older than 10 years of age. The risk was higher for patients with a body mass index (BMI) greater than or equal to the 95th percentile and those receiving asparaginase as compared to pegaspargase.

Asparaginase has historically been available in three forms. Asparaginase (no longer manufactured in the United States) and pegaspargase are isolated from Escherichia coli while Erwinia asparaginase is isolated from Erwinia chrysanthemi. A recombinant E. coli asparaginase and a pegylated form of recombinant Erwinia asparaginase are currently in clinical trials. Pegaspargase is pegylated E. coliasparaginase; pegylation prolongs its duration of activity and allows it to be given less frequently. Pegaspargase is used in most protocols and is preferred over asparaginase because of fewer intramuscular injections, decreased antibody formation, and superior response rates. Pegaspargase is also approved for IV administration. The use of prolonged intensive asparaginase treatment compared with shorter treatment increases absolute EFS by 4% to 17%.28

Asparaginase products are the chemotherapeutic agents most likely to cause hypersensitivity reactions. Depending on the product and coadministered steroid, 8% to 42% of patients develop antibodies to asparaginase. Reactions usually occur during postinduction phases of therapy when asparaginase has not been given for a prolonged period of time.28 The reaction is delayed with pegaspargase and usually occurs 6 to 12 hours following a dose. The hypersensitivity reaction to pegaspargase may also be prolonged and frequently requires hospitalization for 5 to 7 days. Erwinia asparaginase is currently only used for patients who are allergic to other available forms. Patients may also have “silent hypersensitivity” in which they develop neutralizing antibodies that can rapidly inactivate the asparaginase, but the patient does not have a clinical hypersensitivity reaction. Therefore, many centers prefer switching from E. coli derived products to Erwinia asparaginase to avoid this scenario.

Central Nervous System Prophylaxis

CNS prophylaxis is incorporated throughout all phases of therapy. The rationale for CNS prophylaxis is based on two observations. First, many chemotherapeutic agents do not readily cross the blood–brain barrier. Second, results from early clinical trials of ALL showed that 50% to 85% of patients with ALL and no CNS involvement at diagnosis experienced a CNS relapse.7 These observations indicate that the CNS is a potential sanctuary for leukemic cells and undetectable leukemic cells are present in the CNS in many patients at the time of diagnosis. Detectable CNS involvement at the time of diagnosis occurs in 3% of children with ALL.14 Factors that are associated with an increased risk of CNS involvement at diagnosis in children include a high initial WBC count, T-cell phenotype, mature B-cell phenotype, age ≤1 year, African American race, thrombocytopenia, lymphadenopathy, and hepatomegaly or splenomegaly.22

The goal of CNS prophylaxis is to eradicate undetectable leukemic cells from the CNS while minimizing neurotoxicity and late effects. Leukemic meningitis is more easily prevented than treated. Once CNS relapse has occurred, patients are at increased risk of bone marrow relapse and death from refractory leukemia. Initial trials of childhood ALL in the 1960s established craniospinal irradiation as the standard for prevention of CNS relapse.22 However, this approach is associated with long-term sequelae including neuropsychological deficits, precocious puberty, osteoporosis, decreased intellect, thyroid dysfunction, brain tumors, short stature, and obesity. Subsequent trials have demonstrated that irradiation may be replaced by frequent administration of intrathecal chemotherapy in children with ALL.22 Some centers may treat children with CNS disease at diagnosis or very-high-risk disease with cranial radiation.

Images The CNS prophylaxis regimen is selected based on efficacy, toxicity, and risk of CNS disease. Intrathecal chemotherapy, cranial irradiation, dexamethasone, and high-dose IV methotrexate or cytarabine can be used to treat or prevent CNS disease. Current treatment approaches have reduced isolated CNS relapses to less than 5% among children.29 Risk factors for CNS relapse include male sex, hepatomegaly, T-cell phenotype, CNS2 disease (the presence of leukemic blasts in a CSF sample that contains <5 WBC/mm3), age younger than 2 years or older than 6 years, and a bloody diagnostic lumbar puncture.6,29Intrathecal therapy consists of methotrexate and cytarabine, given either alone or in combination. When given together, hydrocortisone is commonly added (triple intrathecal therapy) to decrease the incidence of arachnoiditis. For standard-risk ALL, triple intrathecal therapy decreased relative CNS relapse rates by 30% in comparison to intrathecal methotrexate and no effect on EFS and worse overall survival (OS).29 Triple intrathecal therapy is typically reserved for children with refractory CNS disease. The doses of intrathecal chemotherapy used for childhood ALL are age-based because of differences in the volume of CSF at various ages. For example, intrathecal methotrexate is dosed as 8 mg if <2 years, 10 mg for 2 to 2.99 years, 12 mg for 3 to 8.99 years, and 15 mg for ≥9 years. Liposomal cytarabine induces CNS remission in 57% of relapsed patients, but is associated with a high incidence of arachnoiditis and other CNS-related adverse effects.30 Currently its use is limited to refractory or relapsed CNS disease in children.

Patients with T-cell leukemia have an increased incidence of CNS disease and usually receive systemic therapy that penetrates the CNS such as high-dose methotrexate.26 A WBC count greater than 100,000 cells/mm3 (100 × 109/L) is associated with an increased risk of CNS relapse.6 Patients with T-cell disease have lower methotrexate polyglutamate accumulation and addition of high-dose methotrexate in these patients results in fewer CNS relapses and improves EFS.14

Consolidation Therapy

Consolidation therapy in ALL is started after a CR has been achieved, and refers to continued intensive chemotherapy in an attempt to eradicate clinically undetectable disease in order to secure (consolidate) the remission. Regimens usually incorporate either non–cross-resistant drugs that are different from the induction regimen, or more dose-intensive use of the same drugs.

Randomized trials show that consolidation therapy clearly improves patient outcome in children, but its benefit in adults is less clear.22 The relative benefit of individual components of treatment regimens is difficult to demonstrate because of the overall complexity of therapy in ALL. Standard consolidation lasts 4 weeks and usually consists of vincristine, mercaptopurine, and intrathecal methotrexate. Children with testicular disease usually receive radiation during this phase of therapy if a complete clinical response in the testes is not achieved by the end of induction. In children, the intensity of consolidation therapy is based on the child’s initial risk classification and response to induction therapy. Patients who respond slowly to induction therapy are at higher risk of relapse if they are not treated on more aggressive regimens. Children who are slow early responders or have high-risk disease benefit from intensified consolidation that includes the addition of vincristine and pegaspargase to standard therapy (cyclophosphamide, low-dose cytarabine, mercaptopurine).20

Children with Ph+ ALL, infants with MLL, or children who only achieve a partial remission may undergo allogeneic hematopoietic stem cell transplantation (HSCT) in first remission if a suitable donor is available. Nelarabine is a prodrug of ara-G that preferentially accumulates in T lymphoblasts as ara-guanosine triphosphate (GTP). Children and young adults in first bone marrow relapse had a 55% complete or partial response in the phase II trial.30Nelarabine added to a high-risk backbone for initial therapy of childhood T-cell ALL in Children’s Oncology Group (COG) AALL00P2 was well tolerated and had a 5-year EFS of 69% in slow early responders compared to 35% to 51% in historical controls.31

Reinduction (Delayed Intensification and Interim Maintenance)

One or two delayed intensification phases separated by low-intensity interim maintenance cycles can be added to maintain remission and to decrease cumulative toxicity. Delayed intensification usually consists of drugs used during induction and consolidation or agents that lack cross-resistance with those already received such as cyclophosphamide, methotrexate, and limited amounts of doxorubicin. The methotrexate dose is variable; standard-risk children generally receive 1 to 2 g/m2 while those with T-cell disease generally receive 5 g/m2. Interim maintenance usually consists of dexamethasone, vincristine, weekly methotrexate, mercaptopurine, and intrathecal methotrexate. Delayed intensification improves EFS for standard-risk children.14,20 Delayed intensification with dose intensification improved EFS and decreased late relapses for high-risk childhood ALL, but there was no additional benefit for two delayed intensification cycles.20 Children on the intensified arms of the study received significantly more antimicrobial drugs, blood products, and parenteral nutrition but had no increase in treatment-related mortality.20 The antimetabolite-based regimens may have a reduced risk of late toxicities, but the more intensive regimens appear to result in better survival for some patients, especially those with higher risk disease.

Maintenance Therapy

Images Maintenance therapy allows long-term drug exposure to slowly dividing cells, allows the immune system time to eradicate leukemia cells, and promotes apoptosis (programmed cell death). The goal of maintenance therapy is to further eradicate residual leukemic cells and prolong remission duration. Although maintenance therapy is clearly beneficial in childhood ALL, the benefit in adults has only recently been demonstrated.

Maintenance therapy usually consists of daily mercaptopurine and weekly methotrexate for 12-week courses, at doses that produce relatively little myelosuppression, with monthly “pulses” of vincristine and a steroid for 5 days per month. Based on the results of studies that show a trend toward an increase in late relapse (excluding isolated testicular relapse) among male children treated for 2 years versus 3 years, some centers treat female children for 2 years while males receive maintenance for a total of 3 years of therapy.

Interpatient variability in the pharmacokinetics of oral methotrexate and mercaptopurine may also be an important determinant of the effectiveness and toxicity of maintenance therapy. Patients who take oral methotrexate and mercaptopurine on an evening versus a morning schedule appear to have a superior outcome. Mercaptopurine cannot be given with milk or milk products because of the presence of xanthine oxidase. Children whose adherence rate taking mercaptopurine is less than 95% have a 2.5-fold higher risk of suffering a relapse.32 Factors associated with nonadherence include single-parent household, adolescence, lower socioeconomic status, and Hispanic ethnicity.32To account for the interpatient variability, most clinicians will titrate the dose of either agent to maintain an absolute neutrophil count of 500 to 1,500 cells/mm3 (0.5 to 1.5 × 109/L).6 Some protocols overcome bioavailability and poor adherence issues by administering methotrexate IV or intramuscularly. The importance of these pharmacokinetic issues in adults is not well defined.

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Ph+ ALL has a 45% 7-year EFS and has historically been treated as very-high-risk disease.15 This includes a four-drug induction. The addition of continuous imatinib mesylate, a signal transduction inhibitor that inhibits BCR-ABLkinase, through all phases of treatment resulted in a 3-year EFS of 80% in comparison to 35% for historical controls.33 The results for patients receiving chemotherapy with imatinib were equivalent to those receiving HSCT. Imatinib is currently incorporated into childhood treatment trials for Ph+ ALL in Europe and the United States. Trials are ongoing with the more potent tyrosine kinase inhibitors, nilotinib and dasatinib. Imatinib has been incorporated into consolidation for children with Ph+ disease.

Acute Lymphoblastic Leukemia in Infants

ALL and AML in infants younger than 1 year of age account for less than 5% of the reported acute leukemias in childhood, but they are associated with poor outcomes. OS in infant ALL is 30% to 50%.34About 70 to 80% of infants with acute leukemia have t(4;11) involving the MLL gene.34 MLL gene rearrangements are associated with worse outcome, with only 18% to 34% 4- to 8-year EFS.34 Infants with ALL are more likely to present with a high WBC count, hepatosplenomegaly, and CNS disease.34 Age younger than 6 months at diagnosis and poor response to prednisone alone given prior to starting other agents are poor prognostic indicators.34 Infants with MLL gene rearrangements are more likely to overexpress FLT3, a tyrosine kinase implicated in leukemogenesis. Current trials are testing the efficacy of FLT3 inhibitors in infants with MLL gene rearrangements. Patients with infant ALL may have greater drug resistance to asparaginase, vincristine, and corticosteroids, but increased sensitivity to cytarabine and cladribine.34 Although intensive regimens such as high-dose methotrexate and high-dose cytarabine have improved survival rates they resulted in unacceptably high mortality rates. Lack of pharmacokinetic data for chemotherapy in infants has contributed to toxicity from inappropriate dosing of doxorubicin and vincristine. The use of allogeneic HSCT for infants with ALL remains controversial because of a lack of donors, concerns over the long-term toxicity of total body irradiation, and excessive mortality in some series. The Interfant-99 study showed a benefit for HSCT in a subset of infants with MLL gene rearrangement, age younger than 6 months of age, or WBC greater than 300,000 cells/mm3 (300 × 109/L).35

Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Although ALL is relatively uncommon in adolescents and young adults (AYA) (15 to 39 years AYA), the outcomes are generally worse than for childhood ALL. ALL in AYA has a higher frequency of T-cell immunophenotype and a lower frequency of the t(12;21) (p13;q22) cryptic translocation responsible for hyperdiploidy and the ETV6-RUNX1 fusion gene; about 5% to 7% of ALL in AYA have Ph+ disease (higher than children, but lower than older adults).12,36 A retrospective comparison of 16- to 20-year-old patients treated on pediatric versus adult protocols in the United States resulted in identical CR rates, but the 7-year EFS favored the patients treated on pediatric regimens (64% vs. 34%).36 Patients treated on the pediatric regimens also had a 10% lower CNS relapse rate. The adult regimens studied were more myelosuppressive, while the pediatric regimens intensified steroids and asparaginase and included earlier and more intensive CNS-directed therapy. The adult regimens also had a higher risk of late effects due to higher doses of daunorubicin and use of cyclophosphamide. A current adult intergroup study is using a pediatric regimen for AYA patients and will be able to evaluate some of the other potential reasons for the outcome disparity, such as adherence and psychosocial differences. AYA patients may receive treatment based on an adult or pediatric regimen depending on institutional preferences, but the trend is shifting toward pediatric regimens.37

Acute Lymphoblastic Leukemia in Adults

Treatment risk stratification for adult patients differs depending on age and Philadelphia chromosome status. The National Comprehensive Cancer Network (NCCN) guidelines recommend different strategies for adolescents and young adults (AYA) ages 15 to 39, adults 40 to 65, and adults older than 65 years with or without poor performance status.37 While complete remission is achieved in 70% to 90% of adults with a four-drug induction regimen containing daunorubicin or doxorubicin, vincristine, an asparaginase formulation, and prednisone, long-term EFS is considerably lower and achieved in only 30% to 40% of patients.38 Images Poorer outcomes in adults have been attributed to differences in cytogenetic abnormalities, greater drug resistance, higher risk of treatment-related adverse effects with subsequent nonadherence, and possibly less effective therapy. The value of adding more agents to the basic four-drug induction regimen or higher doses of drugs in the remission induction regimen is not clear. Several different regimens are considered appropriate to use as first-line therapies in adults including the Cancer and Leukemia Group B (CALGB) 8811 (Larson regimen), Eastern Cooperative Oncology Group (ECOG) 2993, or Linker regimen.3941 Some studies suggest that high-dose methotrexate and cytarabine alternating with fractionated cyclophosphamide plus vincristine, doxorubicin, and dexamethasone (hyperCVAD) may improve response and survival in adults with ALL.42 A considerable number of ALL cases occur in patients older than age 65 years, and treatment of this group of patients is an even greater challenge. The response to therapy and durability of response is less than in all other populations. Treatment-related mortality rates during remission induction therapy are also higher in this population.

While the overall incidence of Ph+ positive disease is 25% in adults, the incidence rises with increasing age to over 40% in adults older than the age of 50 years.43 Traditionally, treatment outcomes for patients with Ph+ ALL has been extremely poor with reported OS rates of less than 20% and for those continuing to allogeneic HSCT a 2-year OS of 40% to 50%. As compared with historical control patients treated with standard chemotherapy alone, the addition of BCR-ABL tyrosine kinase therapy to chemotherapy was associated with an increased CR and OS.44,45 No randomized trials have compared imatinib and conventional chemotherapy versus conventional chemotherapy alone. The CR rates seen with tyrosine kinase inhibitors appear to be more durable and allow more patients with Ph+ disease to proceed to allogeneic HSCT. This approach also appears to be tolerated in elderly patients.46,47 For patients older than 65 years of age or for those with a poor performance status, induction regimens may include concurrent chemotherapy with a tyrosine kinase inhibitor, either alone or combined with corticosteroids. Based on these data, the combination of imatinib with concurrent chemotherapy is currently considered as the standard of care for first-line therapy.

Dasatinib has also been studied in combination with concurrent chemotherapy as first-line therapy with demonstrated efficacy.48 Other newer BCR-ABL tyrosine kinase inhibitors, nilotinib, bosutinib, and ponatinib, have also been evaluated in patients with imatinib-resistant Ph+ leukemias. Responses can be achieved, but more data are needed to evaluate their specific role in the treatment of Ph+ ALL.4951 A primary concern with the tyrosine kinase inhibitors is the emergence of resistance, specifically T315I mutations. Ponatinib is the only BCR-ABL tyrosine kinase inhibitor available in the United States with known activity against T315I mutations.52 The use of the BCR-ABLtyrosine kinase inhibitors other than imatinib for first-line therapy is not well established.

In adults with B-cell ALL, about 50% have leukemic cells that express CD20. CD20 expression has been associated with decreased CR rates and OS.53 A phase II study has evaluated hyperCVAD and rituximab versus hyperCVAD alone and reported a higher CR rate (70% vs. 38%) and longer OS (75% vs. 47%) in patients treated with hyperCVAD and rituximab.54 These results are encouraging and support the use of rituximab in patients who have cells that express CD20.

HSCT plays an important role in the treatment of adult patients with ALL. For patients with Ph+ ALL who have a CR after induction therapy, consolidation with allogeneic HSCT should be considered if a human leukocyte antigen (HLA)-matched sibling or matched unrelated donor is available. After HSCT, patients should continue with standard maintenance therapy that includes a tyrosine kinase inhibitor. For patients with Philadelphia chromosome negative (Ph) disease who have MRD after induction therapy or have high-risk features for relapse, allogeneic HSCT should be considered if a matched donor is available.55

Relapsed Acute Lymphoblastic Leukemia

About 20% of children with ALL will relapse.56 The most common site for relapse is the bone marrow (53%), although isolated relapses can occur in the CNS (19%) or testicles (5%), in addition to multiple sites of disease.57Because marrow relapse usually follows isolated CNS or testicular relapses, patients with isolated extramedullary relapses are treated with localized radiation (cranial or testicular) and aggressive systemic chemotherapy similar to that given to patients with a marrow relapse.58

Children who fail to achieve a CR by day 29 of initial remission induction therapy usually receive an additional 2 weeks of four-drug induction therapy. If the children do not achieve a CR with the additional therapy, they are usually treated for bone marrow relapse consisting of intensive induction therapy consisting of at least three cycles of chemotherapy. Examples of regimens include vincristine, pegaspargase, corticosteroid, and doxorubicin; etoposide, cyclophosphamide, and high-dose methotrexate; and high-dose cytarabine and asparaginase.

Patients who have completed treatment and have stayed in remission for longer periods are more likely to be reinduced into remission again. Patients with more favorable risk factors initially, and those who received less intensive initial treatments, are more likely to respond well to reinduction/salvage regimens. The second CR rate is 78% in children who were in continuous complete remission for less than 18 months, 78% if the duration of remission was 18 to 36 months, and 93% if the duration of remission was more than 36 months.56 Three-year OS following bone marrow (28%), CNS (60%), and testicular (60%) relapse is not optimal.58 Overall, 5-year disease-free survival rates are 27% for second complete remission (CR2) and 15% for third complete remission (CR3).56 Clofarabine, a purine antimetabolite, is an option for patients on second or later relapses, but the duration of response is less than 6 months. Current trials are evaluating the place for clofarabine in combination with other agents.

Allogeneic HSCT has traditionally been the treatment of choice for early bone marrow relapse (continuous CR less than 36 months) while children who relapse more than 36 months after completion of initial therapy have traditionally received chemotherapy alone.22 Some more recent analyses have shown HSCT to be an advantage to all relapsed children, while some have not shown a benefit.56 Therefore, the question of who would benefit from HSCT continues to be investigated.

Most patients with relapsed or refractory disease are considered for an allogeneic HSCT with a matched sibling or unrelated donor if they achieve a CR2 following salvage chemotherapy. Most elderly patients are not candidates for standard allogeneic HSCT but are candidates for nonmyeloablative transplant (NMT). Patients who undergo a NMT receive a reduced intensity conditioning regimen. A NMT may produce similar outcomes with less treatment-related morbidity and mortality. The National Marrow Donor Program and the American Society for Blood and Marrow Transplantation have developed guidelines for transplant consultation based on current clinical practice and evidence-based medicine.55,59

For relapsed or refractory disease in Ph+ patients, leukemic cells should be tested for mutations to guide selection of the tyrosine kinase inhibitor. In addition, nelarabine may be an option for adults with relapsed or refractory T-cell disease.

Late Effects of Treatment

Certain late effects associated with cranial or craniospinal irradiation and corticosteroids were discussed earlier. The Childhood Cancer Survivor Study tracks the health status of adults treated for childhood cancer between 1970 and 1986 and has yielded invaluable information on how to monitor adult survivors.60 Leukemia survivors are 3.7 times more likely to develop a severe or life-threatening chronic health condition as compared with healthy siblings, and 2.8 times more likely to report multiple chronic conditions.60

Older ALL regimens that incorporated intensive use of topoisomerase II inhibitors (etoposide and teniposide) are associated with unacceptably high risks of development of secondary leukemia.22 High cumulative doses of anthracyclines used in high-risk or relapsed patients can cause cardiomyopathy. Cranial irradiation is also associated with learning deficits, especially in patients younger than 5 years of age at the time of treatment. Patients who received cranial radiation as children also have higher unemployment rates and lower marital rates among females two decades after diagnosis.60 The Children’s Oncology Group has developed long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers (www.survivorshipguidelines.org).

ACUTE MYELOID LEUKEMIA

Risk Classification

Many clinical and laboratory features at diagnosis are associated with response to treatment, as measured by the CR rate, duration of remission, and long-term survival. Identification of these risk factors may allow the clinician to better understand the disease and to tailor treatment according to risk of disease recurrence. For example, if a patient has many clinical and laboratory features that are associated with a good response to chemotherapy (“good risk”), then the clinician may choose to give less intensive therapy to reduce the risk of long-term toxic effects. Conversely, if a patient is unlikely to respond well to therapy (“high risk”), then the clinician may choose to give more intensive chemotherapy that may include HSCT.

Several prognostic factors have been identified for adults with AML. Images The most important patient factor is age, with younger patients more likely to achieve a CR than patients older than age 60 years.3,61The lower CR rate in older patients results from an increased frequency of fatal infection and bleeding complications and resistance to conventional chemotherapy. The duration of remission is also shorter in older patients as compared to younger patients. Other patient-specific prognostic factors include concurrent infection and any major organ impairment.3 Patients with extramedullary disease, CNS involvement, or underlying MDS have a worse prognosis. Other unfavorable prognostic factors in adult AML include: age older than 60 years, multidrug-resistance gene expression, WBC >100,000 cells/mm3(100 × 109/L), and therapy-related AML.62 Age must be evaluated as a continuous variable when looking at prognostic factors. The clinical difference between a patient 61 years old and one 71 years old, is much greater than a 59-year-old and a 61-year-old. Certain cytogenetic abnormalities are also known to worsen the response rate and survival of patients with AML (Table 111-4).3,63 Chromosome 16 or translocations between chromosome 8 and 21 alter core-binding factor. Core-binding factor is associated with sensitivity to cytarabine.64 In addition, patients who develop a “secondary” leukemia after treatment of another malignancy usually have a very poor response to antileukemic chemotherapy (i.e., therapy-related AML). Another factor that needs consideration for any cancer treatment is performance status. A bedridden patient with a new diagnosis of AML would not be a good candidate for treatment because of high treatment-related morbidity and mortality. Patients with poor performance status may be offered supportive care.

TABLE 111-4 Risk Category According to Cytogenetic and Molecular Abnormalities Present

Images

Cytogenetics may be the most important prognostic factor for a patient newly diagnosed with AML.65 Molecular testing for FLT3-ITD, CEBPA, C-KIT, and NPM1 is becoming more common in commercial laboratories and referral centers, and should be considered for all newly diagnosed AML patients.66 Patients with core-binding factor with t(8;21) (q22;q22) or inv(16) (p13q22)/t(16;16)(p13;q22) treated with a cytarabine-based regimen have a relatively favorable prognosis. Adults and children with chromosomal deletions such as 3q[abn(3q)] or 5q[del(5q)], monosomies of chromosome 5 and/or 7(-5/-7) have a poor prognosis with standard chemotherapy for AML, and may benefit from experimental treatments. The limitations to karyotype as a risk stratification tool include failed cytogenetic analysis and presence of cryptic chromosomal rearrangements. About 40% of cases have a normal karyotype. Molecular mutations, such as FLT3, NPM1 (nucleophosmin), C-KIT, and CEBPA (CCAAT/enhancer-binding protein α), can identify subsets of patients with differing outcome who have normal karyotypes. FLT3 is a receptor tyrosine kinase that is mutated in about one-third of patients with AML, including those with normal karyotype, and is associated with higher presenting WBC, decreased duration of CR, and a poorer prognosis. NPM1 is present in about 30% of patients with AML, even in patients with normal karyotype, and commonly coexists with FLT3, and is associated with a higher CR and reduced relapse risk compared to patients without the mutation. C-KIT mutations have been observed in about 20% of patients with core-binding factor AML and are associated with decreased duration of CR and OS.67 CEBPA is present in about 10% of patients with AML, and is associated with a favorable outcome. The area of cytogenetic and molecular abnormalities is complex and still evolving.

Prognostic factors associated with pediatric AML include response to the first course of remission induction therapy, cytogenetics, and molecular genetics. Poor prognostic factors include monosomy 7, age older than 10 years, black race, internal tandem duplications of FLT3, MLL gene rearrangements, and a diagnosis of AML secondary to prior chemotherapy or radiation therapy.5 Conversely, inversion of chromosome 16, trisomy 21, CBF-AML, PML-RARANPM1, biallelic CEBPA, and RUNX1-RUNX1T1 fusion transcript t(8;21) are associated with a favorable outcome.5,10

AML treatment in the future may be based on cytogenetic and molecular classification. Treatment algorithms based on these newer classifications have been proposed, but they are not currently incorporated into the initial remission induction therapy. These tests do provide prognostic information that may be incorporated into subsequent treatment decisions.10

TREATMENT

Acute Myeloid Leukemia

Desired Outcomes

The short-term goal of treatment for AML is to rapidly achieve a complete clinical and hematologic remission. In the absence of a CR, a rapid and fatal outcome is inevitable. CR is defined as the disappearance of all clinical and bone marrow evidence (normal cellularity >20% with <5% blasts) of leukemia, with restoration of normal hematopoiesis (neutrophils ≥1,000 cells/mm3 [1 × 109/L] and platelets >100,000 cells/mm3 [100 × 109/L]).68 Partial remission is a significant response to treatment (a decrease of at least 50% of blasts), but evidence of residual disease in the bone marrow remains (5% to 25% blasts) and is considered a treatment failure requiring additional therapy. The definition of response for adult AML was reevaluated in 2003, and changes in the definition of response were proposed to include not only CR (morphologic CR with restoration of normal hematopoiesis), but also CR with complete remission with incomplete hematological recovery (CRi), cytogenetic CR ([CRc] patient with normal cytogenetics in which cytogenetics were previously abnormal), and molecular CR ([CRm] molecular studies negative).68 If there is a question of residual leukemia on bone marrow biopsy in adults, a bone marrow aspirate/biopsy should be repeated in one week.

After a CR is achieved, the goal is to maintain the patient in continuous CR. As discussed later, the occurrence of leukemic relapse in the bone marrow significantly reduces the likelihood of cure. Most patients who will die from acute leukemia die within the first 6 years; the survival curve (percentage alive versus time) beyond the sixth year after therapy does not continue to decline as rapidly (“survival plateau”), and at this time patients can be considered “cured.”

With recent advances in chemotherapy and supportive care, 65% to 85% of all patients with AML achieve a CR, and 20% to 40% become long-term survivors.3 Overall, the median duration of remission is 1 to 2 years. In patients 60 years of age or older, the CR rate is lower (39% to 64%), and the median duration of remission is shorter than one year.69 In contrast to ALL, effective therapies used in AML cause severe and often prolonged myelosuppression. As a result, patients with AML, particularly patients older than 60 years of age, are at greater risk for treatment-related fatal infectious and bleeding complications.

The 5-year survival in children with AML has increased from 17% in 1976 to 50% in 2005.26,70 Children with Down’s syndrome and AML receive less intensive therapy and have a 83% EFS.26,70 Treatment of childhood AML, unlike that of ALL, usually consists only of induction and intensive postremission therapy (Fig. 111-2). CNS prophylaxis and maintenance therapy are not routinely given to patients with AML.

Treatment Phases

Remission Induction

As with ALL, the goal of remission induction for AML is to rapidly induce a CR with associated restoration of normal hematopoiesis. Compared to ALL, however, fewer patients with AML achieve CR. Because the CR rate in AML is related to the intensity of the remission induction regimen, the drugs used in AML are given at doses that uniformly cause severe myelosuppression (except tretinoin). One reason for the lower CR rate in AML as compared to ALL is the inability to give optimal doses of chemotherapy because of marrow toxicity. With continued improvement of supportive care for patients undergoing chemotherapy, more intensive treatment regimens are being given in an effort to reduce the high rate of leukemic relapse and increase the proportion of long-term survivors. Most patients achieve a CR after 1 or 2 courses of chemotherapy. Patients who require additional chemotherapy to achieve a CR have been reported to have a poor prognosis, even if remission is ultimately achieved.

Images The most active single agents in AML are the anthracycline antibiotics (daunorubicin, doxorubicin, and idarubicin), mitoxantrone, and the antimetabolite cytarabine. The standard therapy for the treatment of adult AML has not changed in several decades. The most common regimen (“7+3”) combines daunorubicin administered as a short infusion of 45 to 60 mg/m2 per day on days 1 to 3, along with cytarabine administered as a continuous 24-hour infusion of 100 to 200 mg/m2 per day on days 1 to 7.3,71,72 The CR rate with the 7+3 regimen is 65% to 75% in patients 18 to 60 years old. Several trials have attempted to improve on conventional 7+3 therapy, but have shown no improvement by (a) increasing cytarabine to 10 days, (b) shortening cytarabine to 5 days, (c) substituting doxorubicin for daunorubicin, (d) adding thioguanine, or (e) increasing cytarabine dosage to 200 mg/m2 per day (given by continuous infusion).3 The most recent change to the standard 7+3 regimen is to increase the daunorubicin dose. Adults younger than 60 years old with AML who were randomized to receive higher daunorubicin dosages (90 mg/m2per day on days 1 to 3) in combination with 7 days of standard-dose cytarabine (100 mg/m2 per day) had a significantly higher CR rate (71% vs. 57%) and longer overall median survival (23.7 vs. 15.7 months) as compared with those who received the standard 7+3 regimen of daunorubicin (45 mg/m2 per day on days 1 to 3) and cytarabine.73

Idarubicin or mitoxantrone has been evaluated as alternatives to daunorubicin in combination with standard-dose continuous infusion cytarabine. Trials in younger patients reported improved CR rates with these newer anthracyclines (idarubicin) or anthracenediones (mitoxantrone), and one trial reported prolonged survival. Among older adults, the CR rate and OS do not appear to be different among the different anthracyclines or anthracenediones.62,72 Therefore, the anthracycline of choice for the standard 7+3 regimen remains controversial, with many centers adopting idarubicin into the induction regimen in younger AML patients, and the choice in the elderly is based on individual clinician preference and institutional acquisition costs.


Clinical Controversy…

Is there a superior anthracycline to use as part of the induction regimen for acute myeloid leukemia (AML)? Some clinicians believe that idarubicin is superior in attaining a complete remission following one cycle of induction compared to alternative anthracyclines or anthracenediones. Randomized trials in the elderly show similar remission rates with all anthracyclines and anthracenediones. However, randomized trials in younger patients reported higher complete remission (CR) rates with idarubicin or mitoxantrone.

Other strategies that have been evaluated include adding another agent such as etoposide to the induction regimen.3,71,72 A comparison of the standard 7+3 regimen with or without etoposide on days 1 to 7 (“7+3+7”) in newly diagnosed AML patients ages 15 to 70 years showed no difference in CR rates or OS. A subset analysis of patients younger than 55 years of age showed a twofold increase in the duration of remission and OS in the etoposide-containing arm. The 7+3+7 regimen was more toxic in patients older than 55 years of age. These results have been confirmed in other studies, but this regimen has not been adopted as standard therapy in the United States.

Based on experimental tumor models that showed a steep dose–response curve for cytarabine, higher cytarabine doses have also been evaluated as a means to increase the antileukemic activity of remission induction therapy. Several groups, including the Southwest Oncology Group and the Australian Leukemia Study Group, have evaluated the impact of adding high-dose cytarabine to induction therapy. This strategy does not improve the CR rate or OS, but does improve EFS. A retrospective study conducted by the European Group for Blood and Marrow Transplantation demonstrated that the cytarabine dose administered during induction and/or consolidation did not influence the outcome in patients who ultimately went on to receive allogeneic or autologous HSCT.74 These data suggest that high doses of cytarabine during induction may not be needed in patients who receive HSCT as postremission therapy. In summary, the role of high-dose cytarabine during induction remains controversial. If used during induction, high-dose cytarabine is more appropriate in younger patients than in elderly patients because of poor tolerance by elderly patients. Additionally, it may be an option in patients unable to tolerate anthracyclines.

NCCN has published guidelines for the treatment of AML.59,66 The classic 7+3 regimen may be inadequate in adults younger than 60 years of age because the duration of remission is less than that reported in some studies that employed high-dose cytarabine in induction. The NCCN guideline recommends that adults younger than 60 years of age without an antecedent hematologic disorder (i.e., no preexisting hematologic malignancy such as MDS) be treated with either the 7+3 regimen or more aggressive chemotherapy including high-dose cytarabine with an anthracycline or anthracenedione. In patients 60 years of age or older with good performance status, the conventional 7+3 regimen should be used or the patient should be enrolled in a clinical trial. The approach in patients with an antecedent hematologic disorder differs, and younger patients (<60 years) should be offered available clinical trials or proceed to allogeneic HSCT (provided a suitable donor is available).

Older patients (≥60 years) with an antecedent hematologic disorder or those with significant comorbidities unrelated to leukemia should be offered a low-intensity therapy with a hypomethylating agent such as azacitidine or decitabine, a clinical trial or best supportive care because of the dismal outcomes and toxicity risks associated with conventional chemotherapy. Azacitidine and decitabine are pyrimidine nucleoside analogs of cytidine that inhibit DNA methylation. While each agent has shown promising results versus conventional chemotherapy and best supportive care, the agents have not been compared to each other in trials. Azacitidine is usually given 75 mg/m2/dose IV or subcutaneously for 7 days while decitabine is given 20 mg/m2/dose IV for 5 days. Cycles are repeated about every 28 days. A minimum of 4 to 6 cycles of therapy must be given before evaluation of response. Azacitidine has resulted in OS rates of 50% as compared to 16% in those treated with usual care (chemotherapy, low-dose cytarabine, or best supportive care).75,76 These agents are generally well-tolerated with the most significant adverse effect being myelosuppression. Best supportive care includes use of blood product transfusion support.

All adult patients who present with CNS symptoms, and all patients who present with asymptomatic monocytic disease, should have a diagnostic lumbar puncture, and if it is positive, should be treated for disease. Methotrexate 12 to 15 mg, with or without cytarabine, should be administered intrathecally twice a week until clearance of leukemic blasts from the CSF, and then weekly for 4 to 6 weeks. Continued secondary prophylaxis is recommended following treatment for CNS disease.

Intensive Postremission Therapy

Although most adults with AML achieve a CR, the duration of remission is short (6 to 9 months) if no further treatment is given. Relapse is presumably a consequence of the presence of residual, but clinically undetectable, leukemic cells after remission induction therapy. The goal of intensive postremission therapy is to eradicate these residual leukemic cells and to prevent the emergence of drug-resistant disease. Images The need for postremission therapy is based on postmortem analysis and cell kinetic data suggesting that nearly 109 residual leukemic cells remain after effective remission induction therapy. Strategies evaluated as postremission therapy include (a) low-dose, prolonged maintenance therapy, (b) short-course intensive chemotherapy-alone regimens, and (c) high-dose chemotherapy with or without radiation therapy followed by allogeneic or autologous HSCT.

Chemotherapy In the treatment of AML, intensive postremission therapy is often referred to as consolidation therapy. Results of randomized controlled trials in adults clearly show that intensive postremission therapy following remission induction therapy prolongs survival versus no therapy, although the exact duration of postremission therapy is controversial.3,71,72,77,78

The intensity of postremission therapy is important. In a large CALGB trial, all patients who achieve a CR after standard 7+3 induction, were randomized to receive one of three cytarabine-based consolidation regimens: 100 mg/m2 per day or 400 mg/m2 per day as a continuous 24-hour infusion, or 3,000 mg/m2 every 12 hours on days 1, 3, and 5.79 For adults younger than age 60 years, the probability of remaining in CR after 4 years was significantly higher in patients who received high-dose cytarabine (25% vs. 29% vs. 44%, respectively).79 Elderly patients had lower response rates in all arms and did not benefit from the administration of higher cytarabine doses, probably because they were unable to tolerate the high-dose regimen. Dose-limiting neurotoxicity in the high-dose arm was more common in elderly patients and those patients with impaired kidney function.79

It is not clear whether the same agents (cytarabine and an anthracycline) given for remission induction should be used for postremission therapy in higher doses, or whether different agents should be given. If leukemic relapse is caused by a resistant cell line, then the use of different agents that are non–cross-resistant with drugs used in induction might be beneficial.

High-dose cytarabine appears to be an important component of postremission therapy, particularly if it is not used in induction therapy. However, many questions remain, such as the optimal dose (g/m2), number of doses per cycle, and number of cycles of high-dose cytarabine. Among patients with core-binding factor AML, defined as the presence of either t(8;21) or inv(16), it is clear that multiple cycles are beneficial, generally 3 to 4 cycles.80 The NCCN guideline recommends four cycles of high-dose cytarabine for adults younger than 60 years of age and with good cytogenetics or, alternatively, one cycle of high-dose cytarabine followed by autologous HSCT.66 Patients with intermediate-risk cytogenetics should receive 3 to 4 cycles of high-dose cytarabine, one to two cycles of high-dose cytarabine followed by autologous HSCT, or proceed directly to a matched allogeneic HSCT.66 If a patient is 60 years of age or older, standard-dose cytarabine with or without anthracycline for one to two cycles, a reduced-dose high-dose cytarabine regimen (1 to 1.5 g/m2 per day for 4 to 6 doses) for one to two cycles, continuation of low-intensity therapy such as azacitidine or decitabine, or enrollment in a clinical trial is recommended. Patients with high-risk cytogenetics, underlying MDS, or secondary AML should either be enrolled in a clinical trial or be referred for either a matched sibling or alternative donor allogeneic HSCT.66


Clinical Controversy…

Intensive postremission therapy is clearly necessary to prevent relapse and those regimens containing high-dose cytarabine appear to be a key part of postremission therapy. However, the optimal dose of high-dose cytarabine, the number of doses per cycle, and the number of cycles to give remain unknown.

Allogeneic Hematopoietic Stem Cell Transplantation Allogeneic HSCT represents the most aggressive postremission therapy in the management of AML. Much controversy surrounds this treatment approach, specifically the appropriateness, timing, treatment design, and donor selection.

The antileukemic activity of allogeneic HSCT is based on the administration of pretransplant high-dose chemotherapy (or chemoradiotherapy) and the development of a posttransplant immune-based antileukemic response. The immune-based response, referred to as a graft-versus-leukemia (GVL) effect, often accompanies the graft-versus-host disease (GVHD) reaction. The immune-based benefit of allogeneic HSCT has been demonstrated through the observation of consistently lower relapse rates with allogeneic HSCT as compared to autologous or syngeneic HSCT. This potential benefit of allogeneic HSCT can be offset by the risk of posttransplant complications such as GVHD, sinusoidal obstruction syndrome, graft failure, and infections.

Allogeneic HSCT was first evaluated as a treatment modality for AML in refractory patients, but because of initial success in small numbers of patients, it has also been evaluated as intensive postremission therapy in AML patients in first or subsequent remission. Nonrandomized trials of HLA-identical sibling allogeneic HSCT performed in AML patients in first complete remission (CR1) reported 5-year survival rates of 45% to 60% with relapse rates of 10% to 20%.3,71,72,78 Transplant-related mortality following HLA-matched sibling allogeneic HSCT ranges from 15% to 25% in most series. As clinicians have gained more experience in this intensive form of therapy and been provided with more effective immunosuppressive and antibiotic regimens, transplant-related mortality rates have decreased and survival rates have increased. Bone marrow registry data indicate that long-term survival rates in AML patients who receive a matched sibling allogeneic HSCT while in first remission have increased from about 45% in the early 1980s to about 60% in the mid-1990s.

Allogeneic HSCT from an HLA-matched sibling donor for AML patients in CR1 results in long-term EFS in 43% to 55% of patients. Although the results vary, some of the studies show longer EFS and lower relapse rates with allogeneic HSCT in AML in CR1 as compared to chemotherapy-alone postremission regimens. Overall, single center prospective trials have not shown an OS advantage for allogeneic HSCT in all patients with AML CR1. Meta-analyses of clinical trials evaluating allogeneic HSCT versus other consolidation strategies in CR1 shows that allogeneic HSCT does provide an OS advantage for patients with intermediate- and high-risk AML.78

Myeloablative allogeneic HSCT is generally restricted to patients younger than 60 years of age, which limits the number of patients eligible for treatment of a disease that primarily affects older adults. NMT uses reduced intensity preparative regimens and is now being used in AML patients, particularly in older patients and those with comorbid illnesses that would limit their eligibility for conventional allogeneic HSCT. NMT is designed to provide enough immunosuppression in the preparative regimen to allow for engraftment of donor cells, and depends heavily on the development of a GVL effect as a means to treat and prevent relapse of AML. Initial results of NMTs in AML indicate that the procedure is well tolerated in a wide age range of patients, and that it is associated with low rates of regimen-related toxicity.81 A larger trial evaluating 264 patients who had received a NMT from matched related and unrelated donors demonstrated a 5-year OS of 33% and disease-free survival of 32%.82 Because only 30% of patients have an HLA-matched sibling donor, allogeneic HSCT is further restricted as a treatment alternative for AML patients.83 Matched unrelated donor HSCT with a phenotypically HLA-matched donor identified from bone marrow registries is also a treatment option in young adults and pediatric AML patients. This approach is associated with long-term EFS rates of 30% to 40%, which are slightly lower than in AML patients undergoing HLA-matched sibling allogeneic HSCT because of a higher risk of treatment-related mortality with the procedure.3,72

The decision to transplant a patient depends a great deal on which prognostic risk group the patient belongs. Among patients with favorable-risk AML, allogeneic HSCT does not result in better outcomes as compared to high-dose cytarabine-based therapy. All patients with high-risk AML, including those with an antecedent hematologic disorder, treatment-related MDS, or induction failure, should undergo evaluation for HSCT. Similarly, patients in CR1 with high-risk cytogenetics and patients in CR2 and beyond should undergo evaluation for allogeneic HSCT.59

Autologous Hematopoietic Stem Cell Transplantation Compared to allogeneic HSCT, autologous HSCT has the advantage of a lower risk of posttransplant complications because of lack of immunosuppression and GVHD, and more broad applicability because of a lack of donor limitations and fewer age restrictions. Although the preparative regimen still provides antileukemic activity, autologous HSCT is associated with a higher risk of relapse because of a lack of a GVL effect and potential tumor contamination with autologous stem cells. EFS following autologous HSCT for adult AML in CR1 ranges from 40% to 60%, with treatment-related mortality of 5% to 15% and relapse rates of 30% to 50%.84 Long-term response rates decrease proportionally as autologous HSCT is employed in second or subsequent CR. Controversies in autologous HSCT include the optimal timing of therapy, the amount of consolidation therapy needed prior to HSCT, the dose of stem cells needed, and the impact of posttransplant therapy.84 In general, an autologous HSCT may be considered if an allogeneic HSCT is not possible.

Comparisons of Postremission Therapy Options Several randomized trials in AML patients in CR1 have compared outcomes following allogeneic HSCT, autologous HSCT, and/or intensive consolidation chemotherapy. In most trials, eligible patients based on age and donor availability received an allogeneic HSCT and the remaining patients were randomized between autologous HSCT and chemotherapy alone. The European Organization for Research and Treatment of Cancer-GIMEMA (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto) trial observed a EFS advantage and reduced relapse risk for allogeneic HSCT or autologous HSCT as compared to chemotherapy alone, but no differences in OS.3,72 Survival rates were comparable because of a higher relapse rate in the chemotherapy group as compared to a higher treatment-related mortality rate in the allogeneic HSCT group. This is the only trial that has demonstrated superior 4-year EFS with HSCT versus chemotherapy. Interestingly, the response rates in the conventional chemotherapy arm in this trial were lower than those reported in other studies, which may account for the survival benefit in the transplant group. Several other trials have shown no difference in EFS or OS between autologous HSCT, allogeneic HSCT, and conventional chemotherapy. In aggregate, these trials show that either autologous HSCT or allogeneic HSCT can reduce the risk of relapse, although this has not translated into an OS benefit. One trial design issue that might explain this lack of survival benefit was the low percentage of patients who progressed to transplantation when randomized, thus diluting the effect of transplantation. The effect of stem cell source on EFS and OS is controversial. Several comparative trials of bone marrow versus peripheral blood have been completed in patients with hematologic malignancies, and a meta-analysis of nine randomized trials showed a lower relapse rate for those patients receiving peripheral blood stem cells.85

Most transplant centers base their decision to transplant on cytogenetic risk category.3 Patients with high-risk cytogenetics do poorly with conventional chemotherapy or autologous HSCT (EFS <15%), making allogeneic HSCT the treatment of choice in this population. Patients with good-risk cytogenetics should not proceed to transplant in CR1, as neither autologous nor allogeneic HSCT is superior to conventional chemotherapy. The optimal treatment of choice in patients with intermediate-risk cytogenetics is not clear and is based on clinician preference. Many centers consider a relapse probability of 40% to 50% sufficiently high so as to justify the risk of transplant-related mortality. The decision to proceed with HSCT in this group may depend on the results of molecular testing. As discussed in Risk Classification above, several genetic molecular abnormalities have prognostic significance in adults with AML. Abnormalities that are associated with a poor outcome include FLT3 abnormalities; myeloid/lymphoid or MLL abnormalities; BAALC; and WT-1.

According to the NCCN guidelines, the decision to proceed to HSCT depends on unfavorable prognostic risk features including cytogenetics.66 If the patient has a good-risk cytogenetic profile and is younger than age 60 years, then high-dose cytarabine for four cycles or one cycle of high-dose cytarabine-based therapy followed by autologous HSCT is preferred over allogeneic HSCT. If the patient has a high-risk cytogenetic profile and is younger than 60 years of age, then allogeneic HSCT transplantation should be considered early after remission induction. Patients with intermediate-risk cytogenetics should be entered into a clinical trial, but if a clinical trial is not available, either a matched sibling allogeneic HSCT or an autologous HSCT should be considered. Autologous HSCT can be used if a hematologic and cytogenetic remission is achieved. For patients 60 years and older, the NCCN guidelines do not favor HSCT and recommend either enrollment into a clinical trial, or consideration of conventional dose cytarabine with or without an anthracycline or intermediate-dose cytarabine. Clinicians increasingly consider autologous HSCT as a treatment option, and for selected patients older than 60 years of age, NMT is being used more frequently.81,82,86 For the AML patient who relapses early after induction therapy, if a sibling or matched related donor is available, then allogeneic HSCT is the primary reinduction therapy because conventional chemotherapy offers little benefit. If the relapse occurs late, then HSCT can be used as postremission consolidation after conventional induction therapy.66

Acute Myeloid Leukemia in Children

The most effective induction regimens for children include 3 days of an anthracycline and 7 to 10 days of cytarabine yielding a CR of greater than 85% and a 5-year OS of 70%. The Children’s Oncology Group is using risk-adapted therapy for childhood AML based on cytogenetics, molecular markers, and MRD results.5 About 73% of children have t(8;21), no MRD at the end of induction, inversion 16, or other good risk factors leading to a low-risk classification and an 80% OS with chemotherapy alone.87 Children with monosomy 7, 5q deletion, high FLT3-ITD to wild-type allelic ratio, or MRD at the end of induction are considered high risk with a 35% OS.87 The use of intrathecal CNS prophylaxis varies by protocol because of the low CNS relapse rate.70 Cranial radiation is only used for patients with refractory CNS disease.

Following induction therapy, patients should be evaluated for a response. Those not achieving a CR will require additional chemotherapy called reinduction. A bone marrow biopsy is usually performed 7 to 10 days after the completion of chemotherapy to document disease eradication. If there is persistent disease, a second course of therapy is administered. The second course may be identical to the initial induction regimen, or include high-dose cytarabine and asparaginase, or mitoxantrone and cytarabine. If the marrow is aplastic, a repeat marrow biopsy should be performed on hematologic recovery to document a CR.

Following induction, children go onto consolidation therapy. An evidence-based review of the role of HSCT in the treatment of pediatric AML concluded that HSCT was indicated in the following settings: (a) initial CR: matched sibling allogeneic HSCT is superior to autologous HSCT and chemotherapy, but are only available in 25% of children; (b) CR2: allogeneic HSCT is preferable to chemotherapy and autologous HSCT.70,88 Children with high-risk disease and no suitable stem cell donor should receive consolidation chemotherapy including high-dose cytarabine. A recent international expert panel recommended no transplant for favorable risk children in CR1.6 For other risk groups in first remission transplant risks must be weighed against potential benefit. Patients in CR2 generally receive an allogeneic HSCT. AML in children younger than 2 years of age is different from older children and are considered high risk. Poor prognostic factors include t(1;22), high WBC count, and CNS disease. Neonates with Down syndrome may develop transient myeloproliferative disease that usually spontaneously resolves without treatment within a few months. Infants with AML receive the same therapy as children of other ages, with the dosing per kilogram and not per body surface area.

Relapsed or Refractory Acute Myeloid Leukemia

The most common cause of treatment failure in AML patients receiving chemotherapy alone or undergoing HSCT is relapse. In addition, many patients, particularly elderly patients, have refractory disease as defined by the inability to achieve a CR after two courses of induction therapy. In most cases, the preferred method of treatment for relapsed or refractory disease is HSCT. Prolonged EFS is observed in 30% to 40% of patients receiving allogeneic or autologous HSCT in first relapse or CR2. Unfortunately, only a small percentage of relapsed or refractory adult patients will be eligible for HSCT, particularly allogeneic HSCT, because of age and donor restrictions. The role of NMT is also being evaluated in this setting.

The timing of HSCT to treat relapse is controversial. Some studies suggest that outcomes of HLA-matched, related allogeneic HSCT are similar regardless of whether the transplant is performed at the time of early first relapse or in CR2. The difficulty with this approach is identifying a patient in “early relapse,” as often the patient will present in a florid relapse. While performing the allogeneic HSCT in first relapse eliminates the need for and toxicity of salvage chemotherapy, the feasibility of this approach is limited by the lead time required to activate a donor search. Allogeneic HSCT is superior to autologous HSCT in adults younger than age 55 years.

Patients who relapse following allogeneic HSCT have a poor outcome, with a median survival of about 3 to 4 months.89 In this setting, treatment options depend on performance status, clinical condition, and the time since allogeneic HSCT. Patients relapsing less than 100 days following allogeneic HSCT are unlikely to respond to current therapies, and salvage attempts are often associated with a high treatment-related mortality. For selected patients relapsing more than 1 year after allogeneic HSCT, a second allogeneic HSCT may be an alternative, but the likelihood of prolonged survival is generally less than 10% with a second transplant. Other strategies being investigated for the treatment of relapse after allogeneic HSCT include immune manipulation to stimulate a GVL effect through donor lymphocyte infusions, and premature discontinuation of calcineurin inhibitors and other immunosuppressants.

Autologous HSCT is an option at the time of first relapse if cells have been previously collected and stored during first remission. If such cells were not collected, then it is necessary to achieve a CR2 in order to proceed to autologous HSCT. Prolonged EFS of 30% and 20% are reported when autologous HSCT is performed in CR2 and CR3, respectively. The advantages of autologous HSCT are the lack of donor limitations and fewer age-based restrictions; the disadvantage is the need to achieve a CR, which requires exposure to more cytotoxic chemotherapy. If patients relapse following autologous HSCT, allogeneic HSCT from a related or matched unrelated donor is preferred in selected younger patients. NMT or other investigational therapies can be considered for older patients who relapse after autologous HSCT.

If patients with relapsed or refractory disease are not candidates for HSCT, until recently the primary mode of treatment was salvage chemotherapy. The ability to achieve a CR2 with salvage chemotherapy is related to the duration of the first remission. About 50% to 60% of patients who relapse longer than 2 years after induction therapy will achieve a CR2, often with the same induction regimen.3,72 If the patient relapses 1 to 2 years after induction therapy, the CR2 rate decreases to 40%, and only 10% to 20% of patients who relapse within 6 to 12 months following induction are able to achieve a CR2 with alternate salvage chemotherapy regimens. Long-term survival at 3 years ranges from zero in patients who relapse early to 20% to 25% in those who experience a prolonged duration of initial remission. Based on these data, a risk-adapted approach should be taken when considering treatment options.

The most commonly used salvage regimens include high-dose cytarabine given at doses of 2,000 to 3,000 mg/m2 every 12 hours for 8 to 12 doses. High-dose cytarabine schedules that use once-daily doses or alternate-day doses have also been used in an attempt to minimize toxicity.72 Cytarabine has been administered alone or in combination with various agents, including etoposide, fludarabine, topotecan, clofarabine, and an anthracycline, as treatment of relapsed or refractory AML. Response rates to such salvage regimens range from 30% to 50%, but are often short-lived. Patients who received high-dose cytarabine during remission induction may be less likely to benefit from such a regimen for treatment of relapse, and thus require alternate salvage strategies. Patients with remission duration of longer than 1 year appear to benefit most from high-dose cytarabine regimens.3,72 One additional option is clofarabine, a purine analog, which can be used either alone or combined with cytarabine. While studies have shown CR rates of about 50%, median OS is less than 12 months.90

Several classes of new agents are being investigated as alternate treatment approaches for relapsed or refractory AML, including the ubiquitin-proteasome pathway inhibitors (bortezomib), new novel nucleoside analogs (troxacitabine), histone deacetylase inhibitors (phenylbutyrate, vorinostat), and angiogenesis modulators (bevacizumab and thalidomide).91 Arsenic trioxide, which is effective in the treatment of APL, is being investigated for the treatment of AML via its modulation of apoptotic and chromatin remodeling pathways.

In children with AML, about 5% have refractory disease and 30% experience a relapse.6 About one-half the children relapse within 1 year of initial diagnosis and have a poor prognosis.5 Therapy should include and anthracycline and antimetabolite followed by allogeneic HSCT if a CR2 is achieved.

Late Effects of Therapy

Because of the intense therapy received by children with AML, they are at risk for a variety of long-term sequelae. A recent study reported that more than 50% of survivors have growth abnormalities.92 Other findings include neurocognitive deficits, transfusion-associated hepatitis, endocrine disorders, cataracts, and cardiomyopathy (median cumulative anthracycline dose 335 mg/m2). The 20-year cumulative risk for a second malignancy is estimated to be 1.8%.

TREATMENT

Acute Promyelocytic Leukemia

APL is a subclass of AML that accounts for about 10% of all cases, and is the most curable of the AML subtypes. Most patients are diagnosed between the ages of 15 and 60 years. Five-year EFS rates of 70% to 80% are reported with APL.93 APL is clinically unique from the other subclasses because of the common occurrence of severe coagulopathy (characterized by disseminated intravascular coagulation) at diagnosis and during induction therapy, which frequently resulted in intracerebral hemorrhage. In APL, differentiation and maturation arrest are caused by alterations in the retinoic acid receptor (RAR) because of the translocation of chromosomes 15 and 17. The discovery of t(15;17) provides a cytogenetic marker of the disease and is predictive of response to differentiation therapy with tretinoin (commonly referred to as all-trans retinoic acid or ATRA). This translocation leads to a fusion protein of the PML gene on chromosome 15 and the RARα on chromosome 17.

Prior to the availability of tretinoin in the late 1980s, treatment of APL consisted of the same combination chemotherapy regimens used in the treatment of other subclasses of AML. Such standard regimens produced CR rates of 50% to 60%, but were associated with a high treatment-related mortality rate caused by hemorrhagic complications. The introduction of molecularly targeted therapy with tretinoin allows for high CR rates with a significant reduction in life-threatening bleeding complications. Arsenic trioxide targets the PML moiety, resulting in apoptosis, and appears to be synergistic with tretinoin.

The WBC count at initial presentation is the most important prognostic factor in patients with APL. Risk stratification of patients at diagnosis based on WBC count has improved outcomes. Abnormal creatinine, increased peripheral blast count, and presence of coagulopathy are prognostic factors that predict for early death due to hemorrhage.94

Treatment Phases

Induction

Tretinoin, an oral vitamin A analog, is given orally in a dose of 45 mg/m2 per day, as a single dose or divided into two doses, given after a meal. Tretinoin-based regimens achieve CR rates as high as 95% in APL patients within 1 to 3 months. Because tretinoin does not cross the blood–brain barrier, leukemic meningitis should be treated with conventional intrathecal chemotherapy.

Although it is not myelosuppressive, tretinoin therapy is associated with headache, skin and mucous membrane reactions, bone pain, nausea, and the retinoic acid syndrome. When tretinoin is started, rapid onset of differentiation of promyelocytes occurs, which can lead to leukocytosis and retinoic acid syndrome. The retinoic acid syndrome (fever, respiratory distress, interstitial pulmonary infiltrates, pleural effusions, and weight gain) is now referred to as the APL differentiation syndrome or APL hyperleukocytosis syndrome, because it is associated with other treatment modalities in the management of APL. The syndrome is fatal in 5% to 29% of cases. A combination of chemotherapy with tretinoin induction decreases the risk of APL differentiation syndrome, and rapid initiation of dexamethasone 10 mg (0.2 mg/kg per dose in children) twice daily on development of symptoms decreases associated mortality.93

A number of clinical trials have evaluated treatment regimens for APL since the discovery of tretinoin.93 These trials show that tretinoin induction therapy, followed by consolidation chemotherapy, produces similar CR rates but decreased relapse and increased EFS and OS as compared to chemotherapy alone for remission induction and consolidation. However, a significant proportion of patients receiving tretinoin in that study relapsed by 4 years, and 25% of patients experienced the APL differentiation syndrome. In an effort to extend the duration of remission and decrease tretinoin-associated toxicity, other trials have evaluated the sequential and concurrent administration of tretinoin with chemotherapy during induction and consolidation therapy. Additionally, the stratification of therapies based on WBC at diagnosis has been used in trials. A combined analysis of the Programa para el Estudio de la Terapeutica en Hemopatıa Maligna (PETHEMA) 99 and the French APL 2000 trial showed that in patients with WBC <10,000/mm3 (10 × 109/L), the regimen containing tretinoin with idarubicin for induction and tretinoin in consolidation produced similar CR rates with decrease relapse rates, whereas for patients with WBC >10,000/mm3 (10 × 109/L), the induction regimen containing cytarabine resulted in higher CR rates and improved OS rates.93 Images Based on these data, the current NCCN guideline for induction therapy for newly diagnosed APL patients includes selection of one of three options based on WBC and ability to tolerate anthracyclines (tretinoin 45 mg/m2 per day until a CR is achieved, in combination with an anthracycline (either daunorubicin 50 to 60 mg/m2 per dose for 3 or 4 days, or idarubicin 12 mg/m2 per dose every other day for four doses) or tretinoin plus arsenic trioxide for patients unable to tolerate anthracycline therapy.66 Several of the induction regimens also contain cytarabine 200 mg/m2 per dose for 7 days; similar CR rates are observed with daunorubicin or idarubicin. APL cells appear to be more sensitive to anthracyclines, possibly because of decreased P-glycoprotein expression. The NCCN guidelines also emphasize the use of one published regimen consistently throughout induction, consolidation, and maintenance phases.66 Children should also be treated with tretinoin, an anthracycline, and cytarabine with results similar to those achieved in adults.

Another difference in the treatment of APL is the timing of bone marrow biopsy. Assessment of response to treatment of APL is done at the time of count recovery after induction therapy. A day 10 to 14 day bone marrow biopsy, which is usually done for monitoring the effect of induction chemotherapy for other types of AML, is not long enough because leukemic promyelocytes need more time for differentiation. Assessment of molecular remission should be made after consolidation.

Arsenic trioxide is a compound with demonstrated efficacy in relapsed APL. It has been evaluated as part of remission induction therapy in several studies. The concept of a “chemotherapy-free” regimen in this disease is attractive especially for patients unable to tolerate anthracyclines. A combination of tretinoin with arsenic trioxide for induction therapy resulted in CR of 95% of low-risk patients.95

Consolidation Therapy

Consolidation chemotherapy should be administered to patients with APL because of the high relapse rate. Consolidation therapy usually consists of an idarubicin or daunorubicin-based regimen in combination with tretinoin. Arsenic trioxide has also been evaluated in consolidation therapy.

Postconsolidation Therapy

Unlike other subtypes of AML, maintenance therapy is an important component of therapy for APL. Before the advent of tretinoin, nonrandomized trials suggested a benefit of continuous low-dose methotrexate and mercaptopurine in prevention of relapse of APL. Larger prospective randomized trials have demonstrated decreased relapse rates in patients who received maintenance therapy (either tretinoin or combination chemotherapy), and some trials have demonstrated increased EFS and OS.93 In a study that compared maintenance with tretinoin, chemotherapy, or tretinoin plus chemotherapy versus observation, observation was associated with the highest relapse rate and tretinoin plus chemotherapy with the lowest relapse rate.95 Current recommendations for maintenance therapy in adult APL patients include tretinoin 45 mg/m2 per day for 15 days every 3 months, in addition to mercaptopurine 100 mg/m2orally daily and methotrexate 10 mg/m2 per week, for 2 years in all patients. Although the use of maintenance therapy in patients with low-risk disease who have achieved a molecular remission at the end of consolidation is controversial.93 The NCCN guidelines similarly recommend tretinoin maintenance therapy with or without mercaptopurine and methotrexate.66

Relapsed Acute Promyelocytic Leukemia

The incidence of relapsed APL is 10% to 15% overall with rates as high as 20% to 30% in high-risk disease. Most relapses occur in the first 3 years following induction therapy. Arsenic trioxide is the agent of choice for relapsed APL. Multiple studies have shown CR rates of about 85%. It is controversial as to whether adding tretinoin to arsenic therapy is better than just treating with arsenic monotherapy.96

Arsenic trioxide has induced clinical remissions in relapsed APL through its induction of apoptosis and differentiation.96,97 The recommended dose is 0.15 mg/kg per day IV until bone marrow remission, not to exceed 60 doses, followed by consolidation beginning 3 to 6 weeks after completion of induction at the same dose for a total of 25 doses over a period up to 5 weeks. Arsenic trioxide therapy is associated with two specific toxicities. First, it can cause the APL differentiation syndrome, similar to that seen with tretinoin. Management is similar: corticosteroids at first signs of pulmonary distress or a rapidly rising WBC count. The second toxicity is a prolongation of the QTcinterval. Consequently, it is important to obtain a baseline 12-lead electrocardiogram prior to starting therapy with arsenic trioxide, and correct any electrolyte abnormalities, including potassium, calcium, and magnesium. Other medications known to prolong the QTc interval should be avoided, if possible, during arsenic trioxide therapy. The QTc interval should not exceed 500 milliseconds at baseline, and if it increases to more than 500 milliseconds during therapy, the patient should be reevaluated. Arsenic trioxide should not be restarted until the QTc is less than 460 milliseconds. Following induction of a CR2 with arsenic trioxide in relapsed patients, postremission therapy with combination arsenic trioxide and chemotherapy can result in molecular remissions and improved EFS, as compared to chemotherapy or arsenic trioxide alone following remission.96 Additional investigations are underway to evaluate the role of arsenic trioxide in multidrug postremission regimens.

It is recommended for patients to proceed to an autologous HSCT following hematologic and molecular remission after arsenic therapy. Outcomes with autologous HSCT depend on the disease status of the patient at the time of transplant. Autologous HSCT in CR2 (versus CR1) is associated with a lower OS, leukemia-free survival, and increased treatment-related mortality. Allogeneic HSCT is also an option for patients with a HLA-matched related donor in CR2 as consolidation after reinduction with arsenic trioxide.98

Patient Monitoring

In comparison to non-APL AML, molecular and cytogenetic testing at the end of remission induction therapy in APL has no prognostic value. Clinicians should not make decisions based on the presence or absence of any genetic abnormalities at this time. Because terminal differentiation of blasts in APL requires more than 40 days, results of a bone marrow biopsy obtained at the end of remission induction can be misleading because insufficient time has elapsed to determine response. Molecular and cytogenetic response assessment should occur after the completion of consolidation treatment.

Detection of residual PML/RARα transcripts in the bone marrow at the end of consolidation therapy is strongly associated with subsequent hematologic relapse. Achievement of PML/RARα-negative status is associated with a higher probability of cure. The use of this molecular technique allows the clinician to assess response to therapy and also detect relapse earlier, which might prevent the development of overt disease recurrence and is associated with improved outcome compared with delaying treatment until overt morphologic relapse.93 Most experts recommend that APL patients should be routinely evaluated for continuous remission status. Suggested follow-up includes polymerase chain reaction for PML/RARα every 3 to 6 months for 2 years, and then every 6 months for 2 years.66,93

ROLE OF HEMATOPOIETIC GROWTH FACTORS IN ACUTE MYELOID LEUKEMIA

Images Hematopoietic growth factors have been evaluated in AML patients to enhance chemotherapy cytotoxicity, shorten the duration of neutropenia, and reduce the incidence and severity of infection following induction and consolidation chemotherapy. Most studies show limited benefit with the use of colony-stimulating factors as “priming” agents administered during remission induction therapy in an effort to recruit leukemia cells into the cycle to enhance susceptibility to cell-cycle–specific chemotherapy agents, leading to increased cell kill. Use of hematopoietic growth factors concurrently during chemotherapy administration is discouraged outside the setting of a clinical trial and is not recommended for this use in the American Society of Clinical Oncology guidelines.99

Both filgrastim and sargramostim are FDA approved to prevent neutropenic complications in adult AML patients receiving intensive chemotherapy. Myeloid blast cells have receptors for granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, and there was initial concern that the use of these factors would stimulate regrowth of the myeloid leukemia. Although subsequent studies have addressed these concerns, many clinicians do not initiate filgrastim until an initial remission is achieved.

A number of randomized trials, primarily in elderly patients, consistently demonstrate that filgrastim or sargramostim reduces the duration of neutropenia following AML induction chemotherapy.99 While neutropenia can be reduced from 2 to 12 days depending on the trial, results vary in terms of improvements in infectious morbidity and mortality, resource use, and disease response rates. The American Society of Clinical Oncology Guidelines for the Use of White Blood Cell Growth Factors considers the use of hematopoietic growth factors after initial induction therapy reasonable, with the understanding that the effects on length of hospitalization and incidence of severe infection are modest.99 Patients older than age 55 years appear to derive the greatest benefit, and use is appropriate in this population where more rapid marrow recovery might decrease the duration of hospitalization.99 A recent review of 19 trials including a total of 5256 patients showed no difference in the incidence of bacteremias or invasive fungal infections with the use of hematopoietic growth factors.100 It also concluded that the use of hematopoietic growth factors after consolidation did not affect CR duration, relapse rates or OS. Further pharmacoeconomic data are required in this setting, but the body of evidence supports their use following consolidation therapy in adults. Other controversial issues surrounding hematopoietic growth factor use in AML include which growth factor to use, what dose, which day to start after chemotherapy, how long to continue, and should the marrow be examined for leukemia prior to starting a colony-stimulating factor. All hematopoietic growth factors have been evaluated in patients with AML, including sargramostim, filgrastim, and pegfilgrastim. Although pegfilgrastim is not FDA approved for this indication, research supports using it in this setting.101 The use of hematopoietic growth factors can also interfere with the interpretation of the day 14 bone marrow examination. Hematopoietic growth factors should be discontinued at least 7 days prior to a bone marrow aspirate and biopsy to avoid interfering with the interpretation of the results (i.e., may see immature myeloid forms that would suggest residual disease).

SUPPORTIVE CARE

The most common and significant toxic effect of antileukemic agents is marrow suppression. With the exception of corticosteroids, tretinoin, asparaginase/pegaspargase, and vincristine, antineoplastic agents used to treat acute leukemia cause myelosuppression. During AML remission and postremission therapy, daily monitoring of the complete blood count and the absolute neutrophil count is necessary to determine when red cell and platelet transfusions are needed and when neutropenia is achieved. Less frequent monitoring may be sufficient during ALL induction. Marrow hypoplasia from the myelosuppressive regimens usually reaches its lowest point (nadir) after 1 to 2 weeks of therapy and lasts for another 1 to 2 weeks. During this period of hypoplasia, infectious and bleeding complications are major causes of death in leukemic patients. As typical signs and symptoms of infection may be absent in the neutropenic host, frequent monitoring of vital signs (especially fever) and daily physical examination are important.102 Infection control strategies often include routine hand washing; dietary restrictions; reverse isolation and laminar-air flow rooms; fungal, Pneumocystis, and bacterial prophylaxis; and the empiric use of broad-spectrum antibiotics when fever occurs (see Chap. 100).102 In contrast to the practice at many institutions, the NCCN guidelines do not recommend prophylactic antimicrobials or gut decontamination during induction or consolidation, and leave the choice to the discretion of the treating facility based on local infection patterns and concerns.103 Several groups have analyzed the evidence supporting the use of prophylactic antibacterials. In general, prophylactic antibacterials should be reserved for patients who are expected to have prolonged (more than 7 days) and profound (absolute neutrophil count <100 cells/mm3 [100 × 106/L]) neutropenia. Based on these criteria, prophylaxis following induction chemotherapy is warranted and postconsolidation therapy is warranted on a case-by-case basis.

In children, prophylactic antibiotics have not proven useful and have resulted in increased resistance. Pediatric ALL patients on standard induction regimens, which generally are minimally myelosuppressive, often have recovered blood counts earlier and do not require very aggressive measures. However, they do require close monitoring of vital signs and blood counts until their counts recover. Pediatric AML patients are usually admitted for at least 1 month during induction and again for consolidation. Infectious complications, especially fungal, are a major cause of morbidity and mortality. The incidence of viridans streptococci has increased with the intensity of therapy and is most associated with high-dose cytarabine. These infections can lead to meningitis or delayed acute respiratory distress syndrome.

Pneumocystis jiroveci prophylaxis (usually trimethoprim-sulfamethoxazole) is begun in all adults and children with ALL by the end of induction and continues until 6 months after therapy is discontinued. Infants are at high risk for developing Pneumocystis jiroveci pneumonia early in therapy, so should start prophylaxis immediately.34 These infants can receive trimethoprim-sulfamethoxazole despite the risk of kernicterus with careful monitoring.

Acute leukemia patients, particularly those patients with an initial elevated WBC count, are at risk for tumor lysis syndrome. Preventive measures include allopurinol or rasburicase, and adequate hydration (with or without sodium bicarbonate) prior to and during chemotherapy to prevent the development of urate nephropathy from rapid destruction of WBCs. Rasburicase, a recombinant urate-oxidase enzyme produced by genetic modification of Saccharomyces cerevisiae, catalyzes the enzymatic oxidation of uric acid into the inactive soluble metabolite, allantoin. In children, rasburicase more rapidly reduces uric acid levels in patients with aggressive malignancies compared to allopurinol, and reduces the need for dialysis.104 Rasburicase has been evaluated in adults, and some studies in adults show that fixed dosing produces equivalent outcomes to a mg/kg dosing strategy.105 Because of its cost, rasburicase is usually limited to patients with ALL who have a high WBC count or bulky extramedullary disease, aggressive lymphoma, or patients with AML with a high presenting WBC. Most institutions also include an elevated uric acid as part of the criteria for use. Rasburicase has a rapid onset of action and long duration of action, so many institutions also limit its use to a single dose and allow repeat doses as needed. Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. Tumor lysis syndrome may lead not only to hyperuricemia, but also to hyperkalemia, hyperphosphatemia, hypocalcemia and subsequent renal insufficiency.104

Hematologic support consists primarily of platelet and packed red blood cell transfusions. Platelet transfusions are often given for peripheral counts below 10,000 cells/mm3 (10 × 109/L) or clinical signs of bleeding. Transfusions of packed red cells may also be indicated for a hemoglobin less than 8 gm/dL (4.96 mmol/L), profound fatigue, shortness of breath, tachycardia, or chest pain. APL can release procoagulants that can cause disseminated intravascular coagulation, necessitating close monitoring and replacement of coagulation factors with cryoprecipitate. Because of the gastrointestinal toxic effects of chemotherapy, parenteral nutrition may be required. Patients are frequently receiving infusions of antibiotics, fluids, hyperalimentation, opioids, and blood products simultaneously. To provide the total support needed for these patients, a multiple-lumen central venous access device should be considered at the start of therapy.

PERSONALIZED PHARMACOTHERAPY

Treatment of acute leukemia is highly personalized. A risk-adapted approach is used in the treatment of ALL and AML. In ALL, patients are placed into risk categories based on age and disease characteristics. The initial risk category is sometimes changed based on the rapidity and completeness of response to remission induction therapy. The same risk-adapted approach is used in the treatment of AML, but age and cytogenetics are the most important factors in determining the risk category. Molecular mutations are becoming more important in both ALL and AML.

Genetic polymorphisms may affect drug metabolism, receptor expression, drug transportation, drug disposition, and pharmacologic response. These alterations may contribute to acute and chronic toxicity from ALL therapy and to treatment outcome.6,106 The most studied polymorphism involves thiopurine metabolism. Cellular thiopurine S-methyltransferase (TPMT) inactivates thiopurines such as mercaptopurine and thioguanine. About 10% of the population has intermediate TPMT activity as a result of heterozygous polymorphisms in the gene encoding for TPMT, and 1 in 300 has extremely low activity as a result of homozygous presence of this TPMT polymorphism. Deficiency of TPMT activity can result in excessive myelosuppression from standard doses of thiopurines. Patients with low activity (homozygous mutant TPMT genotype) require 85% to 90% dose reductions. About 50% of the heterozygous patients will require dose reductions. TPMT deficiency is also associated with an increased risk of developing secondary AML and radiation-induced brain tumors. Prospective evaluation of TPMT status was complicated in the past, as many ALL patients receive transfusions prior to definitive diagnosis. TPMT status can now be determined directly by DNA-based testing, which may become a standard of care in the near future.

EVALUATION OF THERAPEUTIC OUTCOMES

Appropriate development of a pharmaceutical care plan for the acute leukemia patient begins with establishing the diagnosis and prognosis for the patient. Long-term therapeutic goals for the patient may include long-term EFS, although palliative care is a possibility in some patients. The desired short-term outcome is the establishment of remission. The return of hematologic values to normal and a repeat bone marrow biopsy that demonstrates no evidence of disease serve as documentation that remission has been achieved. Monitoring guidelines for induction or consolidation are similar (Table 111-5). After the appropriate postremission therapy has been completed, the patient may return monthly for 1 year, and then every 3 months, to check hematologic values. If no evidence of disease exists after 5 years from the diagnosis and the patient has been in continuous CR, the patient is considered cured.

TABLE 111-5 Acute Myeloid Leukemia Assessment and Monitoring

Images

Frequent monitoring of fevers, hematologic and chemistry laboratory values, microbiology reports, and the patient’s physical condition are necessary to identify infection, risk of bleeding, and tumor lysis syndrome early. A coagulation screening panel will identify patients with ongoing disseminated intravascular coagulation, a particular risk with APL.

During therapy, the pharmacist can be an important provider of patient and caregiver education. Patients should receive information regarding acute and chronic toxicities of the chemotherapy being administered, as well as possible treatments for those toxicities. Pharmacists should follow patients during consolidation therapy for dosing adjustments and toxicities due to chemotherapy. For example, the pharmacist should make sure the patient is receiving corticosteroid and saline eye drops four times daily while the patient is receiving high-dose cytarabine to prevent the ocular toxicity of cytarabine. The pharmacist can also be an important resource for information regarding antibiotics, antiemetics, nutritional support, hematopoietic growth factors, and other supportive care issues.

Pharmacists should be involved in assessing drug doses and any dose modifications for organ dysfunction or prior toxicity. Pharmacists are often in the best position to recognize the potential for medication errors and drug interactions and to help avoid them. Similarly, pharmacists are often able to identify the possibility that patient problems are secondary to drug treatments.

Numerous late sequelae from leukemia therapy have been recognized and should be included in the monitoring plan after therapy is completed. Chapter 117 discusses the long-term consequences of HSCT.

ABBREVIATIONS

Images

Images

REFERENCES

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63:11–30.

    2. Howlader N, Noone A, Krapcho M, Neyman N, Aminou R. SEER Cancer Statistics Review, 1975–2009. Bethesda, MD: National Cancer Institute. September 29, 2012, http://seer.cancer.gov/csr/1975_2009_pops09/.

    3. Estey E, Dohner H. Acute myeloid leukemia. Lancet 2006;368:1894–1907.

    4. Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer 2008;112:416–432.

    5. Creutzig U, van den Heuvel-Eibrink MM, Gibson B, Dworzak MN. Diagnosis and management of acute myeloid leukemia in children and adolescents: Recommendations from an international expert panel. Blood 2012;120:3187–3205.

    6. Pui C-H, Robison LL, Look AT. Acute lymphoblastic leukemia. Lancet 2008;371:1030–1043.

    7. Faderl S, Jeha S, Kantarjian H. The biology and therapy of adult acute lymphoblastic leukemia. Cancer 2003;98:1337–1354.

    8. Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: A review. Environ Health Perspect 2007;115:138–145.

    9. Caughey RW, Michels KB. Birth weight and childhood leukemia: A meta-analysis and review of the current evidence. Int J Cancer 2009;124:2658–2670.

   10. Mrozek K, Marcucci G, Paschka P, Whitman S, Bloomfield C. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: Are we ready for a prognostically prioritized molecular classification. Blood 2007;109:431–448.

   11. Vardiman JW, Thiele J, Arber DA, Brunning RD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009;114:937–951.

   12. Pui C-H, Deqing P, Campana D, Bowman WP. Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol 2011;29:386–391.

   13. Smith M, Arthur D, Camitta B, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol 1996;14:18–24.

   14. Seibel NL. Treatment of acute lymphoblastic leukemia in children and adolescents: Peaks and pitfalls. Hematology Am Soc Hematol Educ Program 2008;2008:374–80.

   15. Arico M, Schrappe M, Hunger SP, et al. Clinical outcome of children with newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia treated between 1995 and 2005. J Clin Oncol 2010;28:4755–4761.

   16. Moorman AV, Ensor H, Richards S. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: Results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol 2010;11:429–438.

   17. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Semin Hematol 2009;46:100–106.

   18. Schultz KR, Pullen DJ, Sather HN, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: A combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood 2007;109:926–935.

   19. Borowitz MJ, Devidas M, Hunger SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: A Children’s Cancer Group study. Blood 2008;111:5477–5485.

   20. Seibel NL, Steinherz PG, Sather HN, Nachman JB, Cynthia D. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: A report from the Children’s Oncology Group. Blood 2008;111:2548–2555.

   21. Hunger SP, Loh ML, Whitlock JA, et al. Children’s Oncology Group’s 2013 blueprint for research: acute lymphoblastic leukemia. Pediat Blood Cancer 2013;60:957–963.

   22. Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166–178.

   23. Schrappe M, Hunger SP, Pui C-H, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med 2012;366:1371–1381.

   24. Inaba H, Pui C-H. Glucocorticoid use in acute lymphoblastic leukemia. Lancet Oncol 2010;11:1096–1106.

   25. Mitchell CD, Richards S, Kinsey S, et al. Benefit of dexamethasone compared with prednisolone for childhood lymphoblastic Leukaemia: Results of the UK Medical Research Council ALL97 randomised trial. Br J Haematol 2005;129:734–745.

   26. Ravindranath Y. Recent advances in pediatric acute lymphoblastic and myeloid leukemia. Curr Opin Oncol 2003;15:23–35.

   27. Lowas SR, Marks D, Malempati S. Prevalence of transient hyperglycemia during induction chemotherapy for pediatric acute lymphoblastic leukemia. Pediatr Blood Cancer 2009;52:814–818.

   28. Pieters R, Hunger SP, Boos J, et al. L-asparaginase treatment in acute lymphoblastic leukemia. Cancer 2011;117:238–249.

   29. Matloub Y, Lindemulder S, Gaynon PS, et al. Intrathecal triple therapy decreases central nervous system relapse but fails to improve event-free survival when compared with intrathecal methotrexate: Results of the Children’s Cancer Group (CCG) 1952 study for standard-risk acute lymphoblastic leukemia, reported by the Children’s Oncology Group. Blood 2006;108:1165–1173.

   30. Bomgaars L, Geyer JR, Franklin JL, et al. Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis. J Clin Oncol 2004;22:3916–3921.

   31. Dunsmore K, Devidas M, Linda S, et al. Pilot study of nelarabine in combination with intensive chemotherapy in high-risk T-cell acute lymphoblastic leukemia: A report from the Children’s Oncology Group. J Clin Oncol 2012;30:2753–2759.

   32. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: A report from the Children’s Oncology Group. J Clin Oncol 2012;30:2094–2101.

   33. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: A Children’s Oncology Group study. J Clin Oncol 2009;27:5175–5181.

   34. Silverman LB. Acute lymphoblastic leukemia in infancy. Pediatr Blood Cancer 2007;49:1070–1073.

   35. Mann G, Attarbaschi A, Schrappe M, et al. Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of infants with mixed-lineage-leukemia (MLL)-rearranged acute lymphoblastic leukemia: Results from the Interfant-99 Study. Blood 2010;116:2644–2650.

   36. Stock W, La M, Sanford B, Bloomfield CD, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 2008;112:1646–1654.

   37. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 2.2012. December 24, 2012, http://www.nccn.org/professionals/physician_gls/pdf/all.pdf.

   38. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol 2011;29:532–543.

   39. Larson RA, Dodge RK, Burns CP. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: Cancer and leukemia group B study 8811. Blood 1995;85:2025–2037.

   40. Rowe JM, Buck G, Burnett AK. Induction therapy for adults with acute lymphoblastic leukemia: Results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005;106:3760–3767.

   41. Linker C, Damon L, Ries C, Navarro W. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol 2002;20:2464–2471.

   42. Kantarjian H, O’Brien S, Smith T. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000;18:547–561.

   43. Burmeister T, Schwartz S, Bartrum CR. Patients’ age and BCL-ABL frequency in adult-B precursor ALL: A retrospective analysis from the GMALL study group. Blood 2008;112:918–919.

   44. de Labarthe A, Rousselot P, Huguet-Rigal F. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: Results of the GRAAPH-2003 study. Blood 2007;109:1408–1413.

   45. Bassan R, Rossi G, Pogliani EM. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol 2010;28:3644–3652.

   46. Ottmann O, Wassmann B, Pfeifer H. Imatinib compared with chemotherapy as frontline treatment of elderly patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Cancer 2007;109:2068–2076.

   47. Vignetti M, Fazi P, Cimino G. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: Results of the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) LAL0201-B protocol. Blood 2007;109:3676–3678.

   48. Ravandi F, O’Brien S, Thomas D. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood 2010;116:2070–2077.

   49. Talpaz M, Shah N, Kantarjian H. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006;354:2531–2541.

   50. Kantarjian H, Giles F, L W. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 2006;354:2542–2551.

   51. Khoury HJ, Cortes J, Kantarjian HM. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403–3412.

   52. Cortes JE, Kantarjian HM, Shah NL. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 2012;367:2075–2088.

   53. Thomas D, O’Brien S, Jorgenson J. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood 2009;113:6330–6337.

   54. Thomas D, O’Brien S, Faderl S. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-cell lineage acute lymphoblastic leukemia. J Clin Oncol 2010;28:3880–3889.

   55. Oliansky DM, Larson RA, Weisdorf DJ. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of adult acute lymphoblastic leukemia: Update of the 2006 evidence-based review. Biol Blood Marrow Transplant 2012;18:16–17.

   56. Ko RH, Ji L, Barnette P, Bostrom B, et al. Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: A Therapeutic Advances in Childhood Leukemia Consortium study J Clin Oncol 2010;28:648–654.

   57. Harned TM, Gaynon PS. Relapsed acute lymphoblastic leukemia: Current status and future opportunities. Curr Opin Oncol 2008;10:453–458.

   58. Gaynon PS. Childhood acute lymphoblastic leukaemia and relapse. Br J Haematol 2005;131:579–587.

   59. National Marrow Donor Program. 2013, http://www.nmdp.org/.

   60. Mody R, Li S, Dover DC, et al. Twenty-five-year follow-up among survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study. Blood 2008;111:5515–5523.

   61. Deschler B, M L. Acute myeloid leukemia: Epidemiology and etiology. Cancer 2006;107:2099–2107.

   62. Kolitz JE. Acute leukemias in adults. Dis Mon 2008;54:226–241.

   63. Byrd JC, Mrozek K, Dodge RK. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B(CALGB 8461). Blood 2002;100:4325–4336.

   64. Estey EH. Treatment of acute myeloid leukemia. Haematologica 2009;94:10–16.

   65. Grimwade D, Hills R. Independent prognostic factors for AML outcome. Hematology Am Soc Hematol Educ Program 2009;2009:385–395.

   66. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 2.2012. December 24, 2012, http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.

   67. Paschka P, Marcucci G, Ruppert AS. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A Cancer and Leukemia Group B study. J Clin Oncol 2006;24:3904–3911.

   68. Cheson B, Bennett J, Kopecky K. Revised recommendations of the International Working Group for diagnosis, standardization or response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642–4649.

   69. Buchner T, Berdel W, Wormann B. Treatment of older patients with acute myeloid leukemia. Crit Rev Oncol Hematol 2005;56:247–259.

   70. Rubnitz JE, Gibson B, Smith FO. Acute myeloid leukemia. Pediatr Clin North Am 2008;55:21–51.

   71. Kolitz JE. Current therapeutic strategies for acute myeloid leukemia. Br J Haematol 2006;134:555–572.

   72. Milligan DW, Grimwade D, Cullis J. Guidelines on the management of acute myeloid leukemia in adults. Br J Haematol 2006;135:450–474.

   73. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009;361:1249–1259.

   74. Cahn JY, Labopin M, Sierra J. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Acute Leukemia Working Party of the European group for Blood and Marrow Transplant (EBMT). Br J Haematol 2000;110:308–314.

   75. Fenaux P, Mufti GJ, Hellstrom-Lindberg E. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562–569.

   76. Al-Ali HK, Jaekel N, Junghanss C. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012;53:110–117.

   77. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol 2011;29:487–494.

   78. Dohner H, Estey E, Amadori S. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European Leukemia Net. Blood 2010;115:453–474.

   79. Mayer RJ, Davis RB, Schiffer CA. Intensive post-remission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331:896–903.

   80. Byrd JC, Ruppert AS, Mrozek K. Repetitive cycles of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): Results from CALGB 8461. J Clin Oncol 2004;22:1087–1094.

   81. Aoudjhane M, Labopin M, Gorin NC. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: A retrospective survey from the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT). Leukemia 2005;18:2304–2312.

   82. Gyurkocza B, Storb R, Stover BE. Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia. J Clin Oncol 2010;28:859–867.

   83. Estey E, de Lima M, Tibes R. Prospective feasibility analysis of reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HSCT) in elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). Blood 2007;109:1395–1400.

   84. Breems DA, Lowenberg B. Autologous stem cell transplantation in the treatment of adults with acute myeloid leukemia. Br J Haematol 2005;2005:825–833.

   85. Group SCTC. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005;23:5074–5087.

   86. Alyea EP, Kim HT, Ho V. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005;105:1810–1814.

   87. Pui C-H, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol 2011;29:551–565.

   88. Oliansky DM, Rizzo JD, Aplan PD. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: An evidence-based review. Biol Blood Marrow Transplant 2007;13:1–25.

   89. Michallet M, Thomas X, Vernant J-P. Long-term outcome after allogeneic hematopoietic stem cell transplantation for advanced stage acute myeloblastic leukemia: A retrospective study of 379 patients reported to the Societe Francaise de Greffe de Moelle (SFGM). Bone Marrow Transplant 2000;26:1157–1163.

   90. Faderl S, Ravandi F, Huang X. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 2008;112:1638–1645.

   91. Brune M, Castaigne S, Catalano J. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: Results of a randomized phase 3 trial. Blood 2006;108:88–96.

   92. Leung W, Hudson MM, Strickland DK. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000;18:3273–3279.

   93. Ades L, Sanz MA, Chevret S. Treatment of newly diagnosed acute promyelocytic leukemia (APL): A comparison of French-Belgian-Swiss and PETHEMA results Blood 2008;111:1078–1084.

   94. DelaSerna J, Montesinos J, Vellenga E. Causes and prognostic factors of remission induction failure in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and idarubicin. Blood 2008;111:3395–3402.

   95. Estey E, Garcia-Manero G, Ferrajoli A. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006;107:3469–3473.

   96. Soignet S, Frankel S, Douer D. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–3860.

   97. Soignet S, Maslak P, Wang Z. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998;339:1341–1348.

   98. Nabhan C, Mehta J, Tallman MS. The role of bone marrow transplantation in acute promyelocytic leukemia. Bone Marrow Transplant 2001;28:219–226.

   99. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006;24:3187–3205.

  100. Gurion R, Belnik-Plitman Y, Gafter-Gvili A. Colony-stimulating factors for prevention and treatment of infectious complications in patients with acute myelogenous leukemia. Cochrane Database Syst Rev 2012 Jun 13;6:CD008238.

  101. Sierra J, Szer J, Kassis J, et al. A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial. BMC Cancer 2008;8:195.

  102. Freifeld AG, Bow EJ, Sepkowitz KA. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 2011;52:427–431.

  103. NCCN. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 1.2012. December 24, 2012, http://www.nccn.org/professional/physician_gls/pdf/infections.pdf.

  104. Coiffier B, Altman A, Pui C-H, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: An evidence-based review. J Clin Oncol 2008;26:2767–2778.

  105. Trifilio S, Gordon L, Singhal S. Reduced-dose rasburicase (recombinant xanthine oxidase) in adult cancer patients with hyperuricemia. Bone Marrow Transplant 2006;37:997–1001.

  106. Cheok MH, Pottier N, Kager L, Evans WE. Pharmacogenetics in acute lymphoblastic leukemia in children. Semin Hematol 2009;46:39–51.