Nancy Heideman
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Describe the pathogenesis of acute leukemia.
2. Compare the classification systems for acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML).
3. Identify the risk factors associated with a poor outcome for the acute leukemias.
4. Explain the importance of minimal residual disease (MRD) and its implication on early bone marrow relapse.
5. Explain the role of induction, consolidation, and maintenance phases for acute leukemia.
6. Define the role of CNS preventive therapy for acute leukemia.
7. Recognize the treatment complications associated with therapy for acute leukemias.
8. Describe the late effects associated with the treatment of long-term survivors of acute leukemias.
KEY CONCEPTS
The acute leukemias are hematologic malignancies of bone marrow precursors characterized by excessive production of immature hematopoietic cells. This proliferation of “blast” cells eventually replaces normal bone marrow and leads to the failure of normal hematopoiesis and the appearance of leukemia cells in peripheral blood as well as infiltration of other organs.
Acute leukemias are classified according to their cell of origin. Acute lymphocytic leukemia (ALL) arises from the lymphoid precursors. Acute nonlymphocytic leukemia (ANLL) or acute myelogenous leukemia (AML) arises from the myeloid or megakaryocytic precursors.
The goal is to match treatment to risk and minimize over- or undertreatment. Children with ALL are sorted into prognostic categories based on clinical and biological features that mirror their risk of relapse. Risk assessment is an important factor in the selection of treatment.
Minimal residual disease (MRD) is a quantitative assessment of subclinical remnant of leukemic burden remaining at the end of the initial phase of treatment (induction) when a patient may appear to be in a complete morphologic remission. This measure has become one of the strongest predictors of outcome for patients with acute leukemia. The elimination of MRD is a principal objective of postinduction leukemia therapy.
The initial treatment for acute leukemias is called induction. The purpose of induction is to induce a remission, a state where there is no identifiable leukemic cells in the bone marrow or peripheral blood with light microscopy. This definition may change as more sensitive techniques come into play.
The current induction therapy for ALL typically consists of vincristine, asparaginase, and a steroid (prednisone or dexamethasone). An anthracycline is added for higher-risk patients.
Leukemic invasion of the CNS is considered to be an almost universal event in patients, even in those whose cerebrospinal fluid (CSF) cytology shows no apparent disease. Thus, all patients with ALL and AML receive intrathecal chemotherapy. Although this is often referred to as “prophylaxis,” it more realistically represents treatment.
Marrow relapse is a major complication for 15% to 20% of patients with ALL. Current research suggests that this is the result of residual leukemic cells at diagnosis. Thus the importance of MRD.
The current induction therapy for AML usually consists of a combination of cytarabine and an anthracycline daunorubicin or idarubicin, with the frequent addition of a steroid and/or an antimetabolite such as 6-thioguanine. The second phase of treatment for AML is called consolidation. The purpose of this phase is to further enhance remission with more cytoreduction.
Although survival in pediatric cancers has improved dramatically over the last 35 years, 50% to 60% of cancer survivors are estimated to have at least one chronic or late-occurring complication of treatment.
INTRODUCTION
The acute leukemias are hematologic malignancies of bone marrow precursors characterized by excessive production of immature hematopoietic cells. This proliferation of “blast” cells eventually replace normal bone marrow and lead to the failure of normal hematopoiesis and the appearance in peripheral blood as well as infiltration of other organs. These blast cells proliferate in the marrow and inhibit normal cellular elements, resulting in anemia, neutropenia, and thrombocytopenia. Leukemia also may infiltrate other organs, including the liver, spleen, bone, skin, lymph nodes, and CNS. Virtually anywhere there is blood flow, the potential for extramedullary (outside the bone marrow) leukemia exists.
Acute leukemias are classified according to their cell of origin. Acute lymphocytic leukemia (ALL) arises from the lymphoid precursors. Acute nonlymphocytic leukemia (ANLL) or acute myelogenous leukemia (AML) arises from the myeloid or megakaryocytic precursors. As a result of clinical trials defining various prognostic (risk) factors that helped guide treatment modifications, the outcomes of acute leukemias, especially ALL, has improved dramatically over the last 30 years.1 Risk-based treatment strategies that consider multiple phenotypic and biological risk factors and attempt to match the aggressiveness of therapy with the presumed risk of relapse and death are now the standard of care. Currently, the overall survival (OS) of pediatric patients with ALL is about 80%. For AML, it is significantly less at about 50%. If left untreated, most patients with either of these acute leukemias will die of their disease within 2 to 3 months.
EPIDEMIOLOGY AND ETIOLOGY
Epidemiology
Leukemia is a relatively uncommon disease overall. The current overall age-adjusted annual incidence of acute leukemia in the United States has remained relatively stable at 10 per 100,000. Of the estimated 1.4 million new cancers diagnosed in 2009, only 1% to 2% will be acute leukemia, with 760 cases of ALL and about 12,800 cases of AML.2,3 Interesting age-related patterns of disease exist in ALL and AML. The average age of diagnosis for AML is about 65 years and is a result of an increasing incidence of AML with age.4 ALL is a more common process in children than adults and relatively uncommon in adults where its incidence decreases with age.5,6
In the pediatric population, leukemia is a common disease, accounting for almost one-third of all childhood malignancies. ALL accounts for 75% to 80% of all cases of childhood leukemia, whereas AML accounts for no more than 20%. Males generally are affected more often than females in all but the infant age group, and its incidence is higher in whites than among other racial groups. The incidence of AML in children is bimodal: It peaks at 2 years of age, decreases steadily thereafter to age 9 years, and then increases again at around age 16.3
The 5-year event-free survival (EFS) rate for ALL is nearly 80% in children as compared to only 40% for adults.1 The success rate for children with ALL is attributed to enrollment in clinical trials, risk-adapted treatment, and integration of presymptomatic CNS prophylaxis.7 A recent increase in the survival rate for adults has been attributed to the adoption of the principles of treatment that characterize pediatric protocols.8 For patients with AML, a similar pattern exists. Those younger than 20 years of age have a 5-year survival of 50%.6 Patients with AML older than age 60 generally have a poorer prognosis with a 5-year survival of less than 20%.9
Etiology
The causes of the acute leukemias is unknown; multiple influences related to genetics, socioeconomics, infection, environment, hematopoietic development, and chance all may play a role.3 Table 95–1 lists the major conditions that have been associated with the acute leukemias. In most cases, however, there is no identifiable cause of the leukemia.
Table 95–1 Clinical Conditions Associated With an Increased Frequency of Acute Leukemias
While leukemia is rarely a hereditary disease some genetic associations are evident. For example, among identical twins, the concordance for ALL in the initially unaffected twin is 20% to 25% within 1 year. While the incidence in fraternal twins is much less, there is still a fourfold increase in the risk of leukemia in the initially unaffected twin as compared with the normal population. One explanation for this association may be a shared placental circulation, which allows for transmission of disease from one twin to the other. Additionally, leukemia is known to be increased in several chromosomally abnormal populations. Patients with Down’s syndrome have a 20 times increased risk of developing leukemia compared with the rest of the population. Patients with Klinefelter’s syndrome and Bloom’s syndrome also have an increased incidence of leukemias.3
Exposure to environmental agents such as agricultural chemicals, pesticides, and radiation have also been periodically associated with leukemia, however none of these agents is linked conclusively with the development of leukemia. An increased frequency of ALL is associated with higher socioeconomic status. It is postulated that less social contact in early infancy and thus a late exposure to some common infectious agents may have some impact.3In most individual instances, there is no reasonable or obvious explanation for the development of leukemia.
Risk factors for the development of AML include exposure to environmental toxins, Hispanic ethnicity, and genetics.6 Of greater concern is the increased prevalence of AML as a secondary malignancy, resulting from chemotherapy and radiation treatment for other cancers. Alkylating agents, such as ifosfamide and cyclophosphamide, and topoisomerase inhibitors, such as etoposide, are linked to an increased risk of myelodysplastic syndrome(MDS) and AML.9
PATHOPHYSIOLOGY
Hematopoiesis is defined as the development and maturation of blood cells and their precursors. In utero, hematopoiesis may occur in the liver, spleen, and bone marrow; after birth this process occurs exclusively in the bone marrow. All blood cells are generated from a common hematopoietic precursor, or stem cell. These stem cells are self-renewing and pluripotent and thus are able to commit to any one of the different lines of maturation that give rise to platelet-producing megakaryocytes, lymphoid, erythroid, and myeloid cells. The myeloid cell line produces monocytes, basophils, neutrophils, and eosinophils, whereas the lymphoid stem cell differentiates to form circulating B and T lymphocytes, NK cells, and dendritic cells. In contrast to the ordered development of normal cells, the development of leukemia seems to represent an arrest in differentiation at an early phase in the continuum of stem cell to mature cell.1
Both AML and ALL are presumed to arise from clonal expansion of these “arrested” cells. As these cells expand, they acquire one and often more chromosomal aberrations, including translocations, inversions, deletions, point mutations, and amplifications.3 The translocation ETS leukemia acutemyeloid leukemia-1 (TEL–AML1) fusion, found in approximately 25% of cases is associated with a favorable prognosis.7 Another example is the t(9;22) translocation, which underlies the BCR–ABL fusion protein. The normal ABL gene encodes a growth-promoting protein kinase whose activity is tightly controlled. By contrast, the translocation and fusion of the BCR and ABL gene sequences produce a kinase that leads to uncontrolled proliferation, survival, and self-renewal of cells. Imatinib is a tyrosine kinase inhibitor that inhibits the activity of ABL. It has shown great success given the pathogenic role of BCR–ABL tyrosine kinase in chronic myelogenous leukemia (CML), which is characterized by this molecular abnormality. Imatinib also has shown activity in the infrequent, but high-risk patients with ALL in patients who are BCR–ABL positive.3
AML represents a group of disorders in which both failure to differentiate and overproliferation in the stem cell compartment produce an overabundance of nonfunctional cells termed myeloblasts. While the specific cause for this biological abnormality is unknown, an understanding of the genetic influence of leukemia is leading to a wide variety of targeted therapies.10
In AML, there is a substantial difference in clinical and biological features, as well as in response to and tolerance of therapy, by age group. In the elderly, trilineage leukemic involvement is common, indicating that the cell of origin is probably a stem or very early progenitor cell. In the younger population, a more differentiated progenitor becomes malignant, permitting maturation of some granulocytic and erythroid populations. These two forms of AML show different patterns of resistance to chemotherapy, with resistance more frequent in the older adults with AML.6
For patients with MDS or AML as a secondary neoplasm, there are often a number of key features characterized by having had prior alkylator-based or etoposide-based chemotherapy. Patients receiving treatment for Hodgkin’s disease or solid tumors are often trated with this type of chemotherapy. Many of these patients have an abnormal bone marrow, but have not converted to overt leukemia. Instead, they have a myelodysplastic prodrome, which consists of a marrow that is hypoplastic and in which a monosomy 5 or monosomy 7 is often seen. Secondary AML with the use of epipodophyllotoxin (etoposide) demonstrates mainly M4 or M5 morphology and exhibits translocations within the MLL gene with 11q23 chromosomal alterations, which is otherwise an uncommon feature of AML.9
Leukemia Classification
For all newly diagnosed patients with leukemia, an aspirate of the liquid marrow and a bone marrow core biopsy are obtained.5 Morphologic and cytochemical analyses of these samples distinguish three subtypes of ALL (L1, L2, and L3) and eight subtypes of AML (M0–M7) as classified by the French-American-British (FAB) scheme. See Tables 95–2 and 95–3 for the FAB classification of AML and ALL. Another classification system proposed by the World Health Organization (WHO) and the Society of Hematopathology for myeloid neoplasms includes not only morphologic findings, but also genetic, immunophenotypic, biological, and clinical characteristics (Table 95–4). A disadvantage of this system is that it does not account for some of the myeloid disorders in pediatrics.6
Table 95–2 Morphologic (FAB) Classification of AML
Table 95–3 Morphologic (FAB) Classification and Immunophenotype of ALL
Table 95–4 WHO Classification of AML
AML with recurrent genetic abnormalities:
AML with t(8;21)(q22;q22), (AML1/ETO)
AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22), (CBFβ/MYH11)
Acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RARα) and variants
AML with 11q23 (MLL) abnormalities
AML with multilineage dysplasia
Following MDS or MDS/MPD
Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more myeloid lineages
AML and MDSs, therapy related
Alkylating agent/radiation-related type
Topoisomerase II inhibitor-related type (some may be lymphoid)
Others
AML, not otherwise categorized
Classify as:
AML, minimally differentiated
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/acute monocytic leukemia
Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorders.
Adapted from Ref. 6.
Classification methods for leukemia have evolved from simple schemes that were largely phenotypic and considered only age, gender, WBC, and blast morphology to now-complex methods that include biological features such as cell-surface receptors, DNA content (ploidy; more or less then normal chromosomal DNA content), and a variety of cytogenetic abnormalities.
Markers on the cell surface or membrane of the lymphoblast can be used to classify ALL. Among the early classification system was the FAB scheme, which was based purely on morphology and apparent degree of cellular differentiation. This system is no longer used, and the current classification of acute leukemias is based on features that can be identified only by immunological and molecular analyses.3Markers on the cell surface or membranes of the leukemic cell (lymphoblasts) are now more regularly used to classify ALL and to assign prognosis and, in turn, treatment.
Immunophenotyping by flow cytometry has taken on an increasingly important role in the diagnosis of leukemia. Owing to the ease of application, sensitivity, and quantifiable results, flow cytometry is the preferred method for leukemic lineage as well as prognostic assignment.8 This approach takes advantage of the development of monoclonal antibodies (MABs) to many cell-surface antigens that are differentially expressed during hematopoietic differentiation. The antigens are referred to as antibody cluster determinants (CDs) that define cells at various stages of development and can easily separate ALL from AML and T-cell from preB-cell ALL.5,11 The combined approach of flow cytometric identification and cytogenetic DNA content, much of which is also revealed by flow cytometry and fluorescent in-situ hybridization (FISH; microscopic, fluorescence identification of chromosomal features) has facilitated diagnosis and delineation of specific treatments for the major subtypes of the acute leukemias. Common immunophenotypic markers seen in AML and ALL are provided in Table 95–5.
Clinical Presentation and Diagnosis of ALL3,6,11
General
Typically, patients have symptoms for 1 to 3 months before presentation. These include fatigue, fever, and pallor, but patients generally are in no obvious distress.
Symptoms
• The patient may present with weakness, malaise, bleeding, and weight loss.
• Neutropenic patients are often febrile and highly susceptible to infection.
• Anemia usually presents as pallor, tiredness, and general fatigue.
• Patients with thrombocytopenia usually present with bruising, petechiae, and ecchymosis.
• Patients often present with bone pain secondary to expansion of the marrow cavity from leukemic infiltration.
• CNS involvement is common at diagnosis.
Signs
• Temperature may be elevated secondary to an infection associated with a low WBC.
• Petechiae and bleeding are indicative of thrombocytopenia.
• Patients may present with organ involvement, such as peripheral adenopathy, hepatomegaly, and splenomegaly.
• T-lineage ALL may present with a mediastinal mass.
Laboratory Tests
• CBC with differential is performed.
• The anemia is usually normochromic and normocytic. Approximately 50% of children present with platelet counts of less than 50 × 103/mm3 (50 × 109/L). The WBC may be normal, decreased, or high. About 20% of patients have WBCs over 100 × 103/mm3 (100 × 109/L), which places them at risk for leukostasis.
• Uric acid is increased in approximately 50% of patients secondary to rapid cellular turnover.
• Electrolytes: Potassium and phosphorus often are elevated. Calcium usually is low.
• Coagulation disorders: Elevated prothrombin time, partial thromboplastin time, D-dimers; hypofibrinogenemia.
Other Laboratory Tests
Flow cytometric evaluation of bone marrow and peripheral blood is performed to characterize the type of leukemia as well as to detect specific chromosomal rearrangements. The bone marrow at diagnosis usually is hypercellular, with normal hematopoiesis being replaced by leukemic blasts. At diagnosis, a lumbar puncture is performed to determine if CNS leukemia is present.
Table 95–5 Common Immunophenotypes in Acute Leukemia
Prognostic Factors
The goal of treatment is to match treatment to risk and minimize over- or undertreatment. Children with ALL are sorted into prognostic categories based on clinical and biological features that mirror their risk of relapse. Risk assessment is an important factor in the selection of treatment.12 Age, WBC, leukemic cell-surface markers, DNA content, and specific cytogenetic abnormalities predict response to therapy and are used to assign risk and associated treatment.3 On the basis of these prognostic variables, patients are assigned to one of the three risk groups (e.g., standard-, high-, or very high–risk groups) that determine the aggressiveness of treatment.
Patient Encounter, Part 1
RH is a 7-year-old girl who presents to her pediatrician with a 1-week history of runny nose and fever. Her mom has noted a lot of bruising on her lower extremities. Physical examination reveals splenomegaly, multiple petechiae, and pallor. A CBC reveals a normochromic, normocytic anemia with a hemoglobin of 6 g/dL (60 g/L, 3.7 mmol/L; normal 11.7–15.7 g/dL, 117–157 g/L, 7.3–9.7 mmol/L), hematocrit of 18% (0.18; normal 35–47%, or 0.35–0.47), and WBC of 2.6 × 103/mm3 (2.6 × 109/L). The differential on the WBC reveals 75% (0.75) lymphocytes (normal 20–40%, or 0.2–0.4), 20% (0.2) neutrophils (normal 55–62%, or 0.55–0.62), and 5% (0.05) lymphoblasts (normal 0%). Based on this information, a bone marrow aspirate and biopsy are performed, which reveal 85% (0.85) lymphoblasts and a DNA index of 1.17. A lumbar puncture is also performed, which shows no evidence of leukemia.
What information is suggestive of acute lymphocytic leukemia?
What are the prognostic factors for RH?
What is the goal of induction therapy?
Prognostic Factors in ALL
In both children and adults with ALL, clinical trials have identified several risk factors that correlate with outcome (Table 95–6). Prognostic features include age, WBC, cytogenetic abnormalities, ploidy (DNA content), leukemic cell immunophenotype, and degree of initial response to therapy (minimal residual disease, MRD).13 When these factors are combined, they predict groups of patients with varying degrees of risk for treatment failure.
In adults, there is a steady decline in the rate of complete remission (CR) following initial induction therapy with increasing age. When results are corrected for differences in immunophenotype, ALL cells from adults are more resistant to the multiple antileukemic agents than are cells from children in the first decade of life.8 While induction treatment produces 95% CR in children, it declines to no more than 60% in patients older than 60 years of age. This is due in part to decreased tolerance of assertive induction/consolidation regimens in older patients. Other potentially important factors relate to a higher incidence of poor prognostic factors such as the presence of Philadelphia chromosome (Ph+) or t(9;22), in older populations.5 BCR–ABL fusions (Ph+) are strongly associated with chemoresistant leukemia in all age groups but are much more prevalent in adults with ALL than in children (30% versus less than 5%).11
Table 95–6 Prognostic Factors in ALL
The association of age and outcome is nowhere more evident than between infants and older patients. Infants (less than 1 year of age) often possess a poor prognostic genotype represented by the presence of the MLL gene rearrangement. The MLL gene is capable of partnering with many genes, and in virtually every instance the result is a markedly poor prognosis. All cells that have the MLL gene rearrangement are highly resistant to the key antileukemic drugs such as glucocorticoids and L-asparaginase. Thus, investigators are now focusing on protocols specifically aimed at infant ALL.7
Like age, the WBC at presentation is a reliable indicator of CR rate and outcome. The WBC is indicative of tumor burden, although the underlying biological mechanisms that account for the unfavorable outcomes associated with an elevated WBC are unclear. Patients with WBCs of less than 50 × 103/mm3 (50 × 109/L) are considered standard risk and have a better outcome than those with a higher WBC at presentation, which is associated with higher risk of treatment failure (Table 95–6).
Specific chromosomal abnormalities in leukemic cells also possess prognostic significance. Blast cells with a translocation of parts of chromosome 12 and 21 (the TEL–AML1 fusion) or trisomies of 4, 10, and 17 are considered to have favorable genetic features.3 The presence of specific translocations between chromosome 9 and 22 (Ph+) is a high-risk feature, which is present in about 5% of patients with ALL.
The DNA content of blast cells, hyper-, hypo-, or diploid, corresponding to increased-, decreased-, or normal-chromosome numbers, has been considered prognostic. Lower-risk patients with hyperdiploidy (greater than 50 chromosomes per leukemic cell) generally include approximately 25% of children who have B lineage ALL.7 These children are between the ages of 1 and 9 years, whereas the higher-risk patients with normal diploidy (50 chromosomes) generally are older.
Patients with cell-surface markers indicating that the blasts are early in the B-cell lineage (CD markers) are considered favorable and standard risk, whereas those with mature B-cell and T-cell blasts are considered high risk. T-cell ALL is found in approximately 15% of childhood ALL. Compared to B-lineage ALL, T-cell ALL is relatively resistant to different classes of drugs including methotrexate and cytarabine.
Patients completing induction treatment and in apparent remission still harbor malignant cells in their bone marrow, even though they appear disease-free by peripheral blood and bone marrow morphology. Assuming that most patients present with about a 1012 leukemic cell burden at diagnosis, at least 1010 or 1% residual disease remains after induction. These residual leukemic cells are below the limits of detection using standard morphologic examination. Measurement of this population of cells has become an increasingly significant prognostic factor and a determinant of the aggressiveness of postinduction therapy. Through flow cytometric analysis and polymerase chain reaction, it is possible to detect one leukemic cell among 104 normal cells, representing a 100-fold greater sensitivity than morphological examination.
MRD is a quantitative assessment of subclinical remnant of leukemic burden remaining at the end of the initial phase of treatment (induction) when a patient may appear to be in a complete morphologic remission. This measure has become one of the strongest predictors of outcome for patients with acute leukemia. The elimination of MRD is a principal objective of postinduction leukemia therapy.14 Several studies in children, in whom ALL is common, have evaluated disease levels at the end of induction and correlated these values with EFS. For example, a patient with detectable MRD less than 0.1% at the end of induction has a EFS greater than 90% at 3 years. Conversely, a patient with high MRD (1%) has a 3-year EFS of only about 25%.15 Assessment of MRD is also emerging as an important indicator of disease recurrence in the adult population and in patients with AML.
Clinical Presentation and Diagnosis of AML3,6,11
General
Patients may have symptoms of AML for 1 to 3 months prior to presentation. These include fatigue, fever, and pallor, but patients generally are in no obvious distress.
Symptoms
• The patient may present with weakness, malaise, bleeding, and weight loss.
• Neutropenic patients are often febrile and highly susceptible to infection.
• Anemia usually presents as pallor, tiredness, and general fatigue.
• Patients with thrombocytopenia usually present with bruising, petechiae, and ecchymosis.
• Chloromas (localized leukemic deposits named after their color) may be seen, especially in the periorbital regions and as skin infiltrates.
• Gum hypertrophy is indicative of AML M4 and AML M5 subtypes.
• Disseminated intravascular coagulation is common in AML M3 and is associated with generalized bleeding or hemorrhage.
• Lymphadenopathy, massive hepatosplenomegaly, and bone pain are not as common in AML as in ALL.
Signs
• Temperature may be elevated secondary to an infection associated with a low WBC.
• Petechiae and bleeding are indicative of thrombocytopenia.
Laboratory Tests
• CBC with differential is performed.
• The anemia is usually normochromic and normocytic.
• Approximately 50% of children present with platelet counts of less than 50 × 103/mm3 (50 × 109/L).
• The WBC may be normal, decreased, or high. About 20% of patients have WBCs of over 100 × 103/mm3 (100 × 109/L), which places them at risk for leukostasis.
• Uric acid is increased in approximately 50% of patients secondary to rapid cellular turnover.
• Electrolytes: Potassium and phosphorus are often elevated. Calcium is usually low.
• Coagulation disorders: Elevated prothrombin time, partial thromboplastin time, D-dimers; hypofibrinogenemia
Other Diagnostic Tests
Flow cytometric evaluation of bone marrow and peripheral blood to characterize the type of leukemia, as well as to detect specific chromosomal rearrangements. The bone marrow at diagnosis usually is hypercellular, with normal hematopoiesis being replaced by leukemic blasts. The presence of greater than 20% blasts in the bone marrow is diagnostic for AML. At diagnosis, a lumbar puncture is performed to determine if CNS leukemia is present.
Prognostic Factors in AML
The major prognostic factors in newly diagnosed AML are age, subtype, chromosome status, ethnicity, and body mass index. Older adults with AML (greater than 60 years), in comparison with younger patients with the same disease, have a dismal prognosis and represent a distinct population in terms of disease biology, treatment-related complications, and OS. These older patients have a higher incidence of unfavorable chromosomal abnormalities, such as aberrations of chromosomes 5, 7, or 8, and fewer abnormalities that are associated with a more favorable outcome, such as t(8;21) or inv(16) (see Table 95–7).10
Even though chromosomal abnormalities correlate with prognosis in adult AML, they appear to have less influence on outcome. Among children, the male gender, platelet count of less than 20 × 103/mm3 (20 × 109/L), hepatomegaly, more than 15% bone marrow blasts on day 14 of induction, MDS, and FAB subtype M5 all were associated with lower CR rates. The absence of these features and the presence of an abnormal chromosome 16 were associated with more favorable outcomes.16
Recent studies suggest that ethnicity may be an important predictor of outcome in children with AML. Investigators found that African Americans treated with chemotherapy had a significantly worse outcome than whites probably suggesting pharmacogenetic differences among the races. Body mass index may also affect the prognosis of children with AML. Underweight patients and overweight patients were less likely to survive than normoweight patients due to a greater risk of treatment-related deaths.17
TREATMENT
Desired Outcome
The primary objective in treating patients with acute leukemia is to achieve a continuous complete remission (CCR). Remission is defined as the absence of all clinical evidence of leukemia with the restoration of normal hematopoiesis. For both ALL and AML, remission induction is achieved with the use of highly myelosuppressive chemotherapy that initially induces a state of bone marrow aplasia as the leukemic cells die, followed by a slow return and proliferation of normal cells.12 Following this period, hematopoiesis is restored. Failure to achieve remission in the first 7 to 14 days of therapy is highly predictive of later disease recurrence. This again represents the growing importance of MRD in prognosis and treatment.
Nonpharmacologic Therapy
This year, roughly 1.6 million people will be diagnosed with cancer in the United States and Canada. With improvements in detection and treatment, approximately two-thirds of those diagnosed with the disease can expect to be alive in 5 years. With improving longevity, the cumulative adverse effects of both the disease and treatment are becoming an increasingly important issue. “Late-effects” data show that both adult and pediatric cancer survivors are at greater risk for developing second malignancies, cardiovascular disease, diabetes, and osteoporosis than those in the general population. With respect to the growing population of pediatric cancer survivors, data confirm that they are eight times more likely than their siblings to have a severe or life-threatening chronic health condition. For example, the survivors of pediatric ALL have an increased onset of obesity, osteopenia, and associated comorbidities. Thus, it is important to provide supportive care and intervention and counseling related to nutrition, smoking cessation, and exercise as a part of their active treatment. Health care professionals should think beyond the immediate treatment-related issues of their patients and provide appropriate, active assistance to promote healthy lifestyles and encourage patients to take active roles in pursuing general preventive health strategies.18
Pharmacologic Therapy: ALL
The treatment for ALL consists of four main elements: Remission induction (the initial tumor reduction leading to morphologic remission), CNS directed treatment and consolidation, delayed intensification, and maintenance phases of treatment all of which are aimed at complete elimination of the residual, but subclinical disease remaining after induction7 (Table 95–8).
Table 95–7 Risk Category According to Cytogenetic Abnormalities Present
Remission Induction
The initial treatment for acute leukemias is called induction. The purpose of induction is to induce a remission, a state where there is no identifiable leukemic cells in the bone marrow or peripheral blood with light microscopy. This definition may change as more sensitive techniques come into play.19 The current induction therapy for ALL typically consists of vincristine, asparaginase, and a steroid (prednisone or dexamethasone). An anthracycline is added for higher-risk patients. Adults, unlike children, are universally considered to be at high risk for relapse, thus their induction regimens include an anthracycline (daunorubicin or doxorubicin) in addition to the standard steroid and vincristine treatment that have been the backbone of treatment for this disease for the last 40 years.5 Dexamethasone is often replacing prednisone as the steroid of treatment because of its longer half-life and better CNS penetration.6,20 Even though dexamethasone possesses more favorable pharmacologic characteristics than prednisone, its use may be associated with more aseptic osteonecrosis of the femoral and humoral heads as well as an increase in life-threatening infections and septic deaths.20
CNS Prophylaxis
Leukemic invasion of the CNS is considered to be an almost universal event in patients, even in those whose CSF cytology shows no apparent disease. Thus, all patients with ALL and AML leukemia receive intrathecal (IT) chemotherapy. Although this is often referred to as “prophylaxis,” it more realistically represents treatment.6 CNS prophylaxis relies on IT chemotherapy (e.g., methotrexate, cytarabine, and corticosteroids), systemic chemotherapy with dexamethasone and high-dose methotrexate, and craniospinal irradiation (XRT) in selected high-risk patients.11 Cranial radiation was once a common intervention, but it is now reserved for only high-risk patients in whom IT treatment is inadequate. Its use has diminished substantially once the efficacy of IT treatment was evident, and the toxicities associated with radiation, learning disabilities, growth retardation, and secondary malignancies, were recognized. IT therapy has replaced cranial XRT as CNS prophylaxis for all except the very high-risk patients.
Inexplicably, the treatment of CNS leukemia has not had the same remarkable impact on the OS of adults as it has for childhood ALL. Although it reduces the incidence of CNS relapse in adults, it has not been associated with a measurable effect on survival.11
Patient Encounter, Part 2
RH is admitted to the pediatric oncology service. She is started on allopurinol and IV fluids with sodium bicarbonate to prevent tumor lysis syndrome (TLS). According to her risk status, she will receive a three-drug induction with vincristine, dexamethasone, and pegylated asparaginase. She also will receive intrathecal (IT) chemotherapy for CNS prophylaxis with methotrexate, cytarabine, and hydrocortisone.
What is the role of CNS prophylaxis?
Consolidation
After completion of induction and restoration of normal hematopoiesis, patients begin consolidation. The goal of consolidation is to administer dose-intensive chemotherapy in an effort to further reduce the burden of residual leukemic cells.13 It is in this and subsequent treatment phases that the presence of MRD is reduced by increasing the aggressiveness of the drug regimen. Several regimens use agents and schedules designed to minimize the development of drug cross-resistance. Studies have demonstrated that this phase of treatment has proven to be an effective strategy in the prevention of relapse in children with ALL, but its benefits in adults are less clear.
In children, the intensity of the consolidation treatment is now determined not only by the child’s risk classification but also by the rate of cytoreduction during induction.5 Patients who respond slowly to induction therapy (as determined by bone marrow examination early in induction) are at higher risk of relapse and are treated on more aggressive regimens.
Delayed Intensification
The Berlin-Frankfurt-Munster (BFM) Study Group introduced a treatment element called delayed intensification (or reinduction) therapy. This therapy consisted of repetition of the initial remission induction therapy administered approximately 3 months after remission. This, like consolidation, has been adopted as a component of treatment by virtually all institutions.13
Intensification regimens may vary in their aggressiveness and the drugs they use depending on the patient’s risk group and immunophenotype. For example, the use of very-high-dose methotrexate (5 g/m2) appears to improve outcome in patients with T-cell ALL. The use of intensive asparaginase treatment in T-cell ALL patients also has improved outcomes significantly.13
Maintenance
The purpose of maintenance therapy is to further eliminate leukemic cells and produce an enduring CCR. The two most important agents in maintenance chemotherapy are a combination of oral methotrexate and 6-mercaptopurine. Improved outcome has been associated with increasing 6-mercaptopurine dosages to the limits of individual tolerance based on absolute neutrophil count (ANC). The goal is to induce a moderate immunosuppression and leukemic cell kill. 6-Mercaptopurine at usual doses causes significant neutropenia and its use has been associated with increased rates of infection. At lower doses, it is associated with poor leukemic activity and a higher rate of relapse. In both instances, 6-mercaptopurine is associated with the inability to deliver planned appropriate therapy. 6-Mercaptopurine is metabolized by thiopurine methyltransferase (TPMT). TPMT deficiency is inherited as an autosomal recessive trait, with 89% to 94% of whites having high activity, 6% to 11% having intermediate activity, and 0.3% having very low or no activity. This deficiency is explained largely by three polymorphisms in the TPMT gene (*2, *3A, and *3C) that also have a profound influence on 6-mercaptopurine tolerance and dose-intensity in children with ALL. While these polymorphisms are rare, they are certainly important, with case reports of toxic deaths attributed to 6-mercaptopurine dating back several decades.
Patient Encounter, Part 3
RH had a bone marrow aspiration performed on days 15 and 29 that showed morphologic remission. The MRD on day 29 was less than 0.1%. RH completed her induction therapy and started intensification therapy.
What is the significance of MRD?
What is the purpose of intensification therapy?
Table 95–8 Representative Chemotherapy Regimens for Adult ALL
Patient Encounter, Part 4: Creating a Care Plan
After completion of induction and intensification therapy, RH will begin maintenance therapy for 2.5 years.
Which agents are used in maintenance therapy?
Why is maintenance therapy of such a long duration?
Create a care plan to include: (a) monitoring parameters during maintenance therapy; (b) a list of drug-related problems to access toxicity during maintenance therapy; and (c) goals of maintenance therapy.
Children who were homozygous for one of the alleles require 6-mercaptopurine dose reductions of 90%, whereas heterozygotes require a dose reduction of approximately 50%. Children with dose reductions had equivalent OS when compared with children receiving full-dose 6-mercaptopurine, suggesting that TPMT polymorphisms are important for drug metabolism and toxicity but play no role in the pathogenesis of ALL. TPMT screening is recommended for children starting therapy with 6-mercaptopurine, with empirical dose reductions for those with genotypes associated with a deficiency. The addition of intermittent “pulses” of vincristine and a steroid (usually dexamethasone) to the antimetabolite backbone improves outcome and is encouraged in most modern continuation regimens.12
The optimal duration of maintenance therapy in both children and adults is unknown, but most regimens are given for 2 to 3 years; extension of the regimen beyond 3 years has not shown any additional benefit.
ALL in Infants
Infants account for approximately 5% of all children with ALL, and they experience the worst prognosis of any group of children with the disease. These patients have several poor prognostic features at diagnosis, including hyperleukocytosis, hepatomegaly, splenomegaly, and CNS leukemia.6 The bone marrow of infants at day 14 usually shows poor response to therapy. Infants with ALL have increased frequencies of cytogenetic abnormalities; 60% to 70% have a translocation that involves the MLL gene located at 11q23. The 11q23 breakpoint abnormality, t(4,11), is the most common structural karyotypic abnormality in infants with ALL. In vitro, blasts from infants with ALL showed greater drug resistance to prednisolone and L-asparaginase than those from older patients, although they are more sensitive to cytarabine.13 Based on this information, several studies are testing the efficacy of intensified chemotherapy that includes high-dose cytarabine. Another achievement is the prevention of CNS relapse using IT cytarabine in conjunction with high-dose systemic cytarabine. This combination has eliminated the need for cranial XRT in this young population. Even with major advances in cure rates for the general pediatric ALL population, where survival is 80% or more, the long-term EFS of infants is only about 40% (Tables 95–9 and 95–10).
ALL in the Elderly
The proportion of ALL in patients older than age 60 years constitutes between 16% and 31% of all adult leukemias. Treatment of adults largely has followed the conventional chemotherapeutic regimes used in childhood ALL. However, the intensification regimens common in childhood are not suitable for this population because of their associated toxicities in older patients. The adverse prognostic factor, the Ph+, occurs in 15% to 30% of adults and thus is more common in the over 60 age group.21 Based on the experience achieved in CML, the use of imatinib, a potent inhibitor of the Ph+-associated BCR–ABLtyrosine kinase, is becoming a common practice for these older adults. Results show that the combination of imatinib with conventional chemotherapy has improved remission rates compared with the use of conventional chemotherapy alone, although the effect on long-term disease-free survival (DFS) is unclear. With other tyrosine kinase inhibitors, dasatinib and nilotinib, resistance can be overcome, but the remission is not long lasting.7 Improving the outcomes of these elderly patients with ALL continues to be a challenge.
Relapsed ALL
Relapse is the recurrence of leukemic cells at any site after remission has been achieved. Relapse is a major complication for 15% to 20% of patients with ALL. Current research suggests that this is the result of residual leukemic cells at diagnosis. Thus the importance of MRD.22 Bone marrow relapse is the principal form of treatment failure in patients with ALL. Extramedullary sites of relapse include the CNS and the testicles.23 Extramedullary relapse while once common, has decreased to 5% or less because of effective prophylaxis. Site of relapse and the length of the first remission are important predictors of second remission and OS. Marrow relapses occurring less than 18 to 24 months into first remission are associated with a poor survival, while longer periods of remission, greater than 36 months, have a much higher chance of survival.22 Treatment strategies for relapsed ALL include chemotherapy or allogeneic hematopoietic stem cell transplant (allo-HSCT). Even though patients undergoing allo-HSCT are less likely to relapse, treatment-related toxicity leads to a higher incidence of morbidity and mortality as compared to chemotherapy alone.6 Clofarabine, a next-generation deoxyadenosine analog, has shown considerable activity in children and adults with refractory acute leukemias. Of interest, this is the only anticancer drug to receive primary indication for use in pediatrics in the last 10 years.24
Table 95–9 Representative Chemotherapy Regimens for Pediatric ALL
Induction (1 month)
Intrathecal cytarabine on day 0
Prednisone 40 mg/m2/day or dexamethasone 6 mg/m2/day orally for 28 days
Vincristine 1.5 mg/m2/dose (max 2 mg) IV weekly for 4 doses
Pegaspargase 2,500 units/m2/dose IM for 1 dose or asparaginase 6,000 units/m2/dose IM Mon, Wed, and Fri for 6 doses
Intrathecal methotrexate weekly for 2–4 doses
Consolidation (1 month)
Mercaptopurine 50–75 mg/m2/dose orally at bedtime for 28 days
Vincristine 1.5 mg/m2/dose (max 2 mg) IV on day 0
Intrathecal methotrexate weekly for 1–3 doses
Patients with CNS or testicular disease may receive radiation
Interim Maintenance (1 or 2 cycles) (2 months)
Methotrexate 20 mg/m2/dose orally at bedtime weekly
Mercaptopurine 75 mg/m2/dose orally daily on days 0–49
Vincristine 1.5 mg/m2/dose (max 2 mg) IV on days 0 and 28
Dexamethasone 6 mg/m2/day orally on days 0–4 and 28–32
Delayed Intensification (1 or 2 cycles) (2 months)
Dexamethasone 10 mg/m2/day orally on days 0–6 and 14–20
Vincristine 1.5 mg/m2/dose (max 2 mg) IV weekly for 3 doses
Pegaspargase 2,500 units/m2/dose IM for 1 dose
Doxorubicin 25 mg/m2/dose IV on days 0, 7, and 14
Cyclophosphamide 1,000 mg/m2/dose IV on day 28
Thioguanine 60 mg/m2/dose orally at bedtime on days 28–41
Cytarabine 75 mg/m2/dose SC or IV on days 28–31 and 35–38
Intrathecal methotrexate on days 0 and 28
Consolidation Option (2–3-week intervals for 6 courses on weeks 5–24)
Mercaptopurine 50 mg/m2/dose orally at bedtime
Prednisone 40 mg/m2/day for 7 days on weeks 8 and 17
Vincristine 1.5 mg/m2/dose (max 2 mg) IV on the first day of weeks 8, 9, 17, and 18
Methotrexate 200 mg/m2/dose IV + 800 mg/m2/dose over 24 hours on day 1 of weeks 7, 10, 13, 16, 19, and 22
Intrathecal methotrexate on weeks 5, 6, 9, 12, 15, and 18
Late Intensification (weeks 25–52)
Methotrexate 20 mg/m2/dose IM weekly or 25 mg/m2/dose orally every 6 hours for 4 doses every other week
Mercaptopurine 75 mg/m2/dose orally at bedtime
Prednisone 40 mg/m2/day orally for 7 days on weeks 25 and 41
Vincristine 1.4 mg/m2 w/dose (max 2 mg) IV on the first day of weeks 25, 26, 41, and 42
Intrathecal methotrexate on day 1 of weeks 25, 33, 41, and 49
Maintenance (12-week cycles)
Methotrexate 20 mg/m2/dose orally at bedtime or IM weekly
with dose escalation as tolerated
Mercaptopurine 75 mg/m2/dose orally at bedtime on days 0–83
Vincristine 1.5 mg/m2/dose (max 2 mg) IV on days 0, 28, and 56
Dexamethasone 6 mg/m2/day orally on days 0–4, 28–32, and 56–60
Intrathecal methotrexate on day 0
IM, intramuscular; SC, subcutaneous.
Adapted from Leather HL, Bickert B. Acute Leukemias. In: DiPiro JT, Talbert RL, Yee GC, et al., (eds.) Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York: McGraw-Hill; 2005: 2458–2511.
Treatment: AML
As with ALL, the primary aim in treating patients with AML is to induce remission and thereafter prevent relapse. Treatment of AML is conventionally divided into two phases: induction and consolidation. Despite several strategies to increase the intensity of therapy, the OS rate has reached a plateau at 50% to 60%, suggesting that further intensification of therapy will not improve survival rates greatly.12 The current induction therapy for AML usually consists of a combination of cytarabine and daunorubicin, with the frequent addition of a steroid and/or an antimetabolite such as 6-thioguanine. The second phase of treatment for AML is called consolidation. The purpose of this phase is to further enhance remission with more cytoreduction.
Remission Induction
The goal of induction chemotherapy in AML is essentially identical to that in ALL: “Empty” the bone marrow of all hematopoietic precursors, and allow repopulation with normal cells. The combination of an anthracycline (e.g., daunorubicin, doxorubicin, or idarubicin) and the antimetabolite cytarabine forms the backbone of AML induction therapy. The most common induction regimen (7 + 3) combines daunorubicin for 3 days with cytarabine on days 1 to 7. The remission rate for this combination is approximately 80% in children and younger adults but declines to 40% to 50% in patients older than 60 years of age.6 Despite studies that have used alternative anthracyclines or substituted high-dose for conventional-dose cytarabine and added etoposide and/or thioguanine, the 7 + 3 regimen remains the standard induction regimen.
Postremission Therapy
Once an initial remission is achieved, further intensive therapy is imperative to prevent relapse. Induction therapy fails to provide adequate cell kill, and leukemia cells survive the initial treatment. Three options available for patients include high-dose chemotherapy, allog-HSCT from an human leukocyte antigen matched (HLA-matched) related or unrelated donor, and autologous bone marrow transplantation.9
Table 95–10 Chemotherapy for the Acute Leukemias
Postremission Chemotherapy
In AML, postremission chemotherapy is often referred to as consolidation therapy.6 Several cycles of intensive postremission chemotherapy combining noncross-resistant agents given every 4 to 6 weeks improves DFS. One of three cytarabine-based regimens has been used in current treatment programs, either alone or in combination with L-asparaginase, mitoxantrone, or etoposide. The following cytarabine dosing schedule is used: 100 mg/m2/day for 5 days by continuous infusion (standard-dose arm), 400 mg/m2/day for 5 days by continuous infusion (intermediate-dose arm), or 3 g/m2 twice daily over 3 hours on days 1, 3, and 5 (high-dose arm). The higher-dose regimen for cytarabine can be tolerated only by younger patients (younger than 60 years of age). While the optimal number of courses remains to be determined, at least three are probably required.11
Gemtuzumab ozogamicin is an MAB that binds to the CD-33 antigen. Almost all AML cells express this antigen. Phase I and II trials using this agent have shown some success, and current studies using this agent alone or with chemotherapy for the treatment of AML are ongoing.25
Allogeneic Hematopoietic Stem Cell Transplantation
Allo-HSCT has been used in the treatment of pediatric AML in first complete remission. In most clinical trials, the availability of HLA-matched sibling donors determined whether patients underwent HSCT as postremission treatment. To facilitate this process, it is important to obtain HLA typing on all younger patients with AML and siblings shortly after diagnosis. Patients who do not have an HLA-matched sibling will proceed to postremission therapy with chemotherapy alone.
In HSCT, very high doses of chemotherapy with or without total-body radiation (TBI) are given in an attempt to potentiate leukemia cell kill. Hematopoiesis is restored by the infusion of stem cells harvested from an HLA-compatible donor, thereby rescuing the patient from the consequences of total aplasia.15 It is the most effective antileukemic therapy currently available.
Transplantations from nonidentical sources have many complications, including graft-versus-host disease (GVHD), delayed or incomplete engraftment, and an increased likelihood of opportunistic infections that increase morbidity and mortality substantially. An immunological effect of the donor marrow on residual host-leukemic cells may translate into antileukemic activity, however, as indicated by the lower relapse rates in patients with GVHD. This graft-versus-leukemia (GVL) effect also accounts for the success of allo-HSCT.
Transplant-related mortality following matched-sibling allo-HSCT is 20% to 30% in most series. Complications from transplantation increase with age; therefore, patients older than 60 years of age are uncommonly considered to receive a myeloablative allo-HSCT. Since the average age of AML patients is 65 years, most patients with this disease are not candidates for this form of therapy. For older patients up to 70 years, a reduced-intensity (mini or nonmyeloblative allogeneic) transplant may be an option. These transplants use less intensive preparative regimens and rely on the allogeneic GVL effect to eliminate their disease.5
HSCT in first remission is often recommended for patients with a matched-sibling donor because of the lower relapse rate with transplant versus postremission chemotherapy. However, only 30% of patients will have an HLA-matched sibling. Some types of AML patients may be curable with conventional-dose chemotherapy alone. Thus indiscriminate use of allo-HSCT could reduce the rate and quality of survival in these individuals.
Autologous Hematopoietic Stem Cell Transplantation
Since the majority of AML patients lack a HLA-identical donor, investigators began to consider the use of the patient’s own bone marrow, obtained while in CR, as a source of hematopoietic regeneration. However, relapse continues to be a problem secondary to the presence of residual disease in the graft. The DFS for patients undergoing autologous bone-marrow transplantation in first remission has been reported at 40% to 60%, with a relapse rate of 30% to 50%. Thus few investigators recommend the use of autologous transplantation, because it failed to improve outcome substantially versus standard postremission chemotherapy.3,10
CNS Therapy
The prevalence of CNS disease at diagnosis of AML ranges from 5% to 30% in various treatment series. Features associated with the risk of CNS leukemia include hyperleukocytosis, monocytic, or myelomonocytic leukemia (FAB M4 or M5), and young age. In most cases, IT cytarabine with or without methotrexate and systemic high-dose cytarabine provide adequate CNS prophylaxis.3 Results from studies have shown that patients with CNS disease at diagnosis can be cured with IT therapy alone without the use of cranial XRT.11
AML in Infants
AML in infants younger than 12 months shows clinical and biological characteristics different from AML in older children. The phenotype is more commonly monoblastic or myelomonoblastic (M4, M5), and the patients usually present with hyperleukocytosis. Extramedullary involvement is common, often involving skin and other organs. As in infant ALL, there is a high incidence of translocations involving the MLL gene in infant AML. The number of infant AML trials reported is limited, but the EFS is similar to that of older children with AML. This is in marked contrast to the outcomes for infants with ALL, for whom the EFS is much lower than in older children (Tables 92–9and 92–10).26
AML in the Elderly
AML is the most common acute leukemia in the elderly. In comparison with younger patients with the same disease, older adults have a poor prognosis and represent a distinct population with regard to disease biology. Older adults have a lower incidence of favorable chromosomal aberrations and a higher incidence of unfavorable aberrations.10
In older adults, AML is either more likely to arise from a proximal bone marrow–stem cell disorder, such as MDS, or present as a secondary leukemia resulting from treatment with prior chemotherapy or radiation for an earlier malignancy. These forms of AML are notoriously less responsive to chemotherapy and thus have a lower CR rate and EFS.27
Older adults are not as tolerant of or as responsive to remission induction and consolidation chemotherapy as younger patients. Younger adults treated with a standard-induction regimen of an anthracycline and cytarabine have approximately 70% probability of attaining a CR, whereas patients older than 60 years of age have only a 38% to 62% probability. Further, long-term survival for patients older than 60 years is only 5% to 15% compared with 30% DFS for younger adults.10
Relapsed AML
Even though 75% to 85% of patients with AML will achieve a remission, only about 50% will survive. Patients who relapse usually respond less to treatment and have a shorter duration of remission. This is related to drug resistance during induction, certain chromosomal abnormalities, and the length of the first remission. Even though there is no standard therapy for relapse, most studies have shown that the use of high-dose cytarabine containing regimens have considerable activity in obtaining a second remission. Cytarabine has been used in combination with mitoxantrone, etoposide, fludarabine, 2-chlorodeoxyadenosine, and most recently, clofarabine.28 Once a patient has achieved a second remission with conventional chemotherapy, allo-HSCT is the therapy of choice. For patients without an HLA-matched sibling, a matched unrelated donor (MUD) or cord blood transplant may be a reasonable alternative. The combination of myeloablative high-dose chemotherapy and the GVL effect is thought to offer the best chance of survival in AML.
Complications of Treatment
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is an oncological emergency that is characterized by metabolic abnormalities resulting from the death of blast cells and the release of large amounts of purines, pyrimidines, and intracellular potassium and phosphorus. Uric acid, the ultimate breakdown product of purines, is poorly soluble in plasma and urine. Deposition of uric acid and calcium phosphate crystals in the renal tubules can lead to acute renal failure. Many patients with acute leukemia, especially those with a high tumor burden, are at risk for TLS during the first few days of chemotherapy. Measures to prevent TLS include aggressive hydration, alkalinization to help solubilize uric acid, allopurinol, and on some occasions, the use of rasburicase. Rasburicase is an enzyme that catalyzes the oxidation of uric acid to allantoin, which are more soluble and excreted more easily than uric acid.28 Given its high cost, rasburicase generally is restricted to patients with a high WBC (greater than 50 × 103/mm3, 50 × 109/L) and uric acid levels greater than 8 g/dL (476 µmol/L).29
Infection
Infection is a primary cause of death in acute leukemia patients. The majority of chemotherapy used to treat ALL and AML can cause severe myelosuppression, placing the patient at risk for sepsis from otherwise normal bacteria. It is important to recognize that symptoms and signs of infection may be absent in a severely immunosuppressed or neutropenic patient. Fever (greater than 38.3°C [100.9°F]) in a neutropenic patient is a medical emergency. Following chemotherapy, the period of neutropenia usually reaches its nadir approximately 14 days after the beginning of a course of chemotherapy and usually lasts another 7 to 14 days. In a newly diagnosed leukemic, the period of neutropenia may persist until remission is obtained. The most common sites of infection include the GI tract and vascular access devices.6
Because the progression of infection in neutropenic patients can be rapid, empirical antibiotic therapy should be administered quickly to such patients once fever is documented. Currently, the most commonly used initial antibiotic agent is cefepime, a fourth-generation cephalosporin that has good antipseudomonal coverage as well as adequate coverage against viridans streptococci and pneumococci.30
The therapy for AML is extremely myelosuppressive. Children with AML have a 10% to 20% induction mortality rate secondary to infection and bleeding complications. Therefore, patients receiving induction therapy usually are hospitalized for the first 4 to 6 weeks of therapy. The induction therapy for ALL is less myelosuppressive; therefore, these patients recover their counts quicker and usually do not require prolonged hospitalizations.6
Trimethoprim-sulfamethoxazole is started in all patients with acute leukemia for the prevention of Pneumocystis carinii pneumonia. Patients normally continue this therapy for 6 months after completion of treatment. The use of additional antibiotic prophylaxis is not encouraged in all patients with leukemia because of concerns for antibiotic resistance.
Secondary Malignancies
In children, secondary malignancies are a risk of the successful treatment for cancer. The chemotherapy agents used, especially alkylating agents and topoisomerase II inhibitors, predispose the patient to secondary hematopoietic neoplasms. As the aggressiveness of treatment and the number of survivors of ALL increase, the risk of secondary neoplasms also may rise. There are two different types of second malignancies: acute leukemia, which generally is myeloid in origin (or MDS), and solid tumors. The latency period between treatment and the development of a secondary leukemia is often several years, with leukemia being the earlier and solid tumors being the later of such events.
Secondary neoplasms induced by epipodophyllotoxins are characterized by balanced chromosomal translocations and short latency periods (2–4 years). The risk of this leukemia is related to schedule (dose intensity) and the concomitant use of other agents (L-asparaginase, alkylating agents, and possibly antimetabolites). The prognosis for topoisomerase II inhibitor–related secondary leukemia is extremely poor. Only about 10% of these patients survive after chemotherapy, and only 20% survive after HSCT. The incidence of second cancers attributed to alkylators peaks 4 to 6 years after exposure and plateaus after 10 to 15 years. Higher cumulative doses and older age at the time of treatment are risk factors for this type of cancer.31
Ionizing radiation therapy is also a cause of secondary malignancies. These secondary tumors generally develop within or adjacent to the previous radiation field. These cancers often have a prolonged latency, typically 15 to 30 years, but shorter latencies (5–14 years) are known. Higher doses of radiation and younger age are associated with an increased risk of secondary malignancy.
Unlike children, adults may have other factors that predispose them to secondary malignancies. Lifestyle choices such as tobacco use, alcohol use, and diet have been implicated in influencing the development of secondary neoplasms in the adult population.
Now that 80% or more of children survive their primary cancers, the incidence of secondary neoplasms may increase. Recognizing this potential, many treatment regimens for children are being modified appropriately to reduce exposure to alkylators, topoisomerase inhibitors, and radiation. Late effects clinics screen for secondary malignancies and other disease and treatment-related disabilities that accompany childhood cancer. Similar screening and educational opportunities are not currently established in adult survivors. The Lance Armstrong Foundation is raising awareness of the concerns of adult and pediatric cancer survivors by providing grants for research and program development in addressing the long-term issues related to disease and treatment.
Late Effects
With increased success in pediatric clinical trials, the OS rate for pediatric cancers has increased significantly over the last 35 years. For certain disease states, the OS rate for specific pediatric malignancies is now up to 80%. Although survival in pediatric cancers has improved dramatically over the last 35 years, 50% to 60% of cancer survivors are estimated to have at least one chronic or late-occurring complication of treatment.24
In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial XRT causes neuropsychological deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.25
Supportive Care
Because of the need for repeated venous access, a central venous catheter or infusion port is placed prior to starting treatment. These devices are useful not only for delivery of chemotherapy but also to support patients during periods of myelosuppression. Infection and bleeding complications are the primary cause of mortality in patients with leukemia.
Platelet transfusions are used to prevent hemorrhage. Patients with uncomplicated thrombocytopenia can be transfused when the platelet count falls below 10 × 103/mm3 (10 × 109/L). Patients who are either highly febrile or actively bleeding may require transfusions at higher levels. Red blood cell transfusions generally are not necessary for a hemoglobin concentration greater than 8 g/dL (80 g/L, 4.96 mmol/L).
There is much controversy regarding the routine use of colony-stimulating factors (e.g., G-CSF and GM-CSF) in neutropenic patients. Even though several clinical trials have shown the time to ANC recovery is decreased with a colony-stimulating factor, none have demonstrated that CSFs statistically influence infection-related mortality. At present, the use of colony-stimulating factors (G-CSF most commonly) generally is limited to those chemotherapy regimens that place the patient at highest risk for prolonged neutropenia.6
OUTCOME EVALUATION
Developing strategies for the treatment and monitoring of acute leukemias begins with risk stratification. Understanding the likely risk of relapse determines the aggressiveness and length of therapy. Remission status following the induction phase of treatment should be monitored closely by following bone marrow status and MRD. Failure to obtain morphologic bone marrow remission by day 28 is a bad prognostic sign that dictates further induction treatment. For those with morphologic remission, quantification of MRD is being used increasingly as a prognostic factor.
Patient Care and Monitoring
1. Evaluate the patient for response to therapy during induction, consolidation, and maintenance by following hematologic indices closely.
2. Review the treatment plan closely with the patient.
3. Educate the patient on potential adverse reactions and drug interactions.
4. Stress the importance of medication compliance.
5. Provide patient education regarding disease state and drug therapy:
• Possible complications of leukemia, especially infections.
• Potential side effects of drug therapy
• Warning signs to report to the physician (e.g., temperature, bruising, or bleeding)
6. Based on WBCs during ALL maintenance, is the patient receiving the appropriate dose of mercaptopurine?
7. Provide education regarding the long-term sequelae associated with the treatment for the acute leukemias.
It is important to develop a plan to educate patients and families about their drugs and doses. If modifications are necessary secondary to toxicity or inadequate response, establish a plan for treatment change. Remember that individual patients often do not fit the “average” patient profile, and dose modifications are frequently needed. The practitioner should be familiar with dosing ranges, WBC count, and other parameters that indicate “appropriate” treatment response. Based on response to prior phases of treatment, the clinician should recognize potential toxicities in subsequent phases of treatment with the same or different drugs at similar or different doses.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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