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The incidence of acute myeloid leukemia (AML) is ~3.5 per 100,000 people per year, and the age-adjusted incidence is higher in men than in women (4.3 vs 2.9). AML incidence increases with age; it is 1.7 in individuals aged <65 years and 15.9 in those aged >65 years. The median age at diagnosis is 67 years.
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Heredity, radiation, chemical and other occupational exposures, and drugs have been implicated in the development of AML. No direct evidence suggests a viral etiology.
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Certain syndromes with somatic cell chromosome aneuploidy, such as trisomy 21 noted in Down syndrome, are associated with an increased incidence of AML. Inherited diseases with defective DNA repair, e.g., Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia, are also associated with AML. Congenital neutropenia (Kostmann syndrome) is a disease with mutations in the granulocyte colony-stimulating factor (G-CSF) receptor and often neutrophil elastase that may evolve into AML. Myeloproliferative syndromes may also evolve into AML (Chap. 13). Germ-line mutations of CCAAT/enhancer-binding protein α (CEBPA), runt-related transcription factor 1 (RUNX1), and tumor protein p53 (TP53) have also been associated with a higher predisposition to AML in some series.
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High-dose radiation, like that experienced by survivors of the atomic bombs in Japan or nuclear reactor accidents, increases the risk of myeloid leukemias that peak 5–7 years after exposure. Therapeutic radiation alone seems to add little risk of AML but can increase the risk in people also exposed to alkylating agents.
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Chemical and other exposures
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Exposure to benzene, a solvent used in the chemical, plastic, rubber, and pharmaceutical industries, is associated with an increased incidence of AML. Smoking and exposure to petroleum products, paint, embalming fluids, ethylene oxide, herbicides, and pesticides have also been associated with an increased risk of AML.
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Anticancer drugs are the leading cause of therapy-associated AML. Alkylating agent–associated leukemias occur on average 4–6 years after exposure, and affected individuals have aberrations in chromosomes 5 and 7. Topoisomerase II inhibitor–associated leukemias occur 1–3 years after exposure, and affected individuals often have aberrations involving chromosome 11q23. Chloramphenicol, phenylbutazone, and, less commonly, chloroquine and methoxypsoralen can result in bone marrow failure that may evolve into AML.
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The current categorization of AML uses the World Health Organization (WHO) classification (Table 14-1), which includes different biologically distinct groups based on clinical features and cytogenetic and molecular abnormalities in addition to morphology. In contrast to the previously used French-American-British (FAB) schema, the WHO classification places limited reliance on cytochemistry. Since some of the recent literature and some ongoing studies use the FAB classification, a description of this system is also provided in Table 14-1. A major difference between the WHO and FAB systems is the blast cutoff for a diagnosis of AML as opposed to myelodysplastic syndrome it is 20% in the WHO classification and 30% in the FAB. AML with 20–30% blasts as defined by the WHO classification can benefit from therapies for MDS (such as decitabine or 5-azacytidine) that were approved by the U.S. Food and Drug Administration (FDA) based on trials using the FAB criteria. Selected components of the WHO classification are outlined below.
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Immunophenotype and relevance to the WHO classification
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The immunophenotype of human leukemia cells can be studied by multiparameter flow cytometry after the cells are labeled with monoclonal antibodies to cell-surface antigens. This can be important for separating AML from acute lymphoblastic leukemia (ALL) and identifying some types of AML. For example, AML with minimal differentiation that is characterized by immature morphology and no lineage-specific cytochemical reactions may be diagnosed by flow-cytometric demonstration of the myeloid-specific antigens cluster designation (CD) 13 and/or 117. Similarly, acute megakaryoblastic leukemia can often be diagnosed only by expression of the platelet-specific antigens CD41 and/or CD61. While flow cytometry is useful, widely used, and in some cases essential for the diagnosis of AML, it is supportive only in establishing the different subtypes of AML through the WHO classification.
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Clinical features and relevance to the WHO classification
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The WHO classification considers clinical features in subdividing AML. For example, it identifies therapy-related AML as a separate entity that develops after therapy (e.g., alkylating agents, topoisomerase II inhibitors, ionizing radiation). It also identifies AML with myelodysplasia-related changes based in part on medical history of an antecedent MDS or myelodysplastic/myeloproliferative neoplasm. The clinical features likely contribute to the prognosis of AML and have therefore been included in the classification.
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Genetic findings and relevance to the WHO classification
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The WHO classification is the first AML classification to incorporate genetic (chromosomal and molecular) information. Indeed, AML is first subclassified based on the presence or absence of specific recurrent genetic abnormalities. For example, AML FAB M3 is now designated acute promyelocytic leukemia (APL) based on the presence of either the t(15;17)(q22;q12) cytogenetic rearrangement or the PML-RARA fusion product of the translocation. A similar approach is taken with regard to core binding factor (CBF) AML that is now designated based on the presence of t(8;21)(q22;q22) or inv(16)(p13q22) or the respective fusion products RUNX1-RUNX1T1 and CBFB-MYH11. Thus, the WHO classification separates recurrent cytogenetic and/or molecular types of AML and forces the clinician to take the appropriate steps to correctly identify the entity and thus tailor treatment(s) accordingly.
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Chromosomal analysis of the leukemic cell provides the most important pretreatment prognostic information in AML. The WHO classification incorporates cytogenetics in the AML classification by recognizing a category of AML with recurrent genetic abnormalities and a category of AML with myelodysplasia-related changes (Table 14-1). The latter category is diagnosed in part by AML with selected myelodysplasia-related cytogenetic abnormalities (e.g., complex karyotypes and unbalanced and balanced changes involving among others, chromosomes 5, 7, and 11). Only one cytogenetic abnormality has been invariably associated with specific morphologic features: t(15;17)(q22;q12) with APL. Other chromosomal abnormalities have been associated primarily with one morphologic/immunophenotypic group, including inv(16)(p13q22) with AML with abnormal bone marrow eosinophils; t(8;21)(q22;q22) with slender Auer rods, expression of CD19, and increased normal eosinophils; and t(9;11)(p22;q23) and other translocations involving 11q23 with monocytic features. Recurring chromosomal abnormalities in AML may also be associated with specific clinical characteristics. More commonly associated with younger age are t(8;21) and t(15;17) and with older age, del(5q) and del(7q). Myeloid sarcomas (see below) are associated with t(8;21), and disseminated intravascular coagulation (DIC) with t(15;17).
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Molecular classification
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Molecular study of many recurring cytogenetic abnormalities has revealed genes that may be involved in leukemogenesis; this information is increasingly being incorporated into the WHO classification. For instance, t(15;17) results in the fusion gene PML-RARA that encodes a chimeric protein, promyelocytic leukemia (Pml)–retinoic acid receptor α (Rarα), which is formed by the fusion of the retinoic acid receptor α (RARA) gene from chromosome 17, and the promyelocytic leukemia (PML) gene from chromosome 15. The RARA gene encodes a member of the nuclear hormone receptor family of transcription factors. After binding retinoic acid, RARA can promote expression of a variety of genes. The 15;17 translocation juxtaposes PML with RARA in a head-to-tail configuration that is under the transcriptional control of PML. Three different breakpoints in the PML gene lead to various fusion protein isoforms. The Pml-Rarα fusion protein tends to suppress gene transcription and blocks differentiation of the cells. Pharmacologic doses of the Rarα ligand, all-trans-retinoic acid (tretinoin), relieve the block and promote hematopoietic cell differentiation (see below). Similar examples of molecular subtypes of the disease included in the category of AML with recurrent genetic abnormalities are those characterized by the leukemogenic fusion genes RUNX1-RUNX1T1, CBFB-MYH11, MLLT3-MLL, and DEK-NUP214, resulting, respectively, from t(8;21), inv(16), t(9;11), and t(6;9)(p23;q34).
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Two new provisional entities defined by the presence of gene mutations, rather than macroscopic chromosomal abnormalities, have been recently added to the category of AML with recurrent genetic abnormalities: AML with mutated nucleophosmin (NPM1) and AML with mutated CEBPA. AML with fms-related tyrosine kinase 3 (FLT3) mutations is not considered a distinct entity, although determining the presence of such mutations is recommended by WHO in patients with cytogenetically normal AML (CN-AML) because the relatively frequent FLT3-internal tandem duplication (ITD) carries a negative prognostic significance and therefore is clinically relevant (Table 14-2). FLT3 encodes a tyrosine kinase receptor important in the development of myeloid and lymphoid lineages. Activating mutations of FLT3 are present in ~30% of adult AML patients due to ITD in the juxtamembrane domain or mutations of the activating loop of the kinase. Continuous activation of the FLT3-encoded protein provides increased proliferation and antiapoptotic signals to the myeloid progenitor cell. FLT3-ITD, the more common of the FLT3 mutations, occurs preferentially in patients with CN-AML. The importance of identifying FLT3-ITD at diagnosis relates to the fact that it not only is useful in prognostication but also may predict response to specific treatment such as the tyrosine kinase inhibitors that are being tested in clinical trials.
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Other molecular prognostic factors (Table 14-2) in AML include v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) mutations that are found in 25–30% of t(8;21) or inv(16) patients. Others include Wilms' tumor 1 (WT1) mutations found in 10–13% of CN-AML and overexpression of genes such as brain and acute leukemia, cytoplasmic (BAALC), ets erythroblastosis virus E26 oncogene homologue (avian) (ERG), meningioma (disrupted in balanced translocation) 1 (MN1), and MDS1 and EVI1 complex locus (MECOM, also known as EVI1), which predict for poor outcome in CN-AML. The applicability of screening for these molecular aberrations to AML classification and clinical practice is being tested.
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With progress in genomics technology including genomewide investigation of gene mutations and expression levels, additional aberrations are being discovered, underscoring the molecular heterogeneity of AML. The applicability of gene expression profiling to diagnosis and outcome prediction of cytogenetic and molecular subsets of AML patients and to clinical management of AML is under active investigation. MicroRNAs, naturally occurring noncoding RNAs, have been shown to regulate the expression of proteins involved in hematopoietic differentiation and survival pathways by degradation or translation inhibition of target coding RNAs. Deregulated expression levels of microRNAs have been shown to associate with specific cytogenetic and molecular subsets of AML and predict outcome in CN-AML. Finally, massive parallel sequencing of the whole genome from AML patients' blasts is revealing previously unrecognized mutations of genes that are involved in metabolic pathways that have not been previously hypothesized to be disrupted in AML, such as mutations in the isocitrate dehydrogenase 1 (NADP+), soluble (IDH1) and isocitrate dehydrogenase 2 (NADP+), and mitochondrial (IDH2) genes.
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It is likely that once the biologic and clinical significance of these emerging genetic aberrations is understood, AML will be primarily classified molecularly to define specific entities and stratify patients to a corresponding, optimal targeting therapy.
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CLINICAL PRESENTATION
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Patients with AML most often present with nonspecific symptoms that begin gradually or abruptly and are the consequence of anemia, leukocytosis, leukopenia or leukocyte dysfunction, or thrombocytopenia. Nearly half have had symptoms for ≤3 months before the leukemia was diagnosed.
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Half mention fatigue as the first symptom, but most complain of fatigue or weakness at the time of diagnosis. Anorexia and weight loss are common. Fever with or without an identifiable infection is the initial symptom in ~10% of patients. Signs of abnormal hemostasis (bleeding, easy bruising) are noted first in 5% of patients. On occasion, bone pain, lymphadenopathy, nonspecific cough, headache, or diaphoresis is the presenting symptom.
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Rarely, patients may present with symptoms from a myeloid sarcoma that is a tumor mass consisting of myeloid blasts occurring at anatomic sites other than bone marrow. Sites involved are most commonly the skin, lymph node, gastrointestinal tract, soft tissue, and testis. This rare presentation, often characterized by chromosome aberrations (e.g., monosomy 7, trisomy 8, MLL rearrangement, inv[16], trisomy 4, t[8;21]) may precede or coincide with AML.
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Fever, splenomegaly, hepatomegaly, lymphadenopathy, sternal tenderness, and evidence of infection and hemorrhage are often found at diagnosis. Significant gastrointestinal bleeding, intrapulmonary hemorrhage, or intracranial hemorrhage occur most often in APL. Bleeding associated with coagulopathy may also occur in monocytic AML and with extreme degrees of leukocytosis or thrombocytopenia in other morphologic subtypes. Retinal hemorrhages are detected in 15% of patients. Infiltration of the gingivae, skin, soft tissues, or the meninges with leukemic blasts at diagnosis is characteristic of the monocytic subtypes and those with 11q23 chromosomal abnormalities.
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Anemia is usually present at diagnosis and can be severe. The degree varies considerably, irrespective of other hematologic findings, splenomegaly, or duration of symptoms. The anemia is usually normocytic normochromic. Decreased erythropoiesis often results in a reduced reticulocyte count, and red blood cell (RBC) survival is decreased by accelerated destruction. Active blood loss also contributes to the anemia.
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The median presenting leukocyte count is about 15,000/μL. Between 25 and 40% of patients have counts <5000/μL, and 20% have counts >100,000/μL. Fewer than 5% have no detectable leukemic cells in the blood. The morphology of the malignant cell varies in different subsets. In AML, the cytoplasm often contains primary (nonspecific) granules, and the nucleus shows fine, lacy chromatin with one or more nucleoli characteristic of immature cells. Abnormal rod-shaped granules called Auer rods are not uniformly present, but when they are, myeloid lineage is virtually certain (Fig. 14-1). Poor neutrophil function may be noted functionally by impaired phagocytosis and migration and morphologically by abnormal lobulation and deficient granulation.
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Platelet counts <100,000/μL are found at diagnosis in ~75% of patients, and about 25% have counts <25,000/μL. Both morphologic and functional platelet abnormalities can be observed, including large and bizarre shapes with abnormal granulation and an inability of platelets to aggregate or adhere normally to one another.
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Pretreatment evaluation
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When a diagnosis of AML is suspected, a rapid evaluation and initiation of appropriate therapy should follow (Table 14-3). In addition to clarifying the subtype of leukemia, initial studies should evaluate the overall functional integrity of the major organ systems, including the cardiovascular, pulmonary, hepatic, and renal systems. Factors that have prognostic significance, either for achieving complete remission (CR) or for predicting the duration of CR, should also be assessed before initiating treatment, including cytogenetics and molecular markers (at least NMP1 and CEBPA mutations and FLT3-ITD in CN-AML). Leukemic cells should be obtained from all patients and cryopreserved for future use as new tests and therapeutics become available. All patients should be evaluated for infection.
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Most patients are anemic and thrombocytopenic at presentation. Replacement of the appropriate blood components, if necessary, should begin promptly. Because qualitative platelet dysfunction or the presence of an infection may increase the likelihood of bleeding, evidence of hemorrhage justifies the immediate use of platelet transfusion, even if the platelet count is only moderately decreased.
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About 50% of patients have a mild to moderate elevation of serum uric acid at presentation. Only 10% have marked elevations, but renal precipitation of uric acid and the nephropathy that may result is a serious but uncommon complication. The initiation of chemotherapy may aggravate hyperuricemia, and patients are usually started immediately on allopurinol and hydration at diagnosis. Rasburicase (recombinant uric oxidase) is also useful for treating uric acid nephropathy and often can normalize the serum uric acid level within hours with a single dose of treatment. The presence of high concentrations of lysozyme, a marker for monocytic differentiation, may be etiologic in renal tubular dysfunction, which could worsen other renal problems that arise during the initial phases of therapy.
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Many factors influence the likelihood of entering CR, the length of CR, and the curability of AML. CR is defined after examination of both blood and bone marrow. The blood neutrophil count must be ≥1000/μL and the platelet count ≥100,000/μL. Hemoglobin concentration is not considered in determining CR. Circulating blasts should be absent. While rare blasts may be detected in the blood during marrow regeneration, they should disappear on successive studies. The bone marrow should contain <5% blasts, and Auer rods should be absent. Extramedullary leukemia should not be present.
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For patients in morphologic CR, immunophenotyping to detect minute populations of blasts, reverse transcriptase polymerase chain reaction (RT-PCR) to detect AML-associated molecular abnormalities, and either metaphase cytogenetics or interphase cytogenetics by fluorescence in situ hybridization (FISH) to detect AML-associated cytogenetic aberrations are currently being investigated to assess whether residual disease that has clinical significance is present following treatment. Detection of minimal residual disease may become a reliable discriminator between patients in CR who do or do not require additional and/or alternative therapies. In APL, detection of the PML-RARA fusion gene transcript by RT-PCR in bone marrow and/or blood during CR predicts relapse, and this assay is being routinely used in the clinic to anticipate clinical relapse and initiate timely salvage treatment. In other types of AML, the clinical relevance of minimal residual disease requires further investigation.
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Age at diagnosis is among the most important risk factors. Advancing age is associated with a poorer prognosis, in part because of its influence on the patient's ability to survive induction therapy. Age also influences outcome because AML in older patients differs biologically. The leukemic cells in elderly patients more commonly express the multidrug resistance 1 (MDR1) efflux pump that conveys resistance to natural product–derived agents such as the anthracyclines (see below). With each successive decade of age, a greater proportion of patients have more resistant disease. Chronic and intercurrent diseases impair tolerance to rigorous therapy; acute medical problems at diagnosis reduce the likelihood of survival. Performance status, independent of age, also influences ability to survive induction therapy and thus respond to treatment.
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A prolonged symptomatic interval with cytopenias preceding diagnosis or a history of an antecedent hematologic disorder is another pretreatment clinical feature associated with a lower CR rate and shorter survival time. The CR rate is lower in patients who have had anemia, leukopenia, and/or thrombocytopenia for >3 months before the diagnosis of AML compared with those without such a history. Responsiveness to chemotherapy declines as the duration of the antecedent disorder(s) increases. AML developing after treatment with cytotoxic agents for other malignancies is usually difficult to treat successfully.
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A high presenting leukocyte count in some series is an independent prognostic factor for attaining a CR. Among patients with hyperleukocytosis (>100,000/μL), early central nervous system bleeding and pulmonary leukostasis contribute to poor outcome with initial therapy.
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Chromosome findings at diagnosis are currently the most important independent prognostic factor. Patients with t(15;17) have a very good prognosis (approximately 85% cured), and those with t(8;21) and inv(16) a good prognosis (approximately 55% cured), while those with no cytogenetic abnormality have a moderately favorable outcome (approximately 40% cured). Patients with a complex karyotype, t(6;9), inv(3), or -7 have a very poor prognosis.
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For patients lacking prognostic cytogenetic abnormalities, such as those with CN-AML, outcome prediction utilizes molecular genetic abnormalities. NPM1 mutations without concurrent presence of FLT3-ITD, and CEBPA mutations, especially if concurrently present in two different alleles, have been shown to predict favorable outcome, whereas FLT3-ITD predicts a poor outcome. Given the prognostic importance of NPM1 and CEBPA mutations and FLT3-ITD, molecular assessment of these genes at diagnosis have been incorporated in AML management guidelines by the National Comprehensive Cancer Network (NCCN) and the European Leukemia Net (ELN). Other molecular aberrations (Table 14-2) may in the future be utilized for prognostication.
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In addition to pretreatment variables such as age, leukocyte count, and cytogenetics and/or molecular genetic aberrations, several treatment factors correlate with prognosis in AML, including, most importantly, achievement of CR. In addition, patients who achieve CR after one induction cycle have longer CR durations than those requiring multiple cycles.
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TREATMENT: Acute Myeloid Leukemia
Treatment of a newly diagnosed patient with AML is usually divided into two phases, induction and postremission management (Fig. 14-2). The initial goal is to quickly induce CR. When CR is obtained, further therapy must be used to prolong survival and achieve cure. The initial induction treatment and subsequent postremission therapy are often chosen based on the patient's age. Intensifying therapy with traditional chemotherapy agents such as cytarabine and anthracyclines in younger patients (<60 years) appears to increase the cure rate of AML. In older patients the benefit of intensive therapy is controversial; novel therapies are being pursued.
INDUCTION CHEMOTHERAPY The most commonly used CR induction regimens (for patients other than those with APL) consist of combination chemotherapy with cytarabine and an anthracycline. Cytarabine is a cell cycle S-phase–specific antimetabolite that becomes phosphorylated intracellularly to an active triphosphate form that interferes with DNA synthesis. Anthracyclines are DNA intercalators. Their primary mode of action is thought to be inhibition of topoisomerase II, leading to DNA breaks. Cytarabine is usually administered as a continuous intravenous infusion for 7 days. Anthracycline therapy generally consists of daunorubicin intravenously on days 1, 2, and 3 (the 7 and 3 regimen). Treatment with idarubicin for 3 days in conjunction with cytarabine by 7-day continuous infusion is at least as effective as daunorubicin in younger patients. The addition of etoposide may improve the CR duration. When combined with cytarabine in a 7 and 3 regimen, a higher dose of anthracycline (i.e., daunorubicin 90 mg/m2) improves outcome compared with a lower dose (i.e., daunorubicin 45 mg/m2).
After induction chemotherapy, if persistence of leukemia is documented, the patient is usually retreated with cytarabine and an anthracycline in doses similar to those given initially, but for 5 and 2 days, respectively. Our recommendation, however, is to consider changing therapy in this setting.
With the 7 and 3 cytarabine/daunorubicin regimen outlined above, 65–75% of adults with de novo AML younger than age 60 years achieve CR. Two-thirds achieve CR after a single course of therapy, and one-third require two courses. About 50% of patients who do not achieve CR have a drug-resistant leukemia, and 50% do not achieve CR because of fatal complications of bone marrow aplasia or impaired recovery of normal stem cells. A higher induction treatment–related mortality rate and frequency of resistant disease have been observed with increasing age and in patients with prior hematologic disorders (MDS or myeloproliferative syndromes) or chemotherapy treatment for another malignancy.
Patients who fail to attain CR after two induction courses should be treated with an allogeneic hematopoietic stem cell transplant (HSCT) if an appropriate donor exists. Whether achievement of cytoreduction of disease burden with a salvage treatment should be attempted before a patient with refractory disease after two induction courses can proceed to HSCT is controversial.
High-dose cytarabine-based regimens have high CR rates after a single cycle of therapy. When given in high doses, more cytarabine may enter the cells; saturate the cytarabine-inactivating enzymes; and increase the intracellular levels of 1-β-d-arabinofuranylcytosine-triphosphate, the active metabolite incorporated into DNA. Thus, higher doses of cytarabine may increase the inhibition of DNA synthesis and thereby overcome resistance to standard-dose cytarabine. In two randomized studies, high-dose cytarabine with an anthracycline produced CR rates similar to those achieved with standard 7 and 3 regimens. However, the CR duration was longer after high-dose cytarabine than after standard-dose cytarabine.
The hematologic toxicity of high-dose cytarabine-based induction regimens has typically been greater than that associated with 7 and 3 regimens. Toxicity with high-dose cytarabine includes myelosuppression, pulmonary toxicity, and significant and occasionally irreversible cerebellar toxicity. All patients treated with high-dose cytarabine must be closely monitored for cerebellar toxicity. Full cerebellar testing should be performed before each dose, and further high-dose cytarabine should be withheld if evidence of cerebellar toxicity develops. This toxicity occurs more commonly in patients with renal impairment and in those older than age 60 years. The increased toxicity observed with high-dose cytarabine has limited the use of this therapy in elderly AML patients.
Because of the negative impact of age on outcome when treatment with conventional chemotherapy is administered, clinical trials in elderly patients have focused on new agents or alternative approaches such as reduced-intensity allogeneic HSCT. Among these, one promising therapy is decitabine, a nucleoside analogue that inhibits DNA methyltransferase, reverses aberrant DNA methylation, and subsequently induces transcription of otherwise silenced tumor suppressor genes in AML cells. Interestingly, this effect on inhibiting DNA methyltransferase occurs at a much lower dose than previously used with this agent to produce a cytotoxic effect in AML. Low-dose decitabine yields complete responses in older patients with AML, including those with unfavorable karyotypes. Other agents with relatively favorable toxicity profiles such as clofarabine have activity in older patients with AML.
SUPPORTIVE CARE Measures geared to supporting patients through several weeks of granulocytopenia and thrombocytopenia are critical to the success of AML therapy. Patients with AML should be treated in centers expert in providing supportive measures.
Multilumen right atrial catheters should be inserted as soon as patients with newly diagnosed AML have been stabilized. They should be used thereafter for administration of intravenous medications and transfusions, as well as for blood drawing.
Adequate and prompt blood bank support is critical to therapy of AML. Platelet transfusions should be given as needed to maintain a platelet count ≥10,000/μL. The platelet count should be kept at higher levels in febrile patients and during episodes of active bleeding or DIC. Patients with poor posttransfusion platelet count increments may benefit from administration of platelets from human leukocyte antigen (HLA)–matched donors. RBC transfusions should be administered to keep the hemoglobin level >80 g/L (8 g/dL) in the absence of active bleeding, DIC, or congestive heart failure, which require higher hemoglobin levels. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. Blood products should also be irradiated to prevent transfusion associated graft-versus-host disease (GVHD). Cytomegalovirus (CMV)-negative blood products should be used for CMV-seronegative patients who are potential candidates for allogeneic HSCT. Leukodepleted products are also effective for these patients if CMV-negative products are not available.
Infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML. Antibacterial (i.e., quinolones) and antifungal (e.g, fluconazole, posaconazole) prophylaxis in the absence of fever is likely to be beneficial. For patients who are herpes simplex virus– or varicella zoster–seropositive, antiviral prophylaxis should be initiated.
Fever develops in most patients with AML, but infections are documented in only half of febrile patients. Early initiation of empirical broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications (Chap. 29). An antibiotic regimen adequate to treat gram-negative organisms should be instituted at the onset of fever in a granulocytopenic patient after clinical evaluation, including a detailed physical examination with inspection of the indwelling catheter exit site and a perirectal examination, as well as procurement of cultures and radiographs aimed at documenting the source of fever. Specific antibiotic regimens should be based on antibiotic sensitivity data obtained from the institution at which the patient is being treated. Acceptable regimens for empiric antibiotic therapy include monotherapy with imipenem–cilastin, meropenem, piperacillin–tazobactam, or an extended-spectrum antipseudomonal cephalosporin (cefepime or ceftazidime); an aminoglycoside in combination with an antipseudomonal penicillin (e.g., piperacillin); an aminoglycoside in combination with an extended-spectrum antipseudomonal cephalosporin; and ciprofloxacin in combination with an antipseudomonal penicillin. Aminoglycosides should be avoided if possible in patients with renal insufficiency. Empirical vancomycin should be initiated in neutropenic patients with catheter-related infections, blood cultures positive for gram-positive bacteria before final identification and susceptibility testing, hypotension or shock, and increased risk for viridans group streptococcal bacteremia.
Caspofungin (or similar echinocandin) or liposomal amphotericin B should be considered for antifungal treatment if fever persists 4–7 days following initiation of empiric antibiotic therapy in a patient who has received fluconazole prophylaxis. Voriconazole has also been shown to be equivalent in efficacy and less toxic than amphotericin B. Antibacterial and antifungal antibiotics should be continued until patients are no longer neutropenic regardless of whether a specific source has been found for the fever.
Recombinant hematopoietic growth factors have been incorporated into clinical trials in AML. These trials have been designed to lower the infection rate after chemotherapy. Both G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) have reduced the median time to neutrophil recovery. This accelerated rate of neutrophil recovery, however, has not generally translated into significant reductions in infection rates or shortened hospitalizations. In most randomized studies, both G-CSF and GM-CSF have failed to improve the CR rate, disease-free survival, or overall survival. Although receptors for both G-CSF and/or GM-CSF are present on AML blasts, therapeutic efficacy is neither enhanced nor inhibited by these agents. The use of growth factors as supportive care for AML patients is controversial. We favor their use in elderly patients with complicated courses, those receiving intensive postremission regimens, patients with uncontrolled infections, and those participating in clinical trials.
TREATMENT OF PROMYELOCYTIC LEUKEMIA Tretinoin is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells. Tretinoin does not produce DIC but produces another complication called the APL differentiation syndrome. Occurring within the first 3 weeks of treatment, it is characterized by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxemia. The syndrome is related to adhesion of differentiated neoplastic cells to the pulmonary vasculature endothelium. Glucocorticoids, chemotherapy, and/or supportive measures can be effective for management of the APL differentiation syndrome. Temporary discontinuation of tretinoin is necessary in cases of severe APL differentiation syndrome (i.e., patients developing renal failure or requiring admission to the intensive care unit due to respiratory distress). The mortality rate of this syndrome is about 10%.
Tretinoin (45 mg/m2 per day orally until remission is documented) plus concurrent anthracycline-based chemotherapy appears to be among the most effective treatments for APL, leading to CR rates of 90–95%. The addition of cytarabine, although not demonstrated to increase the CR rate, seemingly decreases the risk for relapse. Following achievement of CR, patients should receive at least two cycles of anthracycline-based chemotherapy.
Given the progress made in APL, resulting in high cure rates, the goals are to identify patients with very low risk of relapse where attempts are being made to decrease the amount of therapy administered and to identify patients at greatest risk of relapse in order to develop new approaches to increase cure.
Arsenic trioxide has significant antileukemic activity and is being explored as part of initial treatment in clinical trials of APL. In a randomized trial, arsenic trioxide improved outcome if utilized after achievement of CR and before consolidation therapy with anthracycline-based chemotherapy. Additionally, studies combining arsenic trioxide with tretinoin in the absence of chemotherapy are ongoing and preliminarily have shown promise in those patients "unfit" to receive chemotherapy. Furthermore, combinations of arsenic trioxide, tretinoin, and/or chemotherapy and/or gemtuzumab ozogamicin, a monoclonal CD33 antibody linked to the cytotoxic agent calicheamicin, have shown favorable response in high-risk APL patients (i.e., those presenting with a leukocyte count ≥10,000/μL) at diagnosis. Patients receiving arsenic trioxide are at risk of APL differentiation syndrome, especially when it is administered during induction or salvage treatment after disease relapse. In addition, arsenic trioxide may prolong the QT interval, increasing the risk of cardiac arrhythmias.
Assessment of residual disease by RT-PCR amplification of the t(15;17) chimeric gene product PML-RARA following the final cycle of chemotherapy is an important step in the management of APL patients. Disappearance of the signal is associated with long-term disease-free survival; its persistence documented by two consecutive tests performed 2 weeks apart invariably predicts relapse. Sequential monitoring of RT-PCR for t(15;17) is now considered standard for postremission monitoring of APL.
Patients who continue in molecular remission may benefit from maintenance therapy with tretinoin. Patients in molecular, cytogenetic, or clinical relapse should be salvaged with arsenic trioxide; it produces meaningful responses in up to 85% of patients and can be followed by HSCT.
POSTREMISSION THERAPY Induction of a durable first CR is critical to long-term disease-free survival in AML. However, without further therapy, virtually all patients experience relapse. Once relapse has occurred, AML is generally curable only by HSCT.
Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival. Postremission therapy in AML is often based on age (younger than ages 55–65 years and older than ages 55–65 years). For younger patients, most studies include intensive chemotherapy and allogeneic or autologous HSCT. High-dose cytarabine is more effective than standard-dose cytarabine. The Cancer and Leukemia Group B (CALGB), for example, compared the duration of CR in patients randomly assigned postremission to four cycles of high (3 g/m2, every 12 hours on days 1, 3, and 5), intermediate (400 mg/m2 for 5 days by continuous infusion), or standard (100 mg/m2 per day for 5 days by continuous infusion) doses of cytarabine. A dose-response effect for cytarabine in patients with AML who were aged ≤60 years was demonstrated. High-dose cytarabine significantly prolonged CR and increased the fraction cured in patients with favorable (t[8;21] and inv[16]) and normal cytogenetics, but it had no significant effect on patients with other abnormal karyotypes. For older patients, exploration of attenuated intensive therapy that includes either chemotherapy or reduced-intensity allogeneic HSCT has been pursued. Postremission therapy is a setting for introduction of new agents (Table 14-4).
Allogeneic HSCT is used in patients ages <70–75 years with an HLA-compatible donor who have high-risk cytogenetics. In patients with CN-AML and high-risk molecular features such as FLT3-ITD, allogeneic HSCT is best applied in the context of clinical trials, as the impact of aggressive therapy on outcome is unknown. Relapse following allogeneic HSCT occurs in only a small fraction of patients, but treatment-related toxicity is relatively high; complications include venoocclusive disease, GVHD, and infections. Autologous HSCT can be administered in young and older patients and uses the same preparative regimens. Patients subsequently receive their own stem cells collected while in remission. The toxicity is relatively low with autologous HSCT (5% mortality rate), but the relapse rate is higher than with allogeneic HSCT due to the absence of the graft-versus-leukemia (GVL) effect seen with allogeneic HSCT and possible contamination of the autologous stem cells with residual tumor cells. Purging tumor from the autologous stem cells has not lowered the relapse rate with autologous HSCT.
Randomized trials comparing intensive chemotherapy and autologous and allogeneic HSCT have shown an improved duration of remission with allogeneic HSCT compared with autologous HSCT or chemotherapy alone. However, overall survival is generally not different; the improved disease control with allogeneic HSCT is erased by the increase in fatal toxicity. While stem cells were previously harvested from the bone marrow, virtually all efforts currently collect these from the blood following mobilization regimens. Prognostic factors may help select patients in first CR for whom transplant is most effective.
Our approach includes allogeneic HSCT if feasible in first CR for patients with high-risk karyotypes (Fig. 14-2). Patients with CN-AML who have other poor risk factors (e.g., an antecedent hematologic disorder, or failure to attain remission with a single induction course) and patients lacking a favorable genotype (e.g., patients who do not have CEBPA mutations or NPM1 mutations without FLT3-ITD) are also potential candidates. If a suitable HLA donor does not exist, investigational therapeutic approaches are considered. As FLT3-ITD can be targeted with emerging novel inhibitors, patients with this molecular abnormality should be considered for clinical trials with these agents whenever possible. New transplant strategies, including reduced-intensity HSCT, are being explored for consolidation of high-risk AML patients (Chap. 30). Patients with t(8;21) and inv(16) are treated with repetitive doses of high-dose cytarabine, which offers a high frequency of cure without the morbidity of transplant. In AML patients with t(8;21) and inv(16), those with KIT mutations, who have a worse prognosis, may be considered for novel investigational studies.
Autologous HSCT is generally applied to AML patients only in the context of a clinical trial or when the risk of repetitive intensive chemotherapy represents a higher risk than the autologous HSCT (e.g., in patients with severe platelet alloimmunization).
RELAPSE Once relapse occurs, patients are rarely cured with further standard-dose chemotherapy. Patients eligible for allogeneic HSCT should receive transplants expeditiously at the first sign of relapse. Long-term disease-free survival is approximately the same (30–50%) with allogeneic HSCT in first relapse or in second remission. Autologous HSCT rescues about 20% of relapsed patients with AML who have chemosensitive disease. The most important factors predicting response at relapse are the length of the previous CR, whether initial CR was achieved with one or two courses of chemotherapy, and the type of postremission therapy. Because of the poor outcome of patients in early first relapse (<12 months), it is justified (for patients without HLA-compatible donors) to explore innovative approaches, such as new drugs or immunotherapies (Table 14-4). Patients with longer first CRs (>12 months) generally relapse with drug-sensitive disease and have a higher chance of attaining a CR. However, cure is uncommon, and treatment with novel approaches should be considered if allogeneic HSCT is not possible. New agents that may have clinical activity in AML are needed, and many are being tested in clinical trials (Table 14-4).
For elderly patients (age >60 years) for whom clinical trials are not available, gemtuzumab ozogamicin is another alternative. The CR rate with this agent is ~30%. However, its effectiveness in early relapsing (<6 months) or refractory AML patients is limited, possibly due to calicheamicin being a potent MDR1 substrate. Toxicity, including myelosuppression, infusion toxicity, and venoocclusive disease, can be observed with gemtuzumab ozogamicin. Pretreatment with glucocorticoids can diminish many of the associated infusion reactions. Studies are examining this treatment in combination with chemotherapy for both young and older patients with previously untreated AML. This agent has been withdrawn from the U.S. market at the request of the U.S. FDA due to concerns about the product's safety and clinical benefit as shown in trials subsequent to those leading to its accelerated approval.
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