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AML

Background
Acute myelogenous leukemia (AML) is a malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow. The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. (See Pathophysiology.) Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor. (See Etiology.) Patients with AML present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. (See Clinical.) Workup for AML includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), analysis of genetic abnormalities, and diagnostic imaging. (See Workup.) Current standard chemotherapy regimens cure only a minority of patients with AML. As a result, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy. (See Treatment.) For consolidation chemotherapy or for the management of toxic effects of chemotherapy, readmission is required.

Pathophysiology
The underlying pathophysiology in AML consists of a maturational arrest of bone marrow cells in the earliest stages of development. The mechanism of this arrest is under study, but in many cases, it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.[1, 2] This developmental arrest results in 2 disease processes. First, the production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. Second, the rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, the blood, and, frequently, the spleen and liver.

Etiology

Several factors have been implicated in the causation of AML, including antecedent hematologic disorders, familial syndromes, environmental exposures, and drug exposures. However, most patients who present with de novo AML have no identifiable risk factor.

Antecedent hematologic disorders


The most common risk factor for AML is the presence of an antecedent hematologic disorder, the most common of which is myelodysplastic syndrome (MDS). MDS is a bone marrow disease of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years. Patients with lowrisk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop AML, whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do. Other antecedent hematologic disorders that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.

Congenital disorders
Some congenital disorders that predispose patients to AML include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis. Usually, these patients develop AML during childhood; rarely, some may present in young adulthood. More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to AML. For example, polymorphisms of NAD(P)H:quinone oxidoreductase (NQO1), an enzyme that metabolizes benzene derivatives, are associated with an increased risk of AML.[3] Particularly increased risk exists for AML that occurs after chemotherapy for another disease or for de novo AML with an abnormality of chromosomes 5, 7, or both. Likewise, polymorphisms in glutathione S -transferase are associated with secondary AML after chemotherapy for other malignancies.[4]

Familial syndromes
Germline mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for AML, an autosomal dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.[5] Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein alpha, a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by AML.[6] Taskesen et al evaluated concurrent gene mutations, clinical outcome, and gene expression signatures of CEBPA double versus single mutations in 1182 patients with

cytogenetically-normal AML (CN-AML) (aged 16-60 y).[7] Both double-mutated CEBPA and single-mutated CEBPA were associated with favorable outcome compared with wild type CEBPA (5-year overall survival (OS), 63% and 56% versus 39%; P < .0001 and P=.05, respectively). However, in multivariable analysis, only double=mutated CEBPA was a prognostic factor for favorable outcome. Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia. However, cases of leukemia are less common than the solid tumors that generally characterize these syndromes.

Environmental exposures
Several studies demonstrate a relationship between radiation exposure and leukemia. Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia. Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia. Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia. Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing AML.[8] In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke. Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.

Previous exposure to chemotherapeutic agents


As more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT]), the number of patients with AML increases because of exposure to chemotherapeutic agents. For example, the cumulative incidence of acute leukemia in patients with breast cancer who were treated with doxorubicin and cyclophosphamide as adjuvant therapy was 0.2-1.0% at 5 years.[9] Patients with previous exposure to chemotherapeutic agents can be divided into 2 groups: (1) those with previous exposure to alkylating agents and (2) those with exposure to topoisomerase-II inhibitors. Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of AML. Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7). Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).[10]

The typical latency period between drug exposure and acute leukemia is approximately 35 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.

Epidemiology
It was estimated that 13,410 new cases of AML (7060 in men; 6350 in women) would occur in the United States in 2007. AML is more commonly diagnosed in developed countries, and it is more common in whites than in other populations. The prevalence of AML increases with age. The median age of onset is approximately 70 years. However, AML affects all age groups.[11, 12] AML is more common in men than in women. The difference is even more apparent in older patients. This is likely because MDS is more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of AML in men may be related to occupational exposures (see Etiology).

Prognosis
The prognosis relies on several factors. Increasing age is an adverse factor, because older patients more frequently have a previous antecedent hematologic disorder along with comorbid medical conditions that compromise the ability to give full doses of chemotherapy. A previous antecedent hematologic disorder (most commonly, MDS) is associated with a poor outcome to therapy. Findings from cytogenetic analysis of the bone marrow constitute one of the most important prognostic factors. Patients with t(8;21), t(15;17), or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%. Patients with normal cytogenetic findings have an intermediate prognosis and have a long-term survival rate of approximately 25%. Patients with poor-risk cytogenetic findings (especially -7, -5) have a poor prognosis, with a long-term survival rate of less than 10%. Other cytogenetic abnormalities, including +8, 11q23, and miscellaneous, have been reported to be intermediate risk in some series and poor risk in others. The presence of an FLT3 mutation is associated with a poorer prognosis. Mutations in CEBPA are associated with a longer remission duration and longer overall survival. Mutations in NPM are associated with an increased response to chemotherapy. A study by Metzeler et al determined that TET2 mutations had an adverse prognostic impact in an otherwise favorable-risk patient subset using the European LeukemiaNet (ELN) molecular-risk classification of patients with primary cytogenetically normal AML.[13]

In 2007, an estimated 8990 deaths from AML occurred in the United States. Of these, 5020 occurred in men and 3970 occurred in women. In adults, treatment results are generally analyzed separately for younger (18-60 y) patients with AML and for older patients (>60 y). With current standard chemotherapy regimens, approximately 30-35% of adults younger than 60 years survive longer than 5 years and are considered cured. Results in older patients are more disappointing, with fewer than 10% of surviving over the long term. A study by Kayser et al found that therapy-related AML (t-AML) was an adverse prognostic factor for death in complete remission but not relapse and overall survival in younger intensively treated patients.[14] It was also an adverse prognostic factor for relapse but not death in complete remission in older, less intensively treated patients.

Patient Education
Patients with AML should be instructed to call their healthcare providers immediately if they are febrile or have signs of bleeding. For patient education resources, see the Blood and Lymphatic System Center and the Skin, Hair, and Nails Center, as well as Leukemia and Bruises. Proceed to Clinical Presentation

History
Patients with acute myelogenous leukemia (AML) present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks. Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder, such as myelodysplastic syndrome (MDS).

Symptoms of bone marrow failure


Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia. The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks. Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.

Patients with AML often have decreased neutrophil levels despite an increased total white blood cell (WBC) count. Patients generally present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, < 500 cells/L, especially < 100 cells/L) have the highest risk of infection. Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics. Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both. Potentially life-threatening sites of bleeding include the lungs, gastrointestinal (GI) tract, and the central nervous system.

Symptoms of organ infiltration with leukemic cells


Alternatively, symptoms may be the result of organ infiltration with leukemic cells. The most common sites of infiltration include the spleen, liver, gums, and skin. Infiltration occurs most commonly in patients with the monocytic subtypes of AML. Patients with splenomegaly note fullness in the left upper quadrant and early satiety. Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed. Patients with markedly elevated WBC counts (>100,000 cells/L) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that calls for immediate intervention. Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical Examination
Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in AML patients. Fever and other signs of infection can occur, including lung findings of pneumonia. Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder (eg, DIC). Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses. Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma).

Signs relating to leukostasis include respiratory distress and altered mental status.

Complications
Death may occur in patients with AML as a consequence of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support. The most common complication in AML patients is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because their disease usually does not respond to other chemotherapy regimens. Proceed to Differential Diagnoses

History
Patients with acute myelogenous leukemia (AML) present with symptoms resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells, or both. The time course is variable. Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks. Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder, such as myelodysplastic syndrome (MDS).

Symptoms of bone marrow failure


Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia. The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks. Other symptoms of anemia include dyspnea upon exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient. Patients with AML often have decreased neutrophil levels despite an increased total white blood cell (WBC) count. Patients generally present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, < 500 cells/L, especially < 100 cells/L) have the highest risk of infection. Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics. Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular

coagulation (DIC), or both. Potentially life-threatening sites of bleeding include the lungs, gastrointestinal (GI) tract, and the central nervous system.

Symptoms of organ infiltration with leukemic cells


Alternatively, symptoms may be the result of organ infiltration with leukemic cells. The most common sites of infiltration include the spleen, liver, gums, and skin. Infiltration occurs most commonly in patients with the monocytic subtypes of AML. Patients with splenomegaly note fullness in the left upper quadrant and early satiety. Patients with gum infiltration often present to their dentist first. Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed. Patients with markedly elevated WBC counts (>100,000 cells/L) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that calls for immediate intervention. Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical Examination
Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in AML patients. Fever and other signs of infection can occur, including lung findings of pneumonia. Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities. The petechiae are small, often punctate, hemorrhagic rashes that are not palpable. Areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder (eg, DIC). Purpura is characterized by flat bruises that are larger than petechiae but smaller than ecchymoses. Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy. Occasionally, patients have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis). Chloromata are extramedullary deposits of leukemia. Rarely, a bony or soft-tissue chloroma may precede the development of marrow infiltration by AML (granulocytic sarcoma). Signs relating to leukostasis include respiratory distress and altered mental status.

Complications
Death may occur in patients with AML as a consequence of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.

The most common complication in AML patients is failure of the leukemia to respond to chemotherapy. The prognosis for these patients is poor because their disease usually does not respond to other chemotherapy regimens. Proceed to Differential Diagnoses

Approach Considerations
Workup for acute myelogenous leukemia (AML) includes blood tests, bone marrow aspiration and biopsy (the definitive diagnostic tests), analysis of genetic abnormalities, and diagnostic imaging.

Blood Studies
Complete blood count
A complete blood count (CBC) with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with AML can have high, normal, or low white blood cell (WBC) counts.

Coagulation studies
The most common abnormality is disseminated intravascular coagulation (DIC), which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products. Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.

Peripheral blood smear


Review of the peripheral blood smear confirms the findings from the CBC count. Circulating blasts are usually seen. Schistocytes are occasionally seen if DIC is present.

Blood chemistry profile


Most patients with AML have an elevated lactate dehydrogenase (LDH) level and, frequently, an elevated uric acid level. Liver function tests and blood urea nitrogen (BUN)/creatinine level tests are necessary before the initiation of therapy.

Blood culture
Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.

Human Leukocyte Antigen or DNA Typing


Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential candidates for allogeneic transplantation.

Bone Marrow Aspiration and Biopsy


Bone marrow aspiration and biopsy are the definitive diagnostic tests for AML.

Bone marrow aspiration


A blast count can be performed with bone marrow aspiration. Historically, according to the French-American-British (FAB) classification, AML was defined by the presence of more than 30% blasts in the bone marrow. In the newer World Health Organization (WHO) classification, AML is defined as the presence of greater than 20% blasts in the marrow.[1] (See Histologic Findings.) The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines. Aspiration slides are stained for morphology with either Wright or Giemsa stain. To determine the FAB type of the leukemia, slides are also stained with myeloperoxidase (or Sudan black), terminal deoxynucleotidyl transferase (TdT) (unless performed by another method [eg, flow cytometry]), and double esterase.

Bone marrow biopsy


Bone marrow biopsy is useful for assessing cellularity. Biopsy is most important in patients in whom an aspirate cannot be obtained (dry tap). Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.

Flow Cytometry (Immunophenotyping)


Flow cytometry (immunophenotyping) can be used to help distinguish AML from acute lymphocytic leukemia (ALL and further classify the subtype of AML (see the table below). The immunophenotype correlates with prognosis in some instances. Table 1. Immunophenotyping of AML Cells (Open Table in a new window) Marker CD13 CD33 CD34 HLA-DR CD11b CD14 Lineage Myeloid Myeloid Early precursor Positive in most AML, negative in APL Mature monocytes Monocytes

CD41 Platelet glycoprotein IIb/IIIa complex CD42a Platelet glycoprotein IX CD42b Platelet glycoprotein Ib CD61 Platelet glycoprotein IIIa Glycophorin A Erythroid TdT Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1 CD11c Myeloid CD117 (c-kit) Myeloid/stem cell

Cytogenetic Analysis
Cytogenetic studies performed on bone marrow provide important prognostic information (see the tables below). They are useful for confirming a diagnosis of APL, which bears the t(15;17) chromosome abnormality and is treated differently. Table 2. Common Cytogenetic Abnormalities in AML (Open Table in a new window) Abnormality Genes Involved Morphology Response t(8;21)(q22;q22) AML/ETO M2 Good inv(16)(p13;q22) CBFb/MYH11 M4eo Good Normal Multiple Varies Intermediate -7 Multiple Varies Poor -5 Multiple Varies Poor +8 Multiple Varies Intermediate-poor 11q23 MLL Varies Intermediate-poor Miscellaneous Multiple Varies Intermediate-poor * Multiple complex Multiple Varies Poor * Refers to 3-5 different cytogenetic abnormalities, depending on the classification used. Table 3. Cytogenetic Abnormalities in APL (Open Table in a new window) Translocation t(15;17)(q21;q11) t(11;17)(q23;q11) t(11;17)(q13;q11) t(5;17)(q31;q11) t(17;17) Genes Involved All-Trans-Retinoic Acid Response PML/RARa Yes PLZF/RARa No NuMA/RARa Yes NPM/RARa Yes stat5b/RARa Unknown

Fluorescence in situ hybridization (FISH) studies can be used to get a faster overview of cytogenetic abnormalities than traditional cytogenetic studies. FISH does not replace cytogenetics.

Molecular Marrow Evaluation


Several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. The bone marrow should be evaluated at least for the commercially available tests. Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement. When possible, the bone marrow should be evaluated for Fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations. FLT3 is the most commonly mutated gene in persons with AML and is constitutively activated in one third of AML cases.[15] Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 ITDs have a poor prognosis. Analysis of FLT3 is commercially available. Mutations in NPM1 are associated with increased response to chemotherapy in patients with a normal karyotype.[16] Thiede et al studied FLT3 and NPM1 in 1485 patients with AML.[17] The analysis of the clinical impact in 4 groups (NPM1 and FLT3 -ITD single mutants, double mutants, and wild-type [wt] for both) revealed that patients having only an NPM1 mutation (without a FLT3 -ITD) had a significantly better overall and diseasefree survival and a lower cumulative incidence of relapse.[17] Analysis of NPM1 is commercially available. Mutations in CEBPA are detected in 15% of patients with normal cytogenetics findings and are associated with a longer remission duration and longer overall survival.[18]ERG overexpression is an adverse predictor in cytogenetically normal AML. A study by the Cancer and Leukemia Group B (CALGB) found that high BAALC expression was associated with FLT3-ITD, wild-type NPM1, mutated CEBPA, MLLPTD, absent FLT3-TKD and high ERG expression. In a multivariate analysis, high BAALC expression independently predicted lower complete remission rates when ERG expression and age were adjusted for and shorter survival when FLT3-ITD, NPM1, CEBPA and WBC count were adjusted for. The clinical impact of MLL partial tandem duplication (MLL-PTD) was evaluated in 238 adults aged 18 to 59 years with cytogenetically normal de novo acute myeloid leukemia who were treated by CALGB. Of the patients with MLL-PTD, 92% achieved complete remission compared with 83% of patients without MLL-PTD. Ley et al identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the cells of a patient with AML and a normal karyotype.[19] The authors sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile but were absent in all 79 patients with a favorable-risk cytogenetic profile. The median OS among patients with DNMT3A

mutations was significantly shorter than that among patients without such mutations (12.3 mo vs. 41.1 mo, P < 0.001). Schwind et al measured miR-181a expression in pretreatment marrows in 187 adults (< 60 y) with CN-AML. Higher miR-181a expression was associated with a higher complete remission (CR) rate (P =.04), longer OS (P =.01) and a trend for longer disease-free survival (P =.09). The impact of miR-181a was most striking in poor molecular risk patients with FLT3-internal tandem duplication (FLT3-ITD) and/or NPM1 wild-type, where higher miR-181a expression associated with a higher CR rate (P =.009) and longer disease-free survival (P < .001) and OS (P < .001). In multivariable analyses, higher miR-181a expression was significantly associated with better outcome, both in the whole patient cohort and in patients with FLT3-ITD and/or NPM1 wild-type. These results were also validated in an independent set of older (60 y) patients with CN-AML.[20] Gene-expression profiling is a research tool that allows a comprehensive classification of acute myelogenous leukemia (AML) based on the expression pattern of thousands of genes.

Other Tests
Gene-expression profiling is a research tool that allows a comprehensive classification of AML based on the expression pattern of thousands of genes.[21] Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with AML. Multiple gated acquisition (MUGA) scanning is needed once the diagnosis of AML is confirmed because many chemotherapeutic agents used in treatment are cardiotoxic. Electrocardiography should be performed before treatment of AML.

Histologic Findings
The traditional FAB classification of AML is as follows:

M0 - Undifferentiated leukemia M1 - Myeloblastic without differentiation M2 - Myeloblastic with differentiation M3 - Promyelocytic M4 Myelomonocytic; M4eo - Myelomonocytic with eosinophilia M5 - Monoblastic leukemia; M5a - Monoblastic without differentiation; M5b Monocytic with differentiation M6 - Erythroleukemia M7 - Megakaryoblastic leukemia

The newer WHO classification is as follows[1] :

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), (CBFB/MYH11); APL with t(15;17)(q22;q12), (PML/RARa) and variants; AML with 11q23 (MLL) abnormalities AML with multilineage dysplasia - Following myelodysplastic syndrome (MDS) or MDS/myeloproliferative disease (MPD); without antecedent MDS or MDS/MPD but with dysplasia in at least 50% of cells in 2 or more lineages AML and MDS, therapy related - Alkylating agent or radiation-related type; topoisomerase II inhibitor type; others AML, not otherwise classified - AML, minimally differentiated; AML, without maturation; AML, with maturation; acute myelomonocytic leukemia; acute monoblastic or monocytic leukemia; acute erythroid leukemia; acute megakaryoblastic leukemia; acute basophilic leukemia; acute panmyelosis and myelofibrosis; myeloid sarcoma

Proceed to Treatment & Management

Approach Considerations
Current standard chemotherapy regimens cure only a minority of patients with acute myelogenous leukemia (AML). As a result, all patients should be evaluated for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy (see below). For consolidation chemotherapy or for the management of toxic effects of chemotherapy, readmission is required. When receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections. Any patient with neutropenic fever or infection should immediately be treated with broad-spectrum antibiotics. Appropriate transfusion support must be provided to patients with AML. This includes transfusion of platelets and clotting factors (fresh frozen plasma [FFP], cryoprecipitate) as guided by the patients blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease (GVHD). Patients with AML are best treated at a center whose staff has significant experience in the treatment of leukemia. Patients should be transferred to an appropriate (generally tertiary care) hospital if they are admitted to hospitals without appropriate blood product support, leukapheresis capabilities, or physicians and nurses familiar with the treatment of leukemia patients. Chemotherapy for AML is discussed separately from therapy for acute promyelocytic leukemia (APL) and therapy for relapsed AML (see below).

Chemotherapy for Acute Myelogenous Leukemia


Induction therapy
Various acceptable induction regimens are available. The most common approach, "3 and 7," consists of 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone), combined with 100 mg/m2 of cytarabine (arabinosylcytosine; ara-C) as a 24-hour infusion daily for 7 days. Traditionally, the dosage of idarubicin has been 12 mg/m2/d for 3 days, the dosage of daunorubicin has been 45-60 mg/m2/d for 3 days, and the dosage of mitoxantrone has been 12 mg/m2/d for 3 days. These regimens require adequate cardiac, hepatic, and renal function. On these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% of patients enter remission after a second course of therapy. In a study by Fernandez et al, 657 patients younger than 60 years with untreated AML received either conventional-dose daunorubicin (45 mg/m2/d for 3 d) or high-dose daunorubicin (90 mg/m2/d for 3 d).[22] These induction regimens were administered with cytarabine 100 mg/m2/d for 7 days for the first cycle. A higher rate of complete remission was observed in the high-dose daunorubicin group (70.6%) relative to the conventional dose (57.3%) as well as an improved overall survival (median, 23.7 mo) compared with the group administered the conventional dose (15.7 mo).[22] In a similar study in patients 60 years of age or older by Lowenberg et al, 813 patients received either conventional-dose treatment (daunorubicin 45 mg/m2/d for 3 d) or escalated-dose treatment (daunorubicin 90 mg/m2/d for 3 d), both administered over 3 hours on days 1, 2, and 3.[23] In both cases, patients received cytarabine 200 mg/m2/d as a continuous infusion for 7 days. The complete remission rate was 64% in the escalated-dose group compared with 54% in conventional-dose group. No significant difference was seen between the groups in terms of hematologic toxic effects, 30-day mortality, or other significant adverse events. Although survival endpoints did not differ overall, there was an improvement in complete remission rate, event-free survival, and overall survival in patients aged 60-65 years.[23] Alternatively, high-dose cytarabine combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose cytarabine outside the setting of a clinical trial is considered controversial. However, 2 studies demonstrated improved disease-free survival rates in younger patients who received high-dose cytarabine during induction.

A study of dosing regimens for cytarabine induction therapy determined that lower doses produce maximal antileukemic effects for all response end points.[24] Thus, high-dose cytarabine results in excessive toxic effects with no therapeutic advantage.

Consolidation therapy in younger patients


In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose cytarabine, autologous stem cell transplantation, and allogeneic stem cell transplantation. Mayer et al conducted a randomized study of 3 different doses of cytarabine in patients with AML who achieved remission after standard 3 and 7 induction chemotherapy.[25] Patients received 4 courses of cytarabine at one of the following dosages: (1) 100 mg/m2/d by continuous infusion for 5 days, (2) 400 mg/m2/d by continuous infusion for 5 days, or (3) 3 g/m2 in a 3-hour infusion every 12 hours on days 1, 3, and 5. The probability of remaining in continuous complete remission after 4 years in patients aged 60 years or younger was 24% in the 100-mg group, 29% in the 400-mg group, and 44% in the 3-g group. The outcome in older patients did not differ. On the basis of this study, high-dose cytarabine for 4 cycles is a standard option for consolidation therapy in younger patients.[25] In order to define the best postremission therapy for young patients, several large, randomized studies have compared allogeneic bone marrow transplantation (BMT), autologous BMT, and chemotherapy without BMT. Unfortunately, the results of these studies are conflicting. Some studies suggest an advantage to BMT. In a Dutch study, patients received either allogeneic BMT or autologous BMT, depending on the availability of a human leukocyte antigen (HLA)-matched sibling donor.[26] There was a decreased rate of relapse at 3 years (34%) and an increased overall survival rate (66%) for patients receiving allogeneic BMT compared with those receiving autologous BMT (60% and 37%, respectively). However, the median patient age in the allogeneic BMT group was 10 years younger than that in the autologous BMT group. In the Medical Research Council AML 10 trial, patients without an HLA-matched donor received 4 courses of intensive chemotherapy followed by either no further treatment or autologous BMT.[27] In this study, the number of relapses was lower for patients receiving autologous BMT (37%) versus no further treatment (58%), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT (53%) versus no further treatment (40%).[27] However, no improvement in the overall survival rate at 7 years was observed for autologous BMT (57%) versus no further treatment (45%).

In a European Organization for Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche Maligne dellAdulto (GIMEMA) study, patients with an HLA-identical sibling underwent allogeneic BMT.[28] Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose cytarabine and daunorubicin. The disease-free survival rate at 4 years was 55% for patients who received allogeneic BMT, 48% for patients who received autologous BMT, and 30% for patients who received intensive chemotherapy. Again, the overall survival rate was similar in all 3 groups, because patients who had a relapse after chemotherapy had a response to subsequent autologous BMT. Several other studies, however, have failed to show any advantage to BMT. In a study by Groupe Ouest Est Leucemies Aigues Myeloblastiques, patients as old as 40 years with a matched donor received allogeneic BMT.[29] All other patients received a course of consolidation chemotherapy with high-dose cytarabine and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. The type of postremission therapy had no effect on outcome. In a North American Intergroup study, patients in remission with a matched donor received allogeneic BMT.[30] Other patients randomly received either autologous BMT or one additional course of high-dose cytarabine. In this study, the survival rate was better for patients receiving chemotherapy without BMT than for patients in the other groups. In view of these conflicting results, the following recommendations can be made:

Patients with good-risk AML (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis after consolidation with high-dose cytarabine and should be offered such therapy. This is given as cytarabine at 3 g/m2 twice a day on days 1, 3, and 5 of each cycle, repeated monthly (after recovery from the previous cycle) for 4 consolidation cycles. Alternatively, autologous transplantation can be given after (typically) 1-2 cycles of consolidation therapy. Allogeneic stem cell transplantation should be reserved for patients who relapse. Patients with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission. However, these patients also are at high risk for a relapse following transplantation. The best approach for patients with intermediate-risk cytogenetics findings is controversial. Some refer patients in first remission for transplantation, whereas others give consolidation chemotherapy with high-dose cytarabine for 4 courses and reserve transplantation for patients who relapse. Studies using newer molecular markers, such as FLT3, NPM1, CEBPa, BAALC, and ERG, are helping to define which patients with cytogenetically normal AML should receive standard consolidation therapy versus transplantation. Before referral for allogeneic transplantation, a suitable donor must be identified. Ideally, this is a fully HLA-matched sibling; however, many patients do not have such a donor. In these patients, alternatives include transplantation using a

matched unrelated donor or using cord blood. Newer studies are examining the possibility of transplanting across HLA barriers (ie, with haploidentical-related donors) via intensive conditioning regimens and high doses of infused CD34+ donor cells.

Therapy in older patients


Overall, the results of treatment of AML in elderly patients (particularly those older than 75 years) remain unsatisfactory. In a Cancer and Leukemia Group B (CALGB) study, patients older than 60 years had a complete remission rate of 47% after standard therapy. There were 31% aplastic deaths, and only 9% of patients were alive at 4 years. It should be noted that patients with antecedent hematologic disorders were excluded; accordingly, these results overestimate the benefit of chemotherapy in elderly patients. Many patients are never referred for treatment, because of serious comorbid medical conditions and the knowledge that the treatment results are poor in this group of patients. For example, Menzin et al analyzed Medicare claims for treatment of AML.[31] In this study, only 30% of patients received chemotherapy (44% of patients aged 65-74 y, 24% of patients aged 75-84 y, and only 6% of patients 85 y or older). Despite this, approximately 90% of patients were hospitalized and the patients spent approximately one third of their remaining days in the hospital. Therefore, novel treatments need to be developed for this patient population.[31] There is evidence that patients who are treated have improved survival over those who are not treated. In the study by Menzin et al, the median survival was 6.1 months for patients who received chemotherapy versus 1.7 months for those who did not.[31] Similarly, Lowenberg et al reported a median survival of 21 weeks for elderly patients randomized to therapy compared with 11 weeks for patients randomized to a watch and wait approach.[32] In a Medical Research Council study, the median survival was significantly improved for patients who received low dose ara-C as opposed to hydroxyurea. Some older patients do reasonably well with standard therapy. In an analysis of 998 older patients treated at MD Anderson Cancer Center, age greater than 75 years, poor performance status, previous antecedent hematologic disorder, unfavorable karyotype, renal insufficiency, and/or treatment outside of a laminar flow room were associated with an adverse outcome.[33] Patients with none of these risk factors had a complete remission rate of 72%, 8-week mortality of 10%, and median 2-year survival of 35%, whereas patients with 3 or more risk factors had a complete remission rate of 24%, an 8-week mortality of 57%, and a median 2-year survival of only 3%.[33] Thus, some low-risk elderly patients can benefit from standard intensive chemotherapy.

A recent study in elderly patients with newly diagnosed AML compared conventionaldose daunorubicin (45 mg/m2/d for 3 d) with high-dose daunorubicin (90 mg/m2/d for 3 d).[23] These regimens were administered with cytarabine 200 mg/m2/d for 7 days for the first cycle. A second cycle of cytarabine alone (1000 mg/m2/d for 6 d) was also administered. Complete remission occurred in 64% in the high-dose daunorubicin group compared with 54% in the conventional-dose group[23] ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group. Other therapies are being studied in older patients who are not candidates for intensive chemotherapy.[34] As part of National Cancer Research Institute Acute Myeloid Leukemia 14 Trial, 217 patients who were deemed unfit for intensive chemotherapy were randomized to receive low-dose cytarabine (Ara-C) (20 mg twice daily for 10 d) or hydroxyurea with or without all-trans retinoic acid (ATRA). Low-dose ara-C produced a better remission rate (18% vs 1%; P =.00006) and better overall survival (OR, 0.60; P =.0009) . Overall survival was 80 weeks for patients achieving a complete remission verus 10 weeks for patients with no remission.[35] The hypomethylators azacytidine and decitabine are also options for the treatment of AML in elderly patients. Itzykson et al recently reported prolonged survival for patients with AML treated with azacytidine in 2 different trials. The AZA-001 study included 55 patients with WHO-defined AML randomized to azacytidine treatment, and the French AZA compassionate program (ATU) included 148 patients with WHO-defined AML treated with azacytidine as frontline therapy. Patients received azacytidine, 75 mg/m2/d X 7d/28d for a minimum of 6 cycles in the AZA -001 trial, as did 48% of patients in the ATU for a minimum of 4 cycles. For the 55 patients in the AZA-001 cohort, with a median follow-up of 20.1 months, 11 (20%) of 55 were alive greater that 2 years after beginning azacytidine. None of the 11 patients had achieved complete or prolonged with azacytidine. In the ATU cohort, median follow-up was 15.6 months. Of 148 AML patients, 68 (46%) had entered the study 2 or more years before the reference date of analysis (January, 2010). Of patients with 20-30% bone marrow blasts, 7 (24%) of 29 were alive at 2 years.[36] Decitabine is another hypomethylator with activity in AML. Ansstas et al reported a single institution, retrospective study of patients older than 60 years with either de novo AML or AML arising out of myelodysplastic syndrome who were treated with decitabine at 20 mg/m2 for 5 consecutive days of a 4-week cycle. Patients continued to receive decitabine until disease progression or an unacceptable adverse event occurred. The best response to therapy was complete remission (CR)/CR with incomplete blood count recovery (CRi) 29%, stable disease/partial remission 49%, and progressive disease 22%. The median duration of CR/CRi was 393 days (range, 184-748 d). Median overall survival for patients presenting with WBC less than 10,000 cells/L was 11 months (range, 0.5-59.8 mo) and WBC greater than 10,000 cells/L was 7.1 months (range, 1.932.7 mo).[37]

Clofarabine is a purine analogue that is approved by the US Federal Drug Administration (FDA) for the treatment of relapsed pediatric acute lymphocytic leukemia (ALL). A study of clofarabine and cytarabine in newly diagnosed patients with AML who were 50 years or older yielded a complete response rate of 52% and a CRp rate of 8%. Induction deaths occurred in 7% of patients.[38] No standard consolidation therapy exists for patients older than 60 years. Options include a clinical trial, high-dose ara-C in select patients, or repeat courses of standard-dose anthracycline and cytarabine (2 and 5; ie, 2 d of anthracycline and 5 d of cytarabine). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation. Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with AML, all age groups have a significant risk of death from the procedure. The risk of death increases with age, particularly in patients older than 40 years. However, the median age of patients with AML is 65 years; therefore, only a small percentage of patients with AML are candidates for such aggressive therapy. Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, veno-occlusive disease [VOD]), and GVHD. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini transplants.[39, 40, 41] Nonmyeloablative transplants use conditioning drugs that are immunosuppressive to allow engraftment of donor cells with less direct organ toxicity than that of standard transplants. Patients who receive these transplants also often have less severe acute GVHD than patients who receive standard transplants. These 2 factors result in a day-100 mortality rate of less than 10%. The tolerability of these regimens allows patients aged 70 years or younger to undergo transplantation. However, patients who receive nonmyeloablative transplants still develop significant chronic GVHD, which can be fatal. In addition, relapse rates following nonmyeloablative transplants appear to be higher than those following standard transplants. Further studies are ongoing to determine the best role for these transplants in patients with AML.

Chemotherapy for Acute Promyelocytic Leukemia


APL is a special subtype of AML. It differs from other subtypes of AML in that patients are, on average, younger (median age 40 y) and most often present with pancytopenia rather than with elevated white blood cell (WBC) counts. In fact, WBC counts higher than 5000 cells/L at presentation are associated with a poor prognosis. APL is the subtype of AML that is most commonly associated with coagulopathy due to disseminated intravascular coagulation (DIC) and fibrinolysis. Therefore, aggressive

supportive care is an important component of the treatment of APL. Platelets should be transfused to maintain a platelet count of at least 30,000/L (preferably 50,000/L). Administer cryoprecipitate to patients whose fibrinogen level is less than 100 g/dL. The bone marrow demonstrates the presence of more than 30% blasts resembling promyelocytes. These cells contain large dense cytoplasmic granules along with varying numbers of Auer rods. Although the initial diagnosis of APL is based on morphology, the diagnosis is confirmed on the basis of cytogenetic and molecular studies. Do not delay treatment pending the results of confirmatory tests. In more than 95% of cases of APL, cytogenetic testing reveals t(15;17)(q21;q11). Molecular studies reveal the PML/RARa rearrangement. Patients with either t(15;17) or the PML/RARa rearrangement respond well to all-trans-retinoic acid (ATRA) and chemotherapy. A small percentage of patients have other cytogenetic abnormalities, including t(11;17) (q23;q11), t(11;17)(q13;q11), t(5;17)(q31;q11), or t(17;17). Patients with t(11;17) (q23;q11) are resistant to ATRA. Older studies using standard chemotherapy regimens without ATRA showed that approximately 70% of patients achieved complete response and 30% were disease free at 5 years. Induction failures were due to deaths resulting from hemorrhage caused by DIC, with few actual resistant cases.[42, 43, 44] In the 1980s, reports from China, France, and the United States demonstrated that most patients with APL could enter remission with ATRA as the single agent. Unfortunately, in the absence of further therapy, these remissions were short-lived. In addition, a new toxicity, the retinoic acid syndrome, was discovered.[45] The retinoic acid syndrome results from differentiation of leukemic promyelocytic cells into mature polynuclear cells and is characterized by fever, weight gain, pleural and pericardial effusions, and respiratory distress. The syndrome occurs in approximately 25% of patients, and, in the past, was fatal in 9%. Subsequently, the early addition of chemotherapy resulted in a reduction of deaths caused by retinoic acid syndrome. Studies have also demonstrated that the addition of chemotherapy (idarubicin and cytarabine) to ATRA results in remissions in more than 90% of patients. As many as 70% of these patients are long-term survivors. Currently, the most commonly employed approach is the combination of ATRA and anthracycline-based chemotherapy. Chemotherapy is most effective when added early in induction (ie, day 3) rather than after attainment of a complete response. Initiate chemotherapy on day 1 of therapy for patients with high WBC counts (eg, >5000/L). Once patients with APL are in remission, the standard approach is consolidation therapy followed by maintenance therapy.

A North American Intergroup study evaluated the addition of 2 cycles of consolidation therapy with arsenic trioxide followed by 2 cycles of chemotherapy with cytarabine and daunorubicin to 2 cycles of cytarabine and daunorubicin chemotherapy without arsenic trioxide.[30] Event-free survival, the primary endpoint, was 77% at 3 years in the arsenic trioxide arm (median not reached) compared with 59% at 3 years in the standard arm (median, 63 mo). Overall, 84% of adults were alive at last follow-up. Overall survival was 86% at 3 years in the arsenic trioxide arm compared with 77% at 3 years in the standard arm (medians not reached). Maintenance therapy with ATRA, 6-mercaptopurine (6-MP), and methotrexate is effective in preventing relapses compared with no maintenance therapy; however, the optimal schedule of this therapy is not yet determined. Patients who have a relapse are usually treated with arsenic trioxide. Arsenic trioxide induces complete remission in 85% of patients. Toxicities include the APL differentiation syndrome (similar to that seen with ATRA), leukocytosis, and abnormalities found on electrocardiographs (ECGs). Patients can also be retreated with chemotherapy plus ATRA, depending on the duration of their first remission and cardiac status. Evaluate patients in second remission for allogeneic or autologous stem cell transplantation. Many newer studies have eliminated cytarabine from the induction therapy for newly diagnosed patients.[46] For example, the GIMEMA AIDA regimen (ie, ATRA 45 mg/m2 daily combined with idarubicin 12 mg/m2 on days 2, 4, 6, and 8 until remission) yields remissions in 95% of patients. However, a randomized study from France questioned this approach. Newly diagnosed APL patients younger than 60 years with a WBC count of less than 10,000/L were randomly assigned to receive either ATRA combined with and followed by 3 daunorubicin plus cytarabine courses and a 2-year maintenance regimen (cytarabine group) or the same treatment but without cytarabine (no-cytarabine group). Patients older than 60 years and patients with an initial WBC count of greater than 10,000/L were not randomly assigned but received risk-adapted treatment, with higher dose of cytarabine and central nervous system (CNS) prophylaxis in patients with WBC counts greater than 10,000/L. Overall, 328 (96.5%) of 340 patients achieved complete remission. In the cytarabine and the no-cytarabine groups, the complete remission rates were 99% for the ara-C arm and 94% for the no-cytarabine arm, the 2-year cumulative incidence of relapse (CIR) rates were 4.7% in those who received cytarabine and 15.9% in those who did not receive cytarabine, the event-free survival rates were 93.3% in the cytarabine group and 77.2% in the no-cytarabine group, and survival rates were 97.9% in patients who received cytarabine and 89.6% in those who received no cytarabine.

In patients younger than 60 years with WBC counts more than 10,000/L, the complete response rate was 97.3%, 2-year CIR was 2.9%, event-free survival was 89%, and survival rate was 91.9%. Another trend is the development of risk-adapted approaches to consolidation therapy. In the Programa de Estudio y Traitmiento de las Hemopatias Malignas (PETHEMA) study, patients with intermediate and high risks of relapse (ie, whose baseline WBC count was >10,000/L or platelet count was < 40,000/L) received 3 courses of consolidation therapy with ATRA and increased doses of anthracyclines (idarubicin, month 1; mitoxantrone, month 2; idarubicin, month 3).[47] Other areas of investigation include the use of arsenic in front-line therapy (with or without chemotherapy) and the use of lintuzumab as consolidation therapy. Gemtuzumab ozogamicin was initially intended for use as consolidation therapy, but this agent was withdrawn from the US market in June 2010.

Chemotherapy for Relapsed Acute Myelogenous Leukemia


Patients with relapsed AML have an extremely poor prognosis. Most patients should be referred for investigational therapies. Young patients who have not previously undergone transplantation should be referred for such therapy. Estey et al reported that the chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission.[48] Patients with an initial complete response duration of longer than 2 years had a 73% complete response rate with initial salvage therapy. Patients with an initial complete response duration of 1-2 years had a complete response rate of 47% with initial salvage therapy. Patients with an initial complete response duration of less than 1 year or with no initial complete response had a 14% complete response rate with initial salvage therapy. Patients with an initial complete response duration of less than 1 year (or no initial complete response) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%. These data underscore the need to develop new treatment options for these patients. Response to third-line therapy is even worse. Giles et al studied 594 patients with AML undergoing second salvage therapy from 1980 to 2004. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT), standard-dose cytosine arabinoside (ara-C) combinations, high-dose ara-C combinations, nonara-C combinations, and phase I-II single agents. Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration less than 6 months, second CR duration less than 6 months, salvage therapy not including allogeneic SCT, noninversion

16 AML, platelet counts less than 50 X 109/L, and leukocytosis greater than 50 X 109/L.
[49]

Owing to the poor outcome with salvage therapy, it is important to refer patients for welldesigned clinical trials whenever possible. Agents in late-stage clinical trials include clofarabine, vosaroxin, and elacytarabine. For patients who are unable to participate in a clinical trial, options include high-dose cytarabine-based regimens, hypomethylators, and supportive care. Two standard regimens with high response rates include CLAG-M (cladribine combined with high doses of ara-C, mitoxantrone, and G-CSF) and MEC (mitoxantrone, etoposide, and intermediate dose cytarabine). In a study by the Polish Adult Leukemia Group, the CLAG-M regimen yielded complete remissions in 58% of patients. White blood count cell greater than 10 g/L and age older than 34 years were factors associated with increased risk of treatment failure. Hematological toxicity was the most prominent toxicity of this regimen. The probability of overall survival at 4 years was 14%, and the probability of 4-year disease-free survival was 30% for all 66 patients in complete remission.[50] In an initial study of MEC, 32 patients with refractory acute myeloid leukemia received salvage therapy with mitoxantrone at 6 mg/m2 intravenous (IV) bolus, etoposide at 80 mg/ m2 IV for a period of 1 hour, and cytarabine (Ara-C) at 1 g/ m2 IV for a period of 6 hours daily for 6 days. Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment, 8 patients had relapsed within 6 months from initial remission, and 6 patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a CR. The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients, resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal.[51] In a study by Levis et al, lestaurtinib was administered twice daily to patients with FLT3 mutant AML in first relapse.[52] Because such a small proportion of patients in the trial achieved sustained FLT3 inhibition in vivo, conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not prolong survival or increase response rates in first relapse.

Supportive Care
Replacement of blood products
Patients with AML have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy. The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related GVHD, which is almost invariably fatal.

Packed red blood cells are given when the hemoglobin concentration is lower than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise. Platelets should be transfused if the platelet count is lower than 10,000-20,000/L. Patients with pulmonary or GI hemorrhage should receive platelet transfusions to maintain a value greater than 50,000/L. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000/L. Patients with APL should have their platelet count maintained above 50,000/L, at least until evidence of DIC has resolved. FFP should be given to patients with a significantly prolonged prothrombin time, and cryoprecipitate should be given if the fibrinogen level is less than 100 g/dL.

Antibiotic therapy
Intravenous (IV) antibiotics should be given to all febrile patients. At minimum, antibiotics should include broad-spectrum coverage, such as that provided by a thirdgeneration cephalosporin with or without vancomycin. In addition to this minimum, additional antibiotics should be given to treat specific documented or suspected infections. Patients with persistent fever after 3-5 days of antibacterial antibiotics should receive antifungal antibiotics. In the past, amphotericin was the standard antifungal antibiotic. Patients with fever but without a focus of infection received amphotericin at a dose of 0.5 mg/kg. Patients with sinopulmonary symptoms received 1 mg/kg. In the past few years, however, a number of other antifungal agents have become available. These include the lipid-preparation amphotericins (Abelcet and AmBisome), newer azoles (voriconazole and posaconazole), and the echinocandins (caspofungin, anidulafungin, and micafungin). These drugs have varying roles in the treatment of neutropenic patients with either suspected or proven fungal infections. Prophylactic antibiotics are usually used in nonfebrile patients undergoing intensive chemotherapy. Both the National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) guidelines strongly recommend antifungal prophylaxis in this group of patients. A commonly used regimen is ciprofloxacin, fluconazole, or itraconazole, and acyclovir or valacyclovir. A randomized trial of posaconazole versus either fluconazole or itraconazole (center choice) in patients with AML and MDS undergoing intensive chemotherapy demonstrated a significant reduction in all cause mortality at day 100, as well as a decrease in invasive fungal infections and a decrease in aspergillosis in patients randomized to posaconazole.

Once patients receiving these antibiotics become febrile, the regimen is changed to IV antibiotics, as indicated above. Allopurinol at 300 mg should be given 1-3 times a day during induction therapy until the clearance of blasts and resolution of hyperuricemia. For patients who cannot tolerate oral medications, IV drugs such as rasburicase are an option. Rasburicase should also be considered in patients at high risk of severe tumor lysis (very high lactate dehydrogenase [LDH] level, baseline renal insufficiency).

Growth factors
Several randomized studies have been performed that attempted to determine the effect of growth factors on induction therapy. In an early Japanese study, patients with poor-risk acute leukemia randomly received either granulocyte colony-stimulating factor (G-CSF) derived from Escherichia coli or no drug. Patients in the G-CSF group had a faster neutrophil recovery (20 d) than those receiving no drug (28 d), a smaller number of febrile days (3 d vs 7 d, respectively), and fewer documented infections.[53] No significant difference in response rate or remission duration was observed between the 2 groups. In a French study of G-CSF, the duration of neutropenia was shorter in the G-CSF arm (21 d) compared with those in the placebo arm (27 d), and the complete response rate was higher in those who received G-CSF (70%) than in those who received placebo (47%); however, the overall survival rate was unaffected.[54] In a Southwestern Oncology Group (SWOG) study, a decrease was observed in the time to neutrophil recovery and days with fever in those who received G-CSF; however, no difference in complete remission rate and overall survival rate was observed for patients receiving G-CSF versus no drug.[55] Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy. In an Eastern Cooperative Oncology Group (ECOG) study of yeast-derived GM-CSF in elderly patients with AML, no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed.[56] Neutrophil recovery rate was increased in the GM-CSF group (14 d vs 21 d, respectively), and overall survival was significantly improved (323 d vs 145 d, respectively).[56] In a CALGB study of GM-CSF derived from E coli, no difference was observed in response rates between the GM-CSF group and the placebo group.[57] The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in an EORTC study using GM-CSF derived from E coli, patients who randomly received GM-CSF after

induction had a significantly lower complete rate (48%) than those who did not receive GM-CSF (77%).[58] These data suggest that G-CSF and yeast-derived GM-CSF accelerate neutrophil recovery and decrease the risk of infection in patients who are undergoing induction therapy.[58] For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.

Venous catheter placement


Placement of a central venous catheter (eg, triple lumen, Broviac, Hickman) is necessary.

Dietary Measures
Patients with AML should be on a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely (ie, well done).

Activity Restriction
Patients should limit their activity to what is tolerable. They should refrain from strenuous activities (eg, lifting, exercise).

Long-Term Monitoring
Patients should come to the office for monitoring of disease status and chemotherapy effects. Proceed to Medication

Medication Summary
Medications used for the treatment of acute myelogenous leukemia (AML) cause severe bone marrow depression. Only physicians specifically trained in their use should use these agents. In addition, access to appropriate supportive care (ie, blood banking) is required.

Antineoplastics
Class Summary

Antineoplastic agents are used for induction or consolidation therapy. These agents inhibit cell growth and differentiation. They include cytarabine, daunorubicin, idarubicin, and mitoxantrone. View full drug information

Azacitidine (Vidaza)

Azacitidine is a pyrimidine nucleoside analog of cytidine. It interferes with nucleic acid metabolism. It exerts antineoplastic effects by DNA hypomethylation and direct cytotoxicity on abnormal hematopoietic bone marrow cells. Hypomethylation may restore normal function to genes critical for cell differentiation and proliferation. Nonproliferative cells are largely insensitive to azacitidine. It is indicated to treat myelodysplastic syndromes (MDSs) and is FDA approved for all 5 MDS subtypes. View full drug information

Cytarabine (Cytosar-U)

Cytarabine is an antimetabolite specific for cells in the S-phase of the cell cycle. It acts through inhibition of DNA polymerase and cytosine incorporation into DNA and RNA. View full drug information

Daunorubicin (Cerubidine)

Daunorubicin is a topoisomerase-II inhibitor. It inhibits DNA and RNA synthesis by intercalating between DNA base pairs. View full drug information

Idarubicin (Idamycin)

Idarubicin is a topoisomerase-II inhibitor. It inhibits cell proliferation by inhibiting DNA and RNA polymerase. View full drug information

Mitoxantrone (Novantrone)

Mitoxantrone inhibits cell proliferation by intercalating DNA. It inhibits topoisomerase II. View full drug information

Arsenic trioxide (Trisenox)

Arsenic trioxide is used in patients with relapsed acute promyelocytic leukemia (APL). Its mechanism of action is not completely understood. Arsenic trioxide causes morphologic changes and DNA fragmentation that are characteristic of apoptosis in NB4 human promyelocytic leukemia cells in vitro. Arsenic trioxide also causes damage or degradation of the fusion protein PML-RAR alpha. View full drug information

Fludarabine (Fludara)

Fludarabine contains fludarabine phosphate, a fluorinated nucleotide analog of the antiviral agent vidarabine, 9-b-D-arabinofuranosyladenine (ara-A), that enters the cell and is phosphorylated to form the active metabolite 2-fluoro-ara-ATP, which inhibits DNA synthesis. It is also incorporated into RNA, causing inhibition of RNA and protein synthesis; however, its primary effect may result from activation of apoptosis. It is also relatively resistant to deamination by adenosine deaminase. The dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity. Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs. The optimal duration of treatment is not clearly established. It is recommended that 3 additional cycles of fludarabine be administered following the achievement of maximal response, and then the drug should be discontinued. View full drug information

Cyclophosphamide

Cyclophosphamide is a cyclic polypeptide that suppresses some humoral activity. It is chemically related to nitrogen mustards and is activated in the liver to its active

metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type of reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells. It is biotransformed by cytochrome P450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. The interaction of phosphoramide mustard with DNA is considered cytotoxic. When cyclophosphamide is used in autoimmune diseases, the mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking. In high doses, it affects B cells by inhibiting clonal expansion and suppression of the production of immunoglobulins. With long-term, low-dose therapy, it affects T-cell functions. View full drug information

Cladribine (Leustatin)

Cladribine is a synthetic antineoplastic agent for continuous IV infusion. The enzyme deoxycytidine kinase phosphorylates this compound into an active 5+-triphosphate derivative, which, in turn, brakes DNA strands and inhibits DNA synthesis. It disrupts cell metabolism, causing death to resting and dividing cells. View full drug information

Decitabine (Dacogen)

Decitabine is a hypomethylating agent believed to exert antineoplastic effects by incorporating into DNA and inhibiting methyltransferase, resulting in hypomethylation. Hypomethylation in neoplastic cells may restore normal function to genes critical for cellular control of differentiation and proliferation. It is indicated for myelodysplastic syndromes (MDSs), including previously treated and untreated, de novo, and secondary MDSs of all French-American-British (FAB) subtypes (ie, refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, chronic myelomonocytic leukemia) and International Prognostic Scoring System (IPSS) groups intermediate-1 risk, intermediate2 risk, and high risk.

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