ACUTE MYELOGENOUS LEUKEMIA

Introduction
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.

For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center and Skin, Hair, and Nails Center. Also, see eMedicine's patient education articles Leukemia and Bruises.
Pathophysiology

The underlying pathophysiology in acute myelogenous leukemia (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, blood, and, frequently, the spleen and liver.
Frequency
United States

Estimates of new cases of acute myelogenous leukemia (AML) in the United States in 2007 were 13,410 (7060 men; 6350 women).
International

Acute myelogenous leukemia (AML) is more commonly diagnosed in developed countries.
Mortality/Morbidity

In 2007, an estimated 8990 deaths from acute myelogenous leukemia (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) and older (>60 y) patients with acute myelogenous leukemia (AML).

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.
Race

Acute myelogenous leukemia (AML) is more common in whites than in other populations.
Sex

Acute myelogenous leukemia (AML) is more common in men than in women. The difference is even more apparent in older patients. This is likely because myelodysplastic syndromes (MDSs) are more common in men, and advanced MDS frequently evolves into AML. Some have proposed that the increased prevalence of acute myelogenous leukemia (AML) in men may be related to occupational exposures.
Age

The prevalence of acute myelogenous leukemia (AML) increases with age. The median age of onset is approximately 70 years. However, acute myelogenous leukemia (AML) affects all age groups.
Clinical
History

* Patients with acute myelogenous leukemia (AML) present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
o Some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks.
o Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder (AHD) such as MDS.
* Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
o The most common symptom of anemia is fatigue. Patients often retrospectively note a decreased energy level over past weeks.
o 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.
o Patients often have decreased neutrophil levels despite an increased total white blood cell (WBC) count.
o Patients with acute myelogenous leukemia (AML) 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/µL, especially <100 cells/µL) have the highest risk of infection. o Patients often have a history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics. o Patients present with bleeding gums and multiple ecchymoses. Bleeding may be caused by thrombocytopenia, coagulopathy that results from disseminated intravascular coagulation (DIC), or both. o Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system. * Alternatively, symptoms may be the result of organ infiltration with leukemic cells. o The most common sites of infiltration include the spleen, liver, gums, and skin. o Infiltration occurs most commonly in patients with the monocytic subtypes of acute myelogenous leukemia (AML). o Patients with splenomegaly note fullness in the left upper quadrant and early satiety. o 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. o Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status). Leukostasis is a medical emergency that requires immediate intervention.
o Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Physical

* Physical signs of anemia, including pallor and a cardiac flow murmur, are frequently present in those with acute myelogenous leukemia (AML).
* 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 such as 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 acute myelogenous leukemia (AML) (granulocytic sarcoma).
* Signs relating to leukostasis include respiratory distress and altered mental status.

Causes

* Although several factors have been implicated in the causation of acute myelogenous leukemia (AML), most patients who present with de novo AML have no identifiable risk factor.
* Antecedent hematologic disorders
o The most common risk factor for acute myelogenous leukemia (AML) is the presence of an antecedent hematologic disorder, the most common of which is MDS. MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.
o Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop acute myelogenous leukemia (AML), whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.
o Other antecedent hematologic disorders that predispose patients to acute myelogenous leukemia (AML) include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.
* Congenital disorders
o Some congenital disorders that predispose patients to acute myelogenous leukemia (AML) include Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis.
o Usually, these patients develop acute myelogenous leukemia (AML) during childhood; rarely, some may present in young adulthood.
o More subtle genetic disorders, including polymorphisms of enzymes that metabolize carcinogens, also predispose patients to acute myelogenous leukemia (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 acute myelogenous leukemia (AML) following chemotherapy for other malignancies.4
* Familial syndromes
o Germ-line mutations in the gene AML1 (RUNX1, CBFA2) occur in the familial platelet disorder with predisposition for myelogenous leukemia (AML), an autosomal-dominant disorder characterized by moderate thrombocytopenia, a defect in platelet function, and propensity to develop AML.
o 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 myelogenous leukemia (AML).5
o 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
o Several studies demonstrate a relationship between radiation exposure and leukemia.
o Early radiologists (before the use of appropriate shielding) were found to have an increased likelihood of developing leukemia.
o Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.
o Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.
o Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing myelogenous leukemia (AML). In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.
o 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 for another malignancy
o 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 myelogenous leukemia (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.6
o 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.
o Patients with a previous exposure to alkylating agents, with or without radiation, often have a myelodysplastic phase before the development of myelogenous leukemia (AML). Cytogenetics testing frequently reveals -5 and/or -7 (5q- or monosomy 7).
o Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase. Cytogenetics testing reveals a translocation that involves chromosome band 11q23. Less commonly, patients developed leukemia with other balanced translocations, such as inversion 16 or t(15;17).7
o The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.Differential Diagnoses
Acute Lymphoblastic Leukemia
Lymphoma, B-Cell
Agnogenic Myeloid Metaplasia With Myelofibrosis
Lymphoma, Lymphoblastic
Agranulocytosis
Myelodysplastic Syndrome
Anemia
Myelophthisic Anemia
Aplastic Anemia

Bone Marrow Failure

Chronic Myelogenous Leukemia

Workup
Laboratory Studies

* A complete blood cell (CBC) count with differential demonstrates anemia and thrombocytopenia to varying degrees. Patients with acute myelogenous leukemia (AML) can have high, normal, or low WBC counts.
* Prothrombin time (PT) / activated partial thromboplastin time (aPTT) / fibrinogen / fibrin degradation products
o The most common abnormality is DIC, which results in an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.
o Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of acute myelogenous leukemia (AML) associated with DIC.
* Peripheral blood smear
o Review of THE peripheral blood smear confirms the findings of the CBC count.
o Circulating blasts are usually seen.
o Schistocytes are occasionally seen if DIC is present.
* Chemistry profile
o Most patients with acute myelogenous leukemia (AML) have an elevated lactic dehydrogenase (LDH) level and, frequently, an elevated uric acid level.
o Liver function tests and blood urea nitrogen (BUN)/creatinine level tests are necessary before the initiation of therapy.
o Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.
* Perform human leukocyte antigen (HLA) or DNA typing in patients who are potential candidates for allogeneic transplantation.
* Bone marrow aspiration
o A blast count can be performed with bone marrow aspiration. Historically, by French-American-British (FAB) classification, acute myelogenous leukemia (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
o The bone marrow aspirate also allows evaluation of the degree of dysplasia in all cell lines.
* Bone marrow biopsy is useful to assess cellularity. Biopsy is most important in patients in whom an aspirate can not be obtained (dry tap).
* Flow cytometry (immunophenotyping) can be used to help distinguish acute myelogenous leukemia (AML) from acute lymphocytic leukemia (ALL) and further classify the subtype of AML. The immunophenotype correlates with prognosis in some instances.
* Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL, which bears the t(15;17) chromosome abnormality and is treated differently.
* 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.
* Several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with acute myelogenous leukemia (AML). The bone marrow should be evaluated at least for the commercially available tests.
o Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in persons with acute myelogenous leukemia (AML) and is constitutively activated in one third of AML cases.8 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.
o Mutations in nucleophosmin (NPM1) are associated with increased response to chemotherapy in patients with a normal karyotype. Thiede et al studied FLT3 and NPM1 in 1485 patients with acute myelogenous leukemia (AML).9 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 disease-free survival and a lower cumulative incidence of relapse.9 Analysis of NPM1 is commercially available.
o 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.
o ERG overexpression is an adverse predictor in cytogenetically normal acute myelogenous leukemia (AML).
o 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 (P = 0.003), MLL-PTD (P = 0.009), absent FLT3-TKD and high ERG expression. In a multivariable analysis, high BAALC expression independently predicted lower complete remission rates when adjusting for ERG expression and age, and shorter survival when adjusting for FLT3-ITD, NPM1, CEBPA and WBC count.
o 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 (P = 0.39).
* 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.

Imaging Studies

* Chest radiographs help assess for pneumonia and signs of cardiac disease in individuals with acute myelogenous leukemia (AML).
* Multiple gated acquisition (MUGA) scanning is needed once the diagnosis is of acute myelogenous leukemia (AML) is confirmed, because many chemotherapeutic agents used in treatment are cardiotoxic.

Other Tests

* Electrocardiography should be performed before treatment of acute myelogenous leukemia (AML).

Procedures

* Bone marrow aspiration and biopsy are the definitive diagnostic tests for acute myelogenous leukemia (AML).
o Aspiration slides are stained for morphology with either Wright or Giemsa stain.
o 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 (see Histologic Findings).
* Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.
* Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement.
* When possible, the bone marrow should be evaluated for FLT3 and NPM1 mutations.

Histologic Findings

The older, more traditional, FAB classification of acute myelogenous leukemia (AML) is as follows:

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

The newer WHO classification is as follows1 :

* Acute myelogenous leukemia (AML) with recurrent genetic abnormalities
o AML with t(8;21)(q22;q22), (AML1/ETO)
o AML with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13)(q22), (CBFB/MYH11)
o APL with t(15;17)(q22;q12), (PML/RARa) and variants
o AML with 11q23 (MLL) abnormalities
* AML with multilineage dysplasia
o Following MDS or MDS/myeloproliferative disease (MPD)
o Without antecedent MDS or MDS/myeloproliferative disease (MPD) but with dysplasia in at least 50% of cells in 2 or more lineages
* AML and MDS, therapy related
o Alkylating agent or radiation-related type
o Topoisomerase II inhibitor type
o Others
* AML, not otherwise classified
o AML, minimally differentiated
o AML, without maturation
o AML, with maturation
o Acute myelomonocytic leukemia
o Acute monoblastic or monocytic leukemia
o Acute erythroid leukemia
o Acute megakaryoblastic leukemia
o Acute basophilic leukemia
o Acute panmyelosis and myelofibrosis
o Myeloid sarcoma

Table 1. Common Cytogenetic Abnormalities in AML

Open table in new window
[ CLOSE WINDOW ]
Table

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

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 2. Cytogenetic Abnormalities in APL

Open table in new window
[ CLOSE WINDOW ]
Table
Translocation
Genes Involved

All-Trans-Retinoic Acid Response
t(15;17)(q21;q11)
PML/RARa
Yes
t(11;17)(q23;q11)
PLZF/RARa
No
t(11;17)(q13;q11)
NuMA/RARa
Yes
t(5;17)(q31;q11)
NPM/RARa
Yes
t(17;17)
stat5b/RARa
Unknown
Translocation
Genes Involved

All-Trans-Retinoic Acid Response
t(15;17)(q21;q11)
PML/RARa
Yes
t(11;17)(q23;q11)
PLZF/RARa
No
t(11;17)(q13;q11)
NuMA/RARa
Yes
t(5;17)(q31;q11)
NPM/RARa
Yes
t(17;17)
stat5b/RARa
Unknown


Table 3. Immunophenotyping of AML Cells

Open table in new window
[ CLOSE WINDOW ]
Table

Marker
Lineage
CD13
Myeloid
CD33
Myeloid
CD34
Early precursor
HLA-DR
Positive in most AML, negative in APL
CD11b
Mature monocytes
CD14
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

Marker
Lineage
CD13
Myeloid
CD33
Myeloid
CD34
Early precursor
HLA-DR
Positive in most AML, negative in APL
CD11b
Mature monocytes
CD14
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 cellTreatment
Medical Care

Current standard chemotherapy regimens cure only a minority of patients with acute myelogenous leukemia (AML). As a result, evaluate all patients for entry into well-designed clinical trials. If a clinical trial is not available, the patient can be treated with standard therapy as described below.

Treatment of acute myelogenous leukemia (AML) (excluding acute promyelocytic leukemia)

Induction therapy: Various acceptable induction regimens are available.

* The most common approach is called "3 and 7," which 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 arabinosylcytosine (ara-C) as a 24-hour infusion daily for 7 days. Traditionally the dose of idarubicin has been 12 mg/m2/d for 3 days, the dose of daunorubicin has been 45-60 mg/m2/d for 3 days, and the dose of mitoxantrone has been 12 mg/m2/d for 3 days.
* These regimens require adequate cardiac, hepatic, and renal function.
* Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% of patients enter remission following a second course of therapy.
* In a study by Fernandez et al, 657 patients younger than 60 years with untreated acute myeloid leukemia (AML) received either conventional-dose daunorubicin (45 mg/m2/d for 3 d) or high-dose daunorubicin (90 mg/m2/d for 3 d).10 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%, P <0.001) as well as an improved overall survival (median, 23.7 mo) compared with the group administered the conventional dose (15.7 mo; P = 0.003).10 * 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 3.20 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 (P = 0.002). 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.20 * Alternatively, high-dose ara-C combined with idarubicin, daunorubicin, or mitoxantrone can be used as induction therapy in younger patients. The use of high-dose ara-C 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 ara-C during induction. Consolidation therapy in younger patients: In patients aged 60 years or younger, treatment options for consolidation therapy include high-dose ara-C, autologous stem cell transplantation, or allogeneic stem cell transplantation. * High-dose ara-C therapy o Mayer et al conducted a randomized study of 3 different doses of ara-C in patients with acute myelogenous leukemia (AML) who achieved remission after standard "3 and 7" induction chemotherapy.11 Patients received 4 courses of ara-C at one of the following doses: (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. o 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 (P = 0.002). The outcome in older patients did not differ. Based on this study, high-dose ara-C for 4 cycles is a standard option for consolidation therapy in younger patients.11 * Stem cell transplantation o 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. o Some studies suggest an advantage to BMT. + In a Dutch study, patients received either allogeneic BMT or autologous BMT based on the availability of a sibling donor matched via HLA.12 This study demonstrated a decreased rate of relapse at 3 years for patients receiving allogeneic BMT (34%) versus autologous BMT (60%) (P = 0.03) and an increased overall survival rate at 3 years for patients receiving allogeneic BMT (66%) versus autologous BMT (37%) (P = 0.05). However, the median age of patients who received allogeneic BMT was 10 years younger that those who received autologous BMT. + 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.13 In this study, the number of relapses was lower for patients receiving autologous BMT (37%) versus no further treatment (58%) (P <0.001), and the rate of disease-free survival at 7 years was improved for patients receiving autologous BMT (53%) versus no further treatment (40%) (P = 0.04).13 However, no improvement in the overall survival rate at 7 years was observed for autologous BMT (57%) no further treatment (45%) (P = 0.2). + In a European Organization for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche Maligne dell'Adul study, patients with an HLA-identical sibling underwent allogeneic BMT.14 Other patients randomly received either autologous BMT or a second course of intensive chemotherapy with high-dose ara-C 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 (P = 0.04). 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. o Several other studies 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.15 All other patients received a course of consolidation chemotherapy with high-dose ara-C and an anthracycline and then randomly received either a second course of consolidation chemotherapy or autologous BMT. In this study, the type of postremission therapy had no effect on outcome. + In a US Intergroup study, patients in remission with a matched donor received allogeneic BMT.16 Other patients randomly received either autologous BMT or one additional course of high-dose ara-C. In this study, the survival rate was better for patients receiving chemotherapy without BMT compared with the other groups. In view of these conflicting results, the following recommendations can be made: * Patients with good-risk acute myelogenous leukemia (AML) (ie, t[8;21] or inversion of chromosome 16[inv16]) have a good prognosis following consolidation with high-dose ara-C and should be offered such therapy. This is given as ara-C 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 ara-C 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. Consolidation therapy in older patients 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 ara-C (2 and 5; ie, 2 d of anthracycline and 5 d of ara-C). Select patients can be considered for autologous stem cell transplantation or nonmyeloablative allogeneic transplantation. * Nonmyeloablative allogeneic transplantation o Although allogeneic stem cell transplantation is a potentially curative treatment option for patients with acute myelogenous leukemia (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. o Following ablative allogeneic transplantation, death occurs due to sepsis, hemorrhage, direct organ toxicity (particularly affecting the liver; ie, venoocclusive disease [VOD]), and graft versus host disease. In an attempt to reduce these toxicities, several investigators have developed new, less toxic conditioning regimens known as nonmyeloablative transplants or mini-transplants. o These 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 graft versus host disease than patients who receive standard transplants. These 2 factors result in a day 100 mortality rate of less than 10%. o 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 graft versus host disease, 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 acute myelogenous leukemia (AML). * Other immune therapies o Lintuzumab is a humanized monoclonal antibody that targets CD33, which is present on most AML cells. It induces antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis. Early studies demonstrated activity, although randomized studies of lintuzumab given after chemotherapy did not show a benefit. However, a phase I study of lintuzumab as a single agent in patients with acute myelogenous leukemia (AML) demonstrated a response rate of 28%. o PR1 is a nonomeric HLA-A2-restricted peptide derived from the myeloid leukemia-associated antigens proteinase 3 and neutrophil elastase. PR1-specific cytotoxic T lymphocytes (PR1-CTL) selectively kill MDS, acute myelogenous leukemia (AML), and CML and contribute to complete cytogenetic remission. A study demonstrated that PR1 vaccine-induced immune response is associated with better event-free survival in patients with myeloid leukemia who received the vaccine. Alternative options for elderly patients include the following: * Results of treatment of acute myelogenous leukemia (AML) in the elderly patient (particularly above the age of 75) remain unsatisfactory. In a 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. o It should be noted that patients with antecedent hematologic disorders were excluded so that these results overestimate the benefit of chemotherapy in elderly patients. Many patients are never referred for treatment due to serious comorbid medical conditions and the knowledge that the treatment results are poor in this group of patients. o For example, Menzin et al analyzed Medicare claims for treatment of acute myelogenous leukemia (AML).17 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, there is a need to develop novel treatments in this patient population.17 * There is evidence that patients who are treated have improved survival over those who are not treated. In the study of Menzin, the median survival was 6.1 months for patients who received chemotherapy versus 1.7 months for those who did not.17 Similarly, Lowenberg et al reported a median survival of 21 weeks for elderly patients randomized to therapy versus 11 weeks for patients randomized to a "watch and wait" approach.18 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 >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.19 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%.19 Thus, some low risk elderly patients can benefit from standard intensive chemotherapy.
* A recent study in elderly patients with newly diagnosed acute myeloid leukemia (AML) compared conventional-dose daunorubicin (45 mg/m2/d for d) (n = 411) with high-dose daunorubicin (90 mg/m2/d for 3 d) (n = 402).20 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 (P = 0.002)20 ; remission after the first cycle was 52% in the high-dose daunorubicin group compared with 35% in the conventional-dose group (P <0.001). * Novel agents are being studied in older patients who are not candidates for intensive chemotherapy.21 o Tipifarnib (a farnesyl transferase inhibitor) initially showed promise. However a larger study demonstrated a response rate of only 8%, and a randomized trial comparing tipifarnib with best supportive care showed no benefit to the use of this drug. o Cloretazine is a novel alkylating agent with activity against acute myelogenous leukemia (AML), independent of cytogenetics. In a phase II study in elderly patients, a single dose of 600 mg/m2 resulted in a response rate (CR + complete responses with incomplete platelet recovery [CRp]) of 35%.22 o Clofarabine is a purine analogue that is US Federal Drug Administration (FDA) approved for the treatment of relapsed pediatric ALL. A study of clofarabine and ara-C in newly-diagnosed patients with AML who were 50 years or older yielded a complete response rate of 52% and CRp rate of 8%. Induction deaths occurred in 7% of patients.23 o The hypomethylating agents, azacytidine and decitabine, are approved for use in patients with MDS. However both of these agents have activity in acute myelogenous leukemia (AML) (complete response rates 15-20%). Both drugs are well tolerated and are therefore being used in elderly patients.24,25 o Other agents being studied include CP-4055, a cytarabine 5'-elaidic acid ester that is independent of nucleoside transporters, sapacitabine, a 2'-deoxycytidine nucleoside analogue, and SNS-595, a replication-dependent DNA damaging agent. Treatment of APL APL is a special subtype of acute myelogenous leukemia (AML). APL 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 WBC counts. In fact, WBC counts higher than 5000 cells/µL at presentation are associated with a poor prognosis. APL is the subtype of acute myelogenous leukemia (AML) that is most commonly associated with coagulopathy due to 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/µL (preferably 50,000/µL). 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 based on 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 all-trans-retinoic acid (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.26,27,28 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.29 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 ara-C) 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 standard 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/µL). 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 ara-C and daunorubicin to 2 cycles of ara-C and daunorubicin chemotherapy without arsenic trioxide.16 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 mos; P = 0.0013).

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; P = 0.029). Maintenance therapy with ATRA, 6-mercaptopurine (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 ara-C from the induction therapy for newly diagnosed patients. For example, the GIMEMA AIDA regimen (ie, idarubicin 12 mg/m2 on days 2, 4, 6, and 8 combined with ATRA 45 mg/m2 daily 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/CL were randomly assigned to receive either ATRA combined with and followed by 3 daunorubicin (DNR) plus ara-C courses and a 2-year maintenance regimen (ara-C group) or the same treatment but without ara-C (no ara-C group).

Patients older than 60 years and patients with an initial WBC count of greater than 10,000/μL were not randomly assigned but received risk-adapted treatment, with higher dose of ara-C and central nervous system (CNS) prophylaxis in patients with WBC counts greater than 10,000/μL. Overall, 328 (96.5%) of 340 patients achieved complete remission.

In the ara-C and the no ara-C groups, the complete remission rates were 99% for the ara-C arm and 94% for the no ara-C arm (P = 0.12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% in those who received ara-C and 15.9% in those who did not receive ara-C (P = 0.011), the event-free survival rates were 93.3% in the ara-C group and 77.2% in the no ara-C group (P = 0.0021), and survival rates were 97.9% in patients who receive ara-C and 89.6% in those who received no ara-C (P = 0.0066). In patients younger than 60 years with WBC counts more than 10,000/μL, 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/µL or platelet count was <40,000/µL) received 3 courses of consolidation therapy with ATRA and increased doses of anthracyclines (idarubicin month 1, mitoxantrone month 2, idarubicin month 3).30

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 US Market in June 2010.

Treatment of relapsed AML

Patients with relapsed acute myelogenous leukemia (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.31 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 stress the need to develop new treatment options for these patients.

Many of the agents listed under treatment of elderly acute myelogenous leukemia (AML) are also being studied in patients with relapsed AML.

* Other therapies
o Gemtuzumab ozogamicin was withdrawn from the US Market in June 2010. This agent is a monoclonal antibody against CD33 (a molecule present on most AML cells but not on normal stem cells) conjugated to calicheamicin (a potent chemotherapy molecule). Gemtuzumab ozogamicin had previously been approved by the FDA for the treatment of patients with CD33-positive acute myelogenous leukemia (AML) in first relapse who are aged 60 years or older and who are not considered candidates for other cytotoxic chemotherapy.
o Sievers et al reported the results of gemtuzumab ozogamicin administration in 142 patients with acute myelogenous leukemia (AML) who were in their first relapse and who had no history of an antecedent hematologic disorder.32 Sixteen percent of patients obtained a formal complete response. An additional 13% of patients met criteria for complete response but did not have the required platelet recovery. Toxicity included infusion reactions, myelosuppression, and hepatic toxicity.32
o Later studies have shown that use of gemtuzumab ozogamicin either before or following stem cell transplantation is associated with an increased risk of VOD.33 Additional studies have demonstrated that VOD occurs in patients who receive gemtuzumab ozogamicin but do not undergo stem cell transplantation. Newer studies are investigating the use of gemtuzumab ozogamicin in combination with other chemotherapy agents and in patients with newly diagnosed acute myelogenous leukemia (AML). Although gemtuzumab ozogamicin is an active drug, the response rate is less than that obtained with standard "3 and 7" chemotherapy.

Elements of supportive care include the following:

* Replacement of blood products
o Patients with acute myelogenous leukemia (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 graft versus host disease that is almost invariably fatal.
o Packed red blood cells are given to patients with a hemoglobin level of less than 7-8 g/dL or at a higher level if the patient has significant cardiovascular or respiratory compromise.
o Platelets should be transfused if the level is less than 10,000-20,000 cells/µL. Patients with pulmonary or gastrointestinal hemorrhage should receive platelet transfusions to maintain a value greater than 50,000 cells/µL. Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000 cells/µL. Patients with APL should have their platelet count maintained at more than 50,000 cells/µL, at least until evidence of DIC has resolved.
o Fresh frozen plasma 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.
* Antibiotics
o Intravenous antibiotics should be given to all febrile patients.
o At minimum, antibiotics should include broad-spectrum coverage such as that provided by a third-generation cephalosporin with or without vancomycin.
o In addition to this minimum, additional antibiotics should be given to treat specific documented or suspected infections.
o 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.
o Prophylactic antibiotics are usually used in nonfebrile patients undergoing intensive chemotherapy. 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 acute myelogenous leukemia (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.
+ Both the National Comprehensive Cancer Network (NCCN) and Infectious Diseases Society of America (IDSA) guidelines strongly recommend antifungal prophylaxis in this group of patients.
o Once patients receiving these antibiotics become febrile, the regimen is changed to intravenous antibiotics, as indicated above.
o 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, intravenous drugs such as rasburicase are an option. Rasburicase should also be considered in patients at high risk of severe tumor lysis (very high LDH, baseline renal insufficiency).
* Use of growth factors as supportive care
o Several randomized studies have been performed that attempted to determine the effect of growth factors on induction therapy.
o 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), decreased febrile days (3 d vs 7 d, respectively), and fewer documented infections.34 No significant difference in response rate or remission duration was observed between the 2 groups.
o 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%) compared with those who received placebo (47%); however, the overall survival rate was unaffected.35
o In a Southwestern Oncology Group 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.36
o Other groups have studied the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) on induction therapy.
o In an Eastern Cooperative Oncology Group study of yeast-derived GM-CSF in elderly patients with acute myelogenous leukemia (AML), no significant increase in response rate was observed; however, a significant decrease in the death rate from pneumonia and fungal infection was observed.37 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) (P = 0.048).37
o In a study by the Cancer and Leukemia Group B of GM-CSF that was derived from E coli, no difference was observed in response rates between the groups that received GM-CSF and placebo.38 The risk of severe infection and resistant leukemia was similar in the 2 groups. However, in a European Organization for Research and Treatment of Cancer study using GM-CSF derived from E coli, patients who randomly received GM-CSF after induction had a significantly lower complete rate (48%) compared with patients who did not receive GM-CSF (77%).39
o 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.39 For this reason, most clinicians use either of these growth factors in patients who are at high risk for complications from infection.

Surgical Care

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

Patients with acute myelogenous leukemia (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

Patients should limit their activity to what is tolerable, with no strenuous activities (eg, lifting, exercise).
Medication

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

Antineoplastic agents are used for induction or consolidation therapy.

Cytosine arabinoside, cytarabine (Cytosar-U)

Antimetabolite specific for cells in the S-phase of the cell cycle. Acts through inhibition of DNA polymerase and cytosine incorporation into DNA and RNA.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

100 mg/m2/d IV as a 24-h continuous infusion for 7 d

3 g/m2/d IV as a 3-h infusion bid on days 1, 3, and 5
Pediatric

100-200 mg/m2/d IV for 5-10 d

* Dosing
* Interactions
* Contraindications
* Precautions

Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase cytarabine toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; relatively contraindicated in pregnancy; dose reduction may be required in patients with hepatic insufficiency

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Should be administered only by physicians specifically trained to prescribe antineoplastic agents; if a significant increase in bone marrow suppression occurs, reduce the number of days of treatment; patients with hepatic or renal insufficiencies are at a higher risk for CNS toxicity after a high dose; exercise caution with these patients by reducing the dose

Daunorubicin (Cerubidine)

Topoisomerase-II inhibitor. Inhibits DNA and RNA synthesis by intercalating between DNA base pairs.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

45-60 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric

35-45 mg/m2/d IV for 3 d

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation may occur, resulting in severe tissue necrosis; caution with patients with impaired hepatic, renal, or biliary function; significant dose reduction is required in the presence of hepatic or renal insufficiency

Idarubicin (Idamycin)

Topoisomerase-II inhibitor. Inhibits cell proliferation by inhibiting DNA and RNA polymerase.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric

10-12 mg/m2/d IV for 3 d and repeat q3wk

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; patients with congestive heart failure or reduced ejection fraction; relatively contraindicated in pregnancy

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Should be administered only by physicians specifically trained to prescribe antineoplastic agents; extravasation can result in severe tissue necrosis; caution in patients with preexisting cardiac disease and impaired hepatic function; significant dose reduction is required in the presence of hepatic or renal insufficiency

Mitoxantrone (Novantrone)

Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

12 mg/m2/d IV as a 15- to 30-min infusion for 3 d
Pediatric

18-20 mg/m2 IV q3-4wk

* Dosing
* Interactions
* Contraindications
* Precautions

None reported

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity; relatively contraindicated in pregnancy; significant dose reduction required in the presence of hepatic or renal insufficiency; congestive heart failure or a reduced ejection fraction

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Caution in patients with impaired hepatic function and preexisting cardiac disease (cardiotoxicity commonly observed after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (2-D echo and ejection fraction measurements)

Gemtuzumab ozogamicin (Mylotarg)

Withdrawn from United States market (June 21, 2010). A confirmatory, postapproval clinical trial was begun in 2004. The trial was designed to determine whether adding gemtuzumab to standard chemotherapy demonstrated an improvement in clinical benefit (survival time) to patients with AML. The trial was stopped early when no improvement in clinical benefit was observed and after a greater number of deaths occurred in the group of patients who received gemtuzumab compared with those receiving chemotherapy alone. At initial approval in 2000, gemtuzumab was associated with a serious liver condition called veno-occlusive disease (VOD), which can be fatal. This rate has increased in the postmarket setting.

Chemotherapy agent composed of a recombinant humanized IgG4, k antibody against CD33 conjugated with a cytotoxic antitumor antibiotic, calicheamicin. After binding to the cell, the released calicheamicin derivative binds to DNA in the minor groove, resulting in DNA double-strand breaks and cell death.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

9 mg/m2 IV over 2 h; give total of 2 doses 14 d apart; full hematologic recovery not necessary for administration of second dose; administer 50 mg diphenhydramine PO and 650-1000 mg acetaminophen PO 1 h before administration of each dose; may consider leukoreduction with hydroxyurea or leukapheresis to reduce peripheral WBC count to <30,000/µL before administration of Mylotarg; full recovery from hematologic toxicities not a requirement for administration of second dose
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

None reported; potential for drug-drug interaction with drugs affected by cytochrome P450 enzymes may not be ruled out

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity to drug or calicheamicin derivatives; presence of anti-CD33 antibody

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Postinfusion reactions include hypotension, fever, chills, or dyspnea (acetaminophen, intravenous fluids, and diphenhydramine may be administered to reduce the incidence); severe myelosuppression occurs in all patients at the recommended dosages; caution in patients with renal and hepatic impairment; tumor lysis may occur (risk may be reduced by administering allopurinol prophylactically and maintaining adequate hydration); should be administered under supervision of physicians experienced in the treatment of acute leukemia and in facilities equipped to monitor and treat patients with leukemia

Administration can result in severe hypersensitivity reactions (including anaphylaxis) and other infusion-related reactions, which may include severe pulmonary events (infrequently, hypersensitivity reactions and pulmonary events have been fatal); in most cases, infusion-related symptoms occurred during infusion or within 24 h of administration and resolved

Infusion should be interrupted for patients who experience dyspnea or clinically significant hypotension; monitor patients until signs and symptoms completely resolve; consider discontinuation of treatment for patients who develop anaphylaxis, pulmonary edema, or acute respiratory distress syndrome

Because patients with high peripheral blast counts may be at greater risk for pulmonary events and tumor lysis syndrome, physicians should consider leukoreduction with hydroxyurea or leukapheresis to reduce the peripheral white count to <30,000/µL before the administration of Mylotarg; hepatotoxicity, including severe hepatic veno-occlusive disease (VOD), has been reported in association with use as single agent, as part of a combination chemotherapy regimen, and in patients without a history of liver disease or hematopoietic stem cell transplantation (HSCT)

If administered either before or after HSCT, patients with underlying hepatic disease or abnormal liver function, when received in combinations with other chemotherapy are at increased risk for developing VOD, including severe VOD; death from liver failure and from VOD has been reported; monitor for symptoms of hepatotoxicity, particularly VOD, which include rapid weight gain, right upper quadrant pain, hepatomegaly, ascites, elevations in bilirubin and liver enzymes

Arsenic trioxide (Trisenox)

Used in patients with relapsed APL. The mechanism of action of Trisenox 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.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

Induction: 0.15 mg/kg/d IV until bone marrow remission occurs; maximum induction is 60 doses

Consolidation: 0.15 mg/kg/d IV starting 3-6 wk after completion of induction therapy; maximum consolidation is 25 doses over 5 wk
Pediatric

Not establishedFollow-up
Further Inpatient Care

Patients with acute myelogenous leukemia (AML) require readmission for consolidation chemotherapy or for the management of toxic effects of chemotherapy.
Further Outpatient Care

Patients should come to the office for monitoring of disease status and chemotherapy effects.
Transfer

Patients with acute myelogenous leukemia (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.
Deterrence/Prevention

When receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.
Complications

* Death in patients with acute myelogenous leukemia (AML) may occur because of uncontrolled infection or hemorrhage. This may happen even after use of appropriate blood product and antibiotic support.
* The most common complication 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.

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 is associated with a poor outcome to therapy. The most common antecedent hematologic disorder is MDS.
* Cytogenetic analysis of the bone marrow is 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.

Patient Education

Patients with acute myelogenous leukemia (AML) should be instructed to call their healthcare providers immediately if they are febrile or have signs of bleeding.
Miscellaneous
Medicolegal Pitfalls

* The most important medicolegal pitfall is the failure to rapidly distinguish a patient with acute leukemia from patients with less urgent hematologic disorders. Pancytopenia, for example, can be caused by a large variety of diseases of varying severity, including vitamin deficiencies and autoimmune disease. However, pancytopenia due to acute promyelocytic leukemia (APL) is a life-threatening emergency that must be aggressively treated immediately. The easiest way to avoid misdiagnosis is to review the peripheral blood smear at the time of initial evaluation of all patients with hematologic disorders.
* A second pitfall is failure to immediately treat a patient with neutropenic fever or infection with broad spectrum antibiotics.
* A third pitfall is failure to give appropriate transfusion support to a patient with acute leukemia. This includes transfusion of platelets and clotting factors (fresh frozen plasma, cryoprecipitate) as guided by the patient's blood test results and bleeding history. Blood products must be irradiated to prevent transfusion-associated graft versus host disease.