Acute Myelogenous Leukemia
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\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 3-5 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. 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/µL, especially < 100 cells/µL) 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/µL) 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. Diagnostic Considerations Failure to rapidly distinguish a patient with acute myelogenous leukemia (AML) from a patient with a less urgent hematologic disorder is the most important medicolegal pitfall in this setting. 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 lifethreatening 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. Another condition that should be considered in the evaluation of AML is agranulocytosis, a severe subset of neutropenia. Differentials y Acute Lymphoblastic Leukemia y Agnogenic Myeloid Metaplasia With Myelofibrosis y Anemia y Aplastic Anemia y Bone Marrow Failure y Chronic Myelogenous Leukemia y Lymphoma, B-Cell y Lymphoma, Lymphoblastic y Myelodysplastic Syndrome y Myelophthisic Anemia 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-AmericanBritish (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 CD41 CD42a CD42b CD61 TdT CD11c Myeloid Myeloid Early precursor Positive in most AML, negative in APL Mature monocytes Monocytes Platelet glycoprotein IIb/IIIa complex Platelet glycoprotein IX Platelet glycoprotein Ib Platelet glycoprotein IIIa Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1 Myeloid Lineage
Glycophorin A Erythroid
CD117 (c-kit) Myeloid/stem cell 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 patient¶s 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). hemotherapy 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 conventionaldose 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 conventionaldose 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 ³3 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 dell¶Adulto (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: y 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. y 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. y 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 highdose 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. y 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 ³watch 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 conventional-dose 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 conventionaldose 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/µL was 11 months (range, 0.5-59.8 mo) and WBC greater than 10,000 cells/µL was 7.1 months (range, 1.9-32.7 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 day100 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. 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. 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.
Updated: Jun 13, 2011
http://emedicine.medscape.com/article/197802-treatment#aw2aab6b6b2 Contributor Information and Disclosures Author Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching Specialty Editor Board Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program Disclosure: Takeda Millenium Honoraria Speaking and teaching Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.
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 3-5 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. 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/µL, especially < 100 cells/µL) 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/µL) 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. Diagnostic Considerations Failure to rapidly distinguish a patient with acute myelogenous leukemia (AML) from a patient with a less urgent hematologic disorder is the most important medicolegal pitfall in this setting. 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 lifethreatening 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. Another condition that should be considered in the evaluation of AML is agranulocytosis, a severe subset of neutropenia. Differentials y Acute Lymphoblastic Leukemia y Agnogenic Myeloid Metaplasia With Myelofibrosis y Anemia y Aplastic Anemia y Bone Marrow Failure y Chronic Myelogenous Leukemia y Lymphoma, B-Cell y Lymphoma, Lymphoblastic y Myelodysplastic Syndrome y Myelophthisic Anemia 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-AmericanBritish (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 CD41 CD42a CD42b CD61 TdT CD11c Myeloid Myeloid Early precursor Positive in most AML, negative in APL Mature monocytes Monocytes Platelet glycoprotein IIb/IIIa complex Platelet glycoprotein IX Platelet glycoprotein Ib Platelet glycoprotein IIIa Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1 Myeloid Lineage
Glycophorin A Erythroid
CD117 (c-kit) Myeloid/stem cell 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 patient¶s 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). hemotherapy 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 conventionaldose 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 conventionaldose 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 ³3 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 dell¶Adulto (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: y 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. y 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. y 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 highdose 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. y 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 ³watch 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 conventional-dose 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 conventionaldose 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/µL was 11 months (range, 0.5-59.8 mo) and WBC greater than 10,000 cells/µL was 7.1 months (range, 1.9-32.7 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 day100 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. 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. 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.
Updated: Jun 13, 2011
http://emedicine.medscape.com/article/197802-treatment#aw2aab6b6b2 Contributor Information and Disclosures Author Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching; Celgene Honoraria Speaking and teaching Specialty Editor Board Clarence Sarkodee-Adoo, MD Consulting Staff, Department of Bone Marrow Transplantation, City of Hope Samaritan BMT Program Disclosure: Takeda Millenium Honoraria Speaking and teaching Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.
