Acute myelogenous leukemia (AML)


Acute myelogenous leukemia (AML) is the result of a sequence of somatic mutations in a multipotential primitive hematopoietic cell or, in some cases, a more differentiated progenitor cell. Exposure to radiation, chronic exposure to high doses of benzene, and chronic, heavy inhalation of tobacco smoke increase the incidence of the disease. A small but increasing proportion of cases develop after a patient with lymphoma or a nonhematologic cancer is exposed to intensive chemotherapy, especially with alkylating agents or topoisomerase II inhibitors. The mutant hematopoietic cell gains a growth and/or survival advantage in relationship to the normal pool of stem cells. As the progeny of this mutant, now leukemic, multipotential cell proliferates to form approximately 11 billion or more cells, normal hematopoiesis is inhibited, and normal red cell, neutrophil, and platelet blood levels fall. The resultant anemia leads to weakness, exertional limitations, and pallor; the thrombocytopenia to spontaneous hemorrhage, usually in the skin; and the neutropenia and monocytopenia to poor wound healing and minor infections. Severe infection usually does not occur at diagnosis but will if the disease progresses because of lack of treatment or if chemotherapy intensifies the decrease of blood neutrophil and monocyte levels. The diagnosis is made by measurement of blood cell counts and examination of blood and marrow cells and is based on identification of leukemic blast cells in the marrow and blood. The diagnosis of AML specifically is confirmed by identification of myeloperoxidase activity in blast cells or by identifying characteristic cluster of differentiation (CD) antigens on the blast cells (e.g., CD13, CD33). The leukemic stem cell is capable of imperfect differentiation and maturation. The clone may contain cells that have the morphologic or immunophenotypic features of erythroblasts, megakaryocytes, monocytes, eosinophils, or, rarely, basophils or mast cells, in addition to myeloblasts or promyelocytes. When one cell line is sufficiently dominant, the leukemia may be referred to as acute erythroid, acute megakaryocytic, acute monocytic, and so on. Certain cytogenetic alterations are more frequent and include t(8;21), t(15;17), inversion 16, trisomy 8, and deletions of all or part of chromosome 5 or 7. A translocation involving chromosome 17 at the site of the retinoic acid receptor alpha (RAR-) gene is uniquely associated with acute promyelocytic leukemia. AML usually is treated with cytarabine and an anthracycline antibiotic, although other drugs may be added or substituted in poor-prognosis, refractory, or relapsed patients. The exception to this approach is the treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and an anthracycline antibiotic. High-dose chemotherapy and either autologous stem cell infusion or allogeneic stem cell transplantation may be used in an effort to treat relapse or patients at high risk to relapse after chemotherapy treatment. The probability of remission ranges from approximately 80 percent in children to less than 25 percent in octogenarians. The probability for cure decreases from approximately 50 percent in children to virtually zero in octogenarians.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: AIDS, acquired immunodeficiency syndrome; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; APL, acute promyelocytic leukemia; As2O3, arsenic trioxide; ATRA, all-trans-retinoic acid; CD, cluster of differentiation; CEBPA, CCAAT-enhancer binding protein A; CML, chronic myelogenous leukemia; CNS, central nervous system; FAB, French-American-British classification; FISH, fluorescence in situ hybridization; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; Ig, immunoglobulin; MDR, multidrug resistance; MDS, myelodysplastic syndrome; PAS, periodic acid-Schiff; PCR, polymerase chain reaction; PDGF, platelet-derived growth factor; P-gp, permeability glycoprotein; RT, reverse transcriptase; TdT, terminal deoxynucleotidyl transferase; TMD, transient myeloproliferative disease; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WHO, World Health Organization.

Definition and History

Acute myelogenous leukemia (AML) is a clonal, malignant disease of hematopoietic tissues that is characterized by (1) accumulation of abnormal (leukemic) blast cells, principally in the marrow, and (2) impaired production of normal blood cells. Thus, the leukemic cell infiltration in marrow is accompanied, nearly invariably, by anemia and thrombocytopenia. The absolute neutrophil count may be low or normal, depending on the total white cell count.

The first well-documented case of acute leukemia is attributed to Friedreich,1 but Ebstein2 was the first to use the term acute leukämie in 1889. This work led to the general appreciation of the clinical distinctions between AML and chronic myelogenous leukemia (CML).3 In 1878, Neumann,4 who proposed that marrow was the site of blood cell production, first suggested that leukemia originated in the marrow and used the term myelogene (myelogenous) leukemia. The availability of polychromatic stains, as a result of the work of Ehrlich,5 the description of the myeloblast and myelocyte by Naegeli,6 and the earliest appreciation of the common origin of red cells and leukocytes by Hirschfield7 laid the foundation for our current understanding of the disease.

Although Theodor Boveri proposed a critical role for chromosomal abnormalities in the development of cancer in 1914, a series of technical developments in the 1950s was needed to permit informed examination of the chromosomes of cancer cells. Thereafter, the discovery that a G group chromosome consistently had a foreshortened long arm in the cells of patients with CML (Philadelphia chromosome) supported the concept that chromosome abnormalities may be specifically linked to a cancer phenotype. This finding was followed by the introduction of banding of chromosomes, which enhanced the specific identification of individual chromosomes and the point at which they break in the formation of a translocation, inversion, or deletion. This technologic advance unleashed the power of cancer cytogenetics and initiated an era of leukemia study based not solely on the appearance of cells under the microscope (phenotype) but also by their chromosomal or genetic abnormality (genotype).8 The completion of the major phase of the human genome project further enhanced the specificity of the identification of gene alterations.9 These advances permitted (1) more precise understanding of the molecular pathology of specific leukemia subtypes, (2) improvement of diagnostic and prognostic methods for the study of AML, and (3) identification of molecular targets for therapy.

The introduction to the clinic by Holland, Ellison, and colleagues10 of arabinosyl cytosine (cytarabine) in the late 1960s as the first potent drug for treatment of AML, followed by their introduction of the combination of 7 days of cytosine arabinoside and 3 days of daunomycin in the early 1970s (the “7 and 3 regimen”)11 opened the era of effective therapy for AML. This drug combination or its congeners remains the mainstay of treatment nearly four decades later. The description of allogeneic marrow (stem cell) transplantation as a curative therapy for AML by Thomas and colleagues12 in 1977 ushered in the era of hematopoietic stem cell transplantation as a modality to cure eligible patients with AML.

Etiology and Pathogenesis

Environmental Factors

Table 89–1 lists the major conditions that predispose to development of AML. Only four environmental factors are established causal agents: tobacco smoking, high-dose radiation exposure,13,14 chronic benzene exposure,14–18 and chemotherapeutic (DNA-damaging) agents.19–25 Most patients have not been exposed to an antecedent causative factor. Exposure to high-linear energy transfer radiation from -emitting radioisotopes such as thorium dioxide increases the risk of AML.26 Case-control studies have sometimes found a relationship between AML and organic solvents, petroleum products, radon exposure, pesticides, and herbicides, but these data have been inconsistent, have shown no association in several studies, and have not reached a level comparable to the strong association that exists for benzene, high-dose external irradiation, and certain chemotherapeutic agents.27 The increased incidence of AML related to benzene exposure has not been seen in studies of industrial sites in which stringent regulations regarding benzene exposure have been implemented.14 There is a significant association between tobacco smoking and AML with a relative risk of about 1.5 to 2.0.28–30

Table 89–1. Conditions Pedisposing to Development of Acute Myelogenous Leukemia
Environmental factors
Alkylating agents, topoisomerase II inhibitors, and other cytotoxic drugs14,19–25
Tobacco smoke27,28
Acquired diseases
Clonal myeloid diseases
Chronic myelogenous leukemia (Chap. 90)
Primary myelofibrosis (Chap. 91)
Essential thrombocythemia (Chap. 87)
Polycythemia vera (Chap. 86)
Clonal cytopenias (Chap. 88)
Paroxysmal nocturnal hemoglobinuria (Chap. 40)
Other hematopoietic disorders
Aplastic anemia (Chap. 34)
Eosinophilic fasciitis (Chap. 88)
Other disorders
Human immunodeficiency virus infection34
Thyroid disorders35
Polyendocrine disorders36
Inherited or Congenital Conditions
Sibling with AML37–39
Amegakaryocytic thrombocytopenia, congenital40,41
Bloom syndrome44,45
Congenital agranulocytosis (Kostmann syndrome)46–49
Chronic thrombocytopenia with chromosome 21q 22.12 microdeletion50
Diamond-Blackfan syndrome51,52
Down syndrome53,54
Dubowitz syndrome55
Dyskeratosis congenita56,57
Familial (pure, nonsyndromic) AML58
Familial platelet disorder59,60
Fanconi anemia61,62
Naxos syndrome63
Neurofibromatosis 164,65
Noonan syndrome66,67
Poland syndrome68
Rothmund-Thomson syndrome69,70
Seckel syndrome71
Shwachman syndrome72–74
Werner syndrome (progeria)75–77
Wolf-Hirschhorn syndrome78
WT syndrome79

Evolution from a Chronic Clonal Hemopathy

AML may develop from the progression of other clonal disorders of a multipotential hematopoietic cell, including CML, polycythemia vera, primary myelofibrosis, essential thrombocythemia, and clonal sideroblastic anemia or oligoblastic myelogenous leukemia (MDS; see Table 89–1). Clonal progression can occur spontaneously, although with a different probability of occurrence in each chronic disorder (see Chap. 85). The frequency of clonal progression to AML is enhanced by radiation or chemotherapy in patients with polycythemia vera (see Chap. 86) or essential thrombocythemia (see Chap. 87).23,31

Predisposing Diseases

Patients who develop AML may have an antecedent predisposing nonmyeloid disease, such as aplastic anemia (polyclonal T-cell disorder), myeloma (monoclonal B-cell disorder),32,33 or, rarely, AIDS (HIV-induced polyclonal T-cell disorder).34 An association between immune thyroid diseases and familial polyendocrine disorder and AML has been reported.35,36 A number of inherited conditions carry an increased risk of AML (see Table 89–1).37–79 In the inherited syndromes, at least several pathogenetic types of gene alterations are represented: (1) DNA repair defects, e.g., Fanconi anemia; (2) susceptibility genes favoring a second mutation, e.g., familial platelet syndrome; (3) tumor-suppressor defects, e.g., dyskeratosis congenita; and (4) unknown mechanisms, e.g., ataxia-pancytopenia (see Chap. 34 and reference 46 for further details of each pathogenetic process).

Molecular Pathogenesis

AML results from a series of somatic mutations in either a hematopoietic multipotential cell or, occasionally, a more differentiated, lineage-restricted progenitor cell.78 Some cases of monocytic leukemia, promyelocytic leukemia, and AML in younger individuals more likely arise in a progenitor cell with lineage restrictions (progenitor cell leukemia).80–84 Other morphologic phenotypes and older patients likely have disease that originates in a primitive multipotential cell.78 In the latter case, all blood cell lineages can be derived from the leukemic stem cell because it retains the ability for some degree of differentiation and maturation (see Chap. 85).

The AML stem cell has been defined by its immunophenotype, CD123+CD45dimCD34+CD38–. These stem cells can be isolated from cases of AML at presentation or at relapse. In remission, the AML stem cell can be found using a panel of antigens—CLL-1, CD5, CD7, CD19, CD56—to identify leukemic stem cells bearing CD45dim,CD34+Cd38–.85 Attempts to find agents that selectively target AML stem cells are under way.86

Somatic mutation results from a chromosomal translocation in the majority of patients.87 The translocation results in rearrangement of a critical region of a protooncogene. Fusion of portions of two genes usually does not prevent the processes of transcription and translation; thus, the fusion gene encodes a fusion protein that, because of its abnormal structure, disrupts a normal cell pathway and predisposes to a malignant transformation of the cell. The mutant protein product often is a transcription factor or an element in the transcription pathway that disrupts the regulatory sequences controlling growth rate or survival of blood cell progenitors and their differentiation and maturation.87–89 Examples of genes often mutated are core binding factor, retinoic acid receptor- (RAR-), HOX family, MLL, and others. Core binding factor (CBF) has two subunits: CBF– and RUNX1 (formerlyAML1). Approximately 10 percent of AML cases have translocations involving one or the other of these latter two genes, although the percentage varies depending on the patient’s age at onset. In patients younger than age 50 years, the frequency is approximately 20 percent. In patients older than age 50 years, the frequency is approximately 6 percent. Core binding factor activates genes involved in myeloid and lymphoid differentiation and maturation. These primary mutations are not sufficient to cause AML. Additional activating mutations, for example, in hematopoietic tyrosine kinases FLT3 and KIT or in N-RAS and K-RAS, are required to induce a proliferative advantage in the affected primitive cell.85 Other protooncogene mutations occur in leukemic cells involving FES, FOS, GATA-1, JUN B, MPL, MYC, p53, PU.1, RB, WT1, WNT, NPM1, CEPBA, and other genes.90–101 Their interaction with loss-of-function mutations in hematopoietic transcription factors probably causes the acute leukemia phenotype characterized by a disorder of proliferation, programmed cell death, differentiation, and maturation.89,100 A minimum of two classes of genes has been proposed: class I gene mutations, for example, RUNX1, which lead to a proliferation and survival advantage to the cells in the clone, and class II gene mutations, for example, core binding factor, which interacts with the class I mutation, conferring severely disturbed differentiation and maturation patterns on the mutated cell and fostering the evolution of a classic AML phenotype.89 Because the mutant stem or early progenitor cell can proliferate and retains the capability to differentiate, a wide variety of phenotypes can emerge from a leukemic transformation.

FLT3 encodes a tyrosine kinase receptor in normal myeloid and lymphoid progenitors. Internal tandem duplications of FLT3 on chromosome 13 occurs in approximately one-fourth to one-third of adult AML cases but occurs more frequently in cases of AML with normal cytogenetic patterns, monocytic phenotype, and PML-RAR- or DEK-CAN translocations.102 The FLT3-internal tandem duplication (ITD) mutation confers a poor prognosis if the ratio of mutant to wild-type expression is high.103,104 Hypermethylation of the death-associated protein kinase has been observed in approximately 25 percent of AML cases and is twice as prevalent in cases of AML following cytotoxic therapy.

Deletions of all or part of a chromosome (e.g., chromosome 5, 7, or 9) or additional chromosomes (such as trisomy 4, 8, or 13) are common cytogenetic abnormalities (see Chap. 11), although the specific causative oncogenes or tumor suppressor genes in these latter circumstances have not been defined. Deletions in chromosomes 5 and 7 and complex cytogenetic abnormalities are increased in frequency in older patients and cases of AML following cytotoxic therapy compared to de novo cases.105 Because the genes residing on the undeleted homologous segment of chromosome 5 are not mutated, an epigenetic lesion, such as hypermethylation of a gene allelic to one on the deleted segment on chromosome 5, may result in the leukemogenic event.

In acute promyelocytic leukemia, PML-RAR- fusion protein represses retinoic acid-inducible genes, which prevent appropriate maturation of promyelocytes. The induced disruption, which involves corepressor–histone deacetylase complexes, results in the leukemic phenotype (see “Acute Promyelocytic Leukemia” below).106,107

Deregulated Signaling Pathways

The mutations in AML result in deregulation of any of several signal transduction pathways, which disrupt pathways that ensure the normal behavior of (1) differentiation and maturation, (2) proliferation, and (3) survival signals in hematopoietic cells. The pathways involved are myriad but several represent the majority of cases. These include the (1) PI3K-AKT, (2) RAS-RAF-MEK-ERK, and (3) STAT3 signaling sequences.108 The expectation is that a relative small number of downstream signaling pathways mediate the leukemogenic effect of gene mutations, making the potential targets for therapy less diffuse than suggested by the number of gene mutations involved in AML.

Mode of Inheritance

In most cases, little evidence is seen for a strong influence of inherited factors. The identical twin of a child with acute leukemia has a heightened risk of developing the disease. However, the risk appears to be related to intraplacental metastasis and thus falls to the risk of a nonidentical sibling after the first few years of life.109,110 The risk of AML in a nonidentical sibling in the United States is elevated, perhaps twofold to threefold, compared to the risk of AML in unrelated American children of European descent younger than age 15 years.109,111 Clusters of AML cases in families have been documented, but their frequency is low.58 Clusters of AML in unrelated persons in a community are uncommon and, when investigated, usually prove to be a chance occurrence.


AML is the predominant form of leukemia during the neonatal period but represents a small proportion of cases during childhood and adolescence. Approximately 15,000 new cases of AML occur annually, representing approximately 35 percent of the annual new cases of leukemia in the United States. Approximately 9000 patients with AML in the United States die each year as a result of the disease. The incidence rate of AML is approximately 1.5 per 100,000 in infants younger than 1 year of age, decreases to approximately 0.4 per 100,000 children ages 5 to 9 years, increases gradually to approximately 1.0 persons per 100,000 until age 25 years, and thereafter increases exponentially until the rate reaches approximately 25 per 100,000 persons in octogenarians (Fig. 89–1). The exception to this exponential age-related increase in incidence is acute promyelocytic leukemia (APL), which does not change greatly in incidence with age.112

Figure 89–1.
The annual incidence of acute myelogenous leukemia as a function of age. There is a relatively small increase to about 1.5 cases per 100,000 population in the first year of life year representing congenital, neonatal, and infant AML. The incidence falls to a nadir of 0.4 new cases per 100,000 population over the first 10 years of life and then rises again to 1 case per 100,000 in the second decade of life. From about 25 years of age, the incidence increases exponentially (log-linear) to about 20 cases per 100,000 population in octogenarians.

AML accounts for 15 to 20 percent of the acute leukemias in children and 80 percent of the acute leukemias in adults. It is slightly more common in males. Little difference in incidence is seen between individuals of African or European descent at any age. A somewhat lower incidence is seen in persons of Asian descent. An increase in the frequency of AML is seen in Jews, especially those of Eastern European descent. The acute promyelocytic variant of AML is somewhat more common in Latinos.113,114


Variants of AML can be identified by morphologic features of blood films using polychromatic stains and histochemical reactions,115 monoclonal antibodies against surface markers,115–120 or by the presence of specific chromosome translocations.121 The epitopes on the progenitor cells of several phenotypic variants overlap, and several monoclonal antibodies are required to make specific distinctions among cell types (Table 89–2; see also “Morphologic Variants of Acute Myelogenous Leukemia” and Table 89–4 below). Correlation between morphologic and immunologic phenotyping of AML is poor. However, poor correlation is expected because the former method is more subjective, given to observer variation, and is based on qualitative factors, whereas the latter method, which characterizes surface molecular features, is more accurate and reproducible. The correlation is improved only somewhat if morphology and histochemistry are coupled.122 Gene expression profiling is early in its use as a classification technique for AML but may prove to be more specific and informative than current methods.123,124 The outcome will depend on the simplification and automation of such techniques, and the availability of drugs that make such distinctions in the prognostic category of practical utility. Chapter 85 contains the classification of morphologic variants of AML (see Table 85–1 and Fig. 85–2). The need to consider functional markers for drug resistance, such as MDR expression, has been proposed to separate more-responsive from less-responsive AML. However, a cogent argument has been made that, for practical purposes, a classification that initially considers morphologic phenotype and immunophenotype is advisable. Cytogenetics, molecular genetics, gene expression profiling, MDR expression, and other considerations can, and should, be layered on as available and useful in influencing therapy.125

Table 89–2. Immunologic Phenotypes of AML
Phenotype Usually Positive
Myeloblastic CD11b, CD13, CD15, CD33, CD117, HLA-DR
Myelomonocytic CD11b, CD13, CD14, CD15, CD32, CD33, HLA-DR
Erythroid Glycophorin, spectrin, ABH antigens, carbonic anhydrase I, HLA-DR
Promyelocytic CD13, CD33
Monocytic CD11b, 11c, CD13, CD14, CD33, CD65, HLA-DR
Megakaryoblastic CD34, CD41, CD42, CD61, anti-von Willebrand factor
Basophilic CD11b, CD13, CD33, CD123, CD203c
Mast cell CD13, CD33, CD117
NOTE: Chapter 14 provides the definition of the antigen that represents a cluster of differentiation (CD).

Clinical Features

Signs and Symptoms


Signs and symptoms that signal the onset of AML include pallor, fatigue, weakness, palpitations, and dyspnea on exertion. The signs and symptoms reflect the development of anemia; however, weakness, loss of sense of well-being, and fatigue on exertion can be disproportionate to the severity of anemia.126–130

Easy bruising, petechiae, epistaxis, gingival bleeding, conjunctival hemorrhages, and prolonged bleeding from skin injuries reflect thrombocytopenia and are frequent early manifestations of the disease. Very infrequently, gastrointestinal, genitourinary, bronchopulmonary, or central nervous system (CNS) bleeding occurs at the onset of disease.

Pustules or other minor pyogenic infections of the skin and of minor cuts or wounds are most common. Major infections, such as sinusitis, pneumonia, pyelonephritis, and meningitis, are uncommon presenting features of the disease, partly because absolute neutrophil counts less than 500/L (0.5 x 109/L) are uncommon until chemotherapy starts. With intensification of neutropenia and monocytopenia after chemotherapy, major bacterial, fungal, or viral infections become more frequent. Anorexia and weight loss are frequent findings. Fever is present in many patients at the time of diagnosis.129,131–133 Palpable splenomegaly or hepatomegaly occurs in approximately one-third of patients.126,127,130 Lymphadenopathy is extremely uncommon,130,134,135 except in the monocytic variant of AML.136

Specific Organ System Involvement

Leukemic blast cells circulate and enter most tissues in small numbers. Occasionally, biopsy or autopsy uncovers marked aggregates or infiltrates of leukemic cells. Collections of such cells may cause functional disturbances. Extramedullary involvement is most common in monocytic or myelomonocytic leukemia.137,138

Skin involvement may be of three types: nonspecific lesions, leukemia cutis, or granulocytic (myeloid) sarcoma of skin and subcutis.139–142 Nonspecific lesions include macules, papules, vesicles, pyoderma gangrenosum, vasculitis,143–145 neutrophilic dermatitis (Sweet syndrome),146 cutis vertices gyrata,147 and erythema multiforme or nodosum.140,141 Skin involvement preceding marrow and blood involvement or relapse occurs but is rare.148–151

Sensory organ involvement is very unusual, but retinal, choroidal, iridial, and optic nerve infiltration can occur.152 Otitis externa and interna, inner ear hemorrhage, and mastoid tumors with seventh nerve involvement may be presenting signs.153–155

The gastrointestinal tract may be involved at any point, but functional disturbances are unusual.156,157 The mouth, colon, and anal canal are sites of involvement that most commonly lead to symptoms. Oral manifestations may prompt the patient to visit the dentist. Gingival or periodontal infiltration and dental abscesses may lead to an extraction, followed by prolonged bleeding of an infected tooth socket.158 Ileotyphlitis (enterocolitis), a necrotizing inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a presenting syndrome or occur during treatment.159–162 Fever, abdominal pain, bloody diarrhea, or ileus may be present and occasionally mimic appendicitis. Intestinal perforation, an inflammatory mass, and associated infection with enteric gram-negative bacilli or clostridial species often are associated with a fatal outcome. Isolated involvement of the gastrointestinal tract is rare.163,164 Proctitis, especially common in the monocytic variant of AML, can be a presenting sign or a vexing problem during periods of severe granulocytopenia and diarrhea.156

The respiratory tract can be involved by infiltrates or tumors, leading to laryngeal obstruction, parenchymal infiltrates, alveolar septal infiltration, or pleural seeding. Each of these events can result in severe symptoms and radiologic findings.165–169

Cardiac involvement is frequent but rarely causes symptoms. Symptomatic pericardial infiltrates, transmural ventricular infiltrates with hemorrhage, and endocardial foci with associated intracavitary thrombi can occasionally cause heart failure, arrhythmia, and death.170 Infiltration of the conducting system or valve leaflets or myocardial infarction has occurred.171

The urogenital system can be affected. The kidneys are infiltrated with leukemic cells in a high proportion of cases, but functional abnormalities are rare. Hemorrhage in the pelvis or collecting system is frequent.172,173 Cases of vulvar, bladder neck, prostatic, and testicular involvement have been described.174–176

Osteoarticular symptoms may occur. Bone pain, joint pain, and bone necrosis can occur, and, rarely, arthritis with effusion is present.177 Crystal-induced arthritis of either calcium pyrophosphate dihydrate (pseudogout) or monosodium urate (gout) may be responsible for the synovitis in some cases.178

Central or peripheral nervous system involvement by infiltration of leukemic cells is very uncommon, although meningeal involvement is an important consideration in the treatment of the monocytic type of AML.179,180 An association of CNS involvement and diabetes insipidus in AML with monosomy 7181 and inversion of chromosome 16182,183 has been reported.

Myeloid (Granulocytic) Sarcoma

Myeloid sarcoma (also known as granulocytic sarcoma, chloroma, myeloblastoma, monocytoma) is a tumor composed of myeloblasts, monoblasts, or megakaryocyes.184–189 The tumors may occur as extramedullary masses without evidence of leukemia in blood or marrow, so-called nonleukemic myeloid sarcomas, or in association with AML. When the tumors appear as isolated lesions, they initially may be misdiagnosed as extranodal lymphoma because they look like lymphoid cells on biopsy.186 They may be found in virtually any location, including the skin; orbit; paranasal sinuses; bone; chest wall; breast; heart; gastrointestinal, respiratory, or genitourinary tract; central or peripheral nervous system; or lymph nodes and spleen. The tumors originally were called chloromas because of the green color imparted by the high concentration of the enzyme myeloperoxidase present in myelogenous leukemic cells. Biopsy specimens are positive for chloracetate esterase, lysozyme, myeloperoxidase, and cluster of differentiation (CD) markers of myeloid cells. When myeloid sarcomas are the initial manifestation of AML, the appearance of the disease in the blood and marrow may follow weeks or months later. Abnormalities in chromosome 8 are the most frequent cytogenetic disturbance in nonleukemic sarcomas.187 Systemic chemotherapy, rather than local therapy, should be used for treatment, although the long-term outcome in such cases usually is poor.189–191 Patients having AML with t(8;21) have a propensity to develop extramedullary leukemia,192–195 and such patients with myeloid sarcomas have a poorer outcome after treatment.192,194

Laboratory Features

Blood Cell Findings

Anemia is a constant feature.126–130 Red cell life span may be mildly shortened, but the principal cause of anemia is inadequate production of red cells. The reticulocyte count usually is between 0.5 and 2.0 percent. Occasionally patients have rapid destruction of autologous and transfused red cells as a result of an unknown mechanism (milieu hemolysis). The presence of red cell autoantibodies (positive Coombs test) is very uncommon and may be nonspecific (anti-C3), perhaps related to circulating immune complexes. Red cell morphology is mildly abnormal, with exaggerated variation in cell size and occasional poikilocytes. Nucleated red cells or stippled erythrocytes may be present. Less often, extreme abnormalities of red cell size, shape, and hemoglobin content occur (AML with trilineage dysmorphia), but these changes are seen more often in oligoblastic myelogenous leukemia (see Chap. 88).

Thrombocytopenia is nearly always present at the time of diagnosis. The mechanism of thrombocytopenia is a combination of inadequate production and decreased survival of platelets. More than half of patients have a platelet count less than 50,000/L (50 x 109/L) at the time of diagnosis.196 Giant platelets and poorly granulated platelets with functional abnormalities can occur.197 Defects in platelet aggregation and 5-hydroxytryptamine release are frequent.197

The total leukocyte count is less than 5000/L (5 x 109/L) in approximately half of patients at the time of diagnosis.126–130 The absolute neutrophil count is less than 1000/L (1 x 109/L) in more than half of cases at diagnosis.126–130 Patients with very elevated total leukocyte counts have a low proportion of mature neutrophils but may have a normal absolute neutrophil count. Hypersegmented, hyposegmented, and hypogranular mature neutrophils may be present. Cytochemical abnormalities of blood neutrophils include low or absent myeloperoxidase or low alkaline phosphatase activity.198 Defects in phagocytosis or microbial killing are common.199

Myeloblasts almost always are present in the blood but may be infrequent in severely leukopenic patients. Diligent search may uncover the myeloblasts, or examination of a white cell concentrate (buffy coat) may permit their identification. Classic leukemic blast cells are agranular, but mixtures of immature cells, including agranular and slightly granular cells ranging up to overt progranulocytes, can occur. Auer rods are elliptical cytoplasmic inclusions approximately 1.5 m long and 0.5 m wide that derive from azurophilic granules (see Fig. 89–2B). The inclusions are present in the blast cells of approximately 15 percent of cases. When present, the inclusions are found in only a small percentage of blast cells when examined with polychrome stains.115,200 An exception is APL, in which a high proportion of cells have Auer rods and some have multiple (bundles) of rods. This finding can be dramatic if peroxidase stain is used to highlight the Auer rods.Marrow Findings


The marrow always contains leukemic blast cells. From 3 to 95 percent of marrow cells are blasts at the time of diagnosis or relapse. The World Health Organization (WHO) has invoked an arbitrary breakpoint of 20 percent of marrow nucleated cells being blast cells to distinguish polyblastic AML (≥20% blasts) from oligoblastic myelogenous leukemia (<20% blasts).126–130,200 The latter situation is referred to as refractory anemia with excess blasts, a myelodysplastic syndrome (see Chap. 88). The WHO choice of ≥20 percent blasts is an arbitrary, inconsistent, and confusing standard. Acute monocytic leukemia, acute promyelocytic leukemia, acute erythroid leukemia, and other variants often have less than 20 percent blast cells at the time of diagnosis. Moreover, relapse of AML can be identified at any increase in blast count >1 percent. Myeloblasts are distinguished from lymphoblasts by any of three pathognomonic features: reactivity with specific histochemical stains; Auer rods in the cells; or reactivity with a panel of monoclonal antibodies against epitopes present on myeloblasts (e.g., CD13, CD33, CD117). Leukemic myeloblasts give positive histochemical reactions for peroxidase, Sudan black B, or naphthyl AS-D-chloroacetate esterase stains. Auer rods can be found in the marrow blast cells in approximately one-sixth of cases. Blast cells may express granulocytic (CD15, CD65) or monocytic (CD11b, CD11c, CD14, CD64) surface antigens. They typically do not express either lymphoid surface markers or membrane or cytoplasmic immunoglobulin. No immunoglobulin gene rearrangement or T-lymphocyte receptor gene rearrangement is evident with molecular probes (see “Hybrid and Mixed Leukemias” below). In a proportion of otherwise typical cases of AML, the cells may contain terminal deoxynucleotidyl transferase (TdT).201,202 Variations in marrow findings are discussed further below in “Morphologic Variants of Acute Myelogenous Leukemia.” Normal erythropoiesis, megakaryocytopoiesis, and granulopoiesis are decreased or absent in the marrow aspirate. The biopsy may contain residual islands of erythroblasts or megakaryocytes. Dysmorphic changes in hematopoietic cells, including very small or large erythroblasts with nuclear fragmentation or binucleation or delayed nuclear condensation; small or monolobed megakaryocytes; or hypogranulated, bilobed, or monolobed neutrophils, may occur in 30 to 50 percent of patients with de novo AML.203 Marrow reticulin fibrosis is common but usually is slight to moderate except in cases of megakaryoblastic leukemia, in which intense fibrosis is the rule.204 Increased blood vessel density (angiogenesis) is present in the marrow of patients with AML compared to normal subjects.205,206 Various angiogenic factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, angiogenin, and angiopoietin-1, are increased. VEGF detected histochemically in human marrow is closely correlated with the prevalence of leukemic myeloblasts in the various AML subtypes.207 AML cytogenetic variants may result in marrow basophilia (usually t(6;9))208 or marrow eosinophilia (usually inv16 or t(16;16)).209

Marrow Cell Culture

Progenitor cells for granulocytes, monocytes and macrophages, or both granulocytes and macrophages form colonies when normal marrow cells are grown in a viscous medium with a source of growth factors. Marrow cells from patients with AML have heterogeneous growth patterns. The marrow of approximately 85 percent of patients does not have colony-forming cells, but the marrow of 60 percent of patients has cells capable of forming small clusters (4–40 cells) in vitro. Approximately 15 percent of patients retain colony-forming cells, but often in reduced numbers and with abnormal maturation patterns.210,211 Restoration of colony-forming cells in the marrow of treated patients often precedes morphologic evidence of remission.212 The correlation of pretreatment marrow colonial growth pattern in vitro with the outcome of intensive chemotherapy is insufficiently strong to use growth pattern as a prognostic variable.213

Cytogenetic and Genic Features

An abnormal number (aneuploidy) or structure (pseudodiploidy) of chromosomes or both are evident in approximately 60 percent of cases.214–217 The most prevalent abnormalities are trisomy 8, monosomy 7, monosomy 21, trisomy 21, and loss of an X or Y chromosome. However, any chromosome can be rearranged, added, or lost. In cases of AML following chemotherapy or radiotherapy, loss of part or all of chromosome 5 is a common feature,218–220 as are the cytogenetic findings noted above for AML, occurring de novo. Table 89–3 lists the most frequent abnormalities and translocations seen in AML (see Chap. 11). The translocations 8;21 and 15;17 and inversion 16 confer a more favorable outcome on average. Deletion of all or part of chromosomes 5 and 7 or the presence of complex changes confers an unfavorable prognosis. Other findings (e.g., normal karyotype, +8, 11q23) generally confer an intermediate prognosis (see Chap. 11 for further details).214–216

Table 89–3. Clinical Correlates of Frequent Cytogenetic Abnormalities Observed in AML
Chromosome Abnormality Genes Affected Clinical Correlation
Loss or Gain of Chromosome
Deletions of part or all of chromosome 5 or 7 Not defined Frequent in patients with AML occurring de novo and in patients with history of chemical, drug, or radiation exposure and/or previous hematologic disease.214,215,218,219
Trisomy 8 Not defined Very common abnormality in acute myeloblastic leukemia. Poor prognosis, often a secondary change.215,222
t(8;21) (q22;q22) RUNX1(AML1)RUNX1T1(ETO) Present in ~8% of patients <50 years old and in 3% of patients >50 years old with AML.220 Approximately 75% of cases have additional cytogenetic abnormalities, including loss of Y in males or X in females. Secondary cooperative mutations of KRAS, NRAS, KIT common. Present in ~40% of myelomonocytic phenotype. Higher frequency of myeloid sarcomas.192–195
t(15;17) (q31; q22) PML-RAR- Represents ~6% of cases of AML.220 Translocation involving chromosome 17, t(15;17), (t11;17), or t(5;17) is present in most cases of promyelocytic leukemia.106,107,223,224
t(9;11); (p22; q23) MLL(especially MLLT3) Present in ~7% of cases of AML.225–229 Associated with monocytic leukemia.226–227 11q23 translocations in 60% of infants with AML and carries poor prognosis. Rearranges MLL gene.225–229 Many translocation partners for 11q23 translocation.228–231 MLL1,MLL4,MLL10 may also result in AML phenotype.
t(9;22) (q34; q22) BCR–ABL Present in ~2% of patients with AML232,233
t(1;22)(p13;q13) RBMIS-MKL1 <1% of cases of AML. Admixture of myeloblasts, megakaryoblasts, micromegakaryocytes with cytoplasmic blebbing, dysmorphic megakaryocytes. Reticulin fibrosis common.234
Inv (16) (p13.1;q22) or t(16;16) (p13.1;q22) CBF-MYH11 Present in ~8% of patients <50 years of age and in ~3% of patients >50 years of age with AML220; often acute myelomonocytic phenotype; associated with increased marrow eosinophils; predisposition to cervical lymphadenopathy,235 better response to therapy.236–239 Predisposed to myeloid sarcoma.
Inv(3)(q21q26.2) RPN1-EVI1 ~1% of cases of AML. Approximately 85% of cases with normal or increased platelet count. Marrow has increased dysmorphic, hypolobulated megakaryocytes. Hepatosplenomegaly more frequent than usual in AML.240

Approximately 50 percent of cases of AML contain cells that are cytogenetically normal. When five genes—NPM1, FLT3, CEPBA, MLL, and NRAS—were examined in 872 adults who were younger than 60 years of age with a normal karyotype, approximately 85 percent had a mutation in at least one of these genes. Mutations in NPM1 or CEPBA were associated with more favorable outcomes, analogous to the category of favorable cytogenetics noted above. Mutations in FLT3 resulting from an internal tandem duplication (ITD) or wild-type expression of NPM1 and CEPBA in patients’ cells without a FLT3 mutation (triple wild-type) had poor outcomes.101

The microarray expression signature in patients with AML younger than age 60 years who have cytogenetically normal cells but high-risk molecular features, especially FLT3-ITD and/or wild-type NMP1 expression, is correlated with outcome of therapy. MicroRNAs regulate gene expression and the downregulation of the microRNA-181 family predicts a poor outcome. The microRNAs studied also revealed several important gene families that appear to be involved in the pathogenesis of AML, including genes involved in innate immunity (e.g., toll-like receptors and interleukin-1B expression and regulation).221 (See Chaps. 10 and 85 for further discussion of gene array profiling and microRNA analysis.)

Plasma Chemical Findings

Prior to treatment, mild to moderate increases in serum uric acid and lactic dehydrogenase levels are frequent. Both levels are higher in myelomonocytic and monocytic AML than in other AML phenotypes.129,130 Occasional patients have very elevated uric acid levels, which usually occur after chemotherapy if proper precautions are not taken (e.g., hypouricosemic agents and hydration therapy).241 Abnormalities of sodium, potassium, calcium, or hydrogen ion concentration are infrequent and usually mild.242,243 Severe hyponatremia associated with inappropriate antidiuretic hormone secretion has occurred at presentation.242,243 Severe hypernatremia as a consequence of diabetes insipidus can be an initial event.244 Hypokalemia is a more frequent finding at presentation and is related to kaliuresis, although the reason for the proximal renal tubular dysfunction is unclear.242,243,245 The hypokalemia can be severe and often is worsened by the effects of treatment, especially use of kaliuretic antibiotics.245 Factitious elevations in serum potassium levels have been reported in patients with hyperleukocytosis as a result of leakage from white cells in vitro.246,247 Factitious hypoglycemia and spurious hypoxia from the effects of high blast cell counts in blood can occur.244,248

Hypercalcemia can occur. The pathogenesis probably is multifactorial,249 but cases with increased ectopic parathormone-like activity in the plasma have been described.250 Severe lactic acidosis prior to treatment has been reported.242,251,252 Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur.253 Ectopic adrenocorticotropic hormone secretion,254 circulating immune complexes,255 and abnormal concentrations of coagulation factors or their inhibitors256 may be present.

Although prothrombin and partial thromboplastin times usually are normal or near normal, abnormal concentrations of coagulation factors are frequent. Elevations of platelet factor 4 and thromboxane B2 occur often.257 Decreases in 2-antiplasmin, protein C, and antithrombin III levels occur often257 and may be associated with venous thrombosis.258 Acute promyelocytic and acute monocytic leukemia are associated with hypofibrinogenemia and other indicators of activation of coagulation or fibrinolysis (see “Morphologic Variants of Acute Myelogenous Leukemia” below).259

The levels of the shed form of L-selectin260 and anticardiolipin antibodies261 in plasma frequently are elevated as are the levels of soluble VEGF receptor-1 (VEGFR-1) and VEGFR-2. The ratio of soluble VEGFR-1 to VEGF correlates with greater leukemic blast cell burden and with less favorable outcome.262

Special Clinical Features


Leukocyte count is an independent prognostic factor in the outcome of AML treatment.263 Approximately 5 percent of patients with AML develop signs or symptoms attributable to a markedly elevated blood blast cell count, usually greater than 100 x 109/L (see Chap. 85).264 The circulations of the CNS, lungs, and penis are most sensitive to the effects of leukostasis. Intracerebral hemorrhage from vascular occlusion, invasion, and disruption, sometimes complicated by thrombocytopenia and vascular insufficiency are the most virulent manifestations of the syndrome.265–269 Dizziness, stupor, dyspnea, and priapism may occur.246–251 Diabetes insipidus is another association.270,271 Other severe organ involvement may occur infrequently, also. A high early mortality in patients with AML correlates with hyperleukocytosis greater than 100 x 109/L.267–269,272,273 Chemotherapy in hyperleukocytic patients may lead to a pulmonary leukostatic syndrome, presumably from the effects of rigid, effete blast cells, or the discharge of large amounts of cell contents and resultant cell aggregation or other effects.274–276 Larger-vessel vascular occlusion as a result of white thrombi or masses of leukemic cells is rare.277–281 The upregulation of endothelial cell intercellular adhesion molecule-1 and of leukemic blast cell lymphocyte function-associated antigen-1 may mediate the vessel wall interaction contributing to leukostasis.282

Hypoplastic Leukemia

Approximately 10 percent of patients with AML present with a syndrome that includes pancytopenia, often with inapparent blood blast cells, and absence of hepatic, splenic, or lymph nodal enlargement.283–285 If one corrects for the decrease in marrow cellularity with age, hypoplastic AML occurs in approximately 2 percent of cases.286 Approximately 75 percent of these patients are men older than 50 years of age. Marrow biopsy is hypocellular, which is the unusual feature of the syndrome, but leukemic blast cells are evident and present in a proportion of 10 to 90 percent of marrow cells. Response to intensive chemotherapeutic treatment, often with low-dose cytarabine because of the patients’ very advanced age, has been relatively good, and 3-year survival rates are approximately the same as the rates of other age-matched patients.287

Oligoblastic (Subacute, Smoldering) Leukemia

In approximately 10 percent of cases, usually in patients older than 50 years of age, myelogenous leukemia is manifested by anemia and often thrombocytopenia. The leukocyte count may be low, normal, or increased, and a small proportion of blast cells are present in the blood (0–15%) and marrow (3–20%). Such cases have been referred to as oligoblastic myelogenous leukemia, subacute, or smoldering leukemia,288–290 or classified as a myelodysplastic syndrome, particularly refractory anemia with excess blasts. The clinical course of the untreated disease can be protracted. The disease has a high morbidity and mortality from infection and hemorrhage and can evolve into overt (polyblastic) AML. The smoldering or oligoblastic leukemias historically have been grouped with the clonal cytopenias as part of the myelodysplastic syndromes (refractory anemia with excess blasts); thus, the diagnosis and treatment of these variants are discussed in Chap. 88. Biologically and clinically, the disorders in this subset of the myelodysplastic syndrome with blast cell proportions in the marrow above normal are leukemias, not dysplasias, but they have a slower rate of progression than polyblastic myelogenous leukemia. Dysmorphogenesis of red cells, neutrophils, and platelets is more frequent and more striking than in the average case of polyblastic AML (see Chap. 88), but such dysmorphogenesis also occurs in polyblastic leukemia, so-called AML with trilineage dysmorphia.203

Ph-Chromosome–Positive Acute Myelogenous Leukemia

Approximately 2 percent of patients with acute myelogenous leukemias have the Ph (Philadelphia) chromosome t(9;22)(q34;q11) in a significant proportion (10–100%) of leukemic blast cells.291–293 The blast cells have surface antigens, such as CD13 and CD33, characteristic of myeloid leukemias.294,295 One interpretation of the concurrence of AML with t(9;22) is that it represents CML presenting in myeloid blast crisis.296–298 The arguments in favor of this proposal are as follows: (1) Blast crisis may occur within days after diagnosis of Ph-chromosome–positive CML. (2) Cases can present with additional cytogenetic changes comparable to CML in blast crisis.296,298 (3) Marked hepatosplenomegaly, uncharacteristic of AML, may be present.297,298 (4) Platelet counts may be normal, and basophils can be increased.296,298 (5) A long prodromal period of weakness and weight loss may occur, and some features of CML, such as granulocytosis, can appear after treatment with chemotherapy.299 (6) Ph-chromosome–positive AML has a very poor prognosis, as in myeloid blast crisis of CML. (7) The breakpoint on chromosome 22 in the M-bcr may be typical of CML, and the product of the fusion BCR-ABL gene is a p210 tyrosine kinase identical to that in classic CML.295,297–303 (8) Occasional cases express p210 and p190 tyrosine kinases, now known to be features of CML.303 (9) Some patients enter a remission by converting to a phenotype analogous to chronic phase CML. An alternative view has been promulgated because (1) cases of Ph-chromosome–positive AML can be a mosaic (normal and abnormal karyotypes),295 (2) the Ph chromosome may appear later in the course of the disease,304 (3) additional chromosomal abnormalities often are different from those seen in the myeloblastic crisis of CML,295,305,306 and (4) in some cases, the BCR-ABL gene is not encoding a p210 but a p190 mutant tyrosine kinase,292,300,302,303,307 the former being most characteristic of CML. Moreover, Ph-chromosome–positive AML has developed following Ph-chromosome–negative oligoblastic leukemia.292,308,309 Many cases of Ph-chromosome–positive acute leukemia are myeloid-lymphoid hybrids.299,303,305,310 Thus, Ph-chromosome–positive AML comes in two varieties: one with a break in M-BCR of chromosome 22 with a p210 product, which could be considered analogous to acute blast crisis of CML, and one with a molecular pathology resulting in the oncogene product being a p190 protein (m-BCR) that could be considered a de novo case.

Marrow Necrosis

Necrosis of the marrow is an uncommon event and can be seen in a wide variety of malignant and nonmalignant clinical disorders, but about two-thirds of cases are associated with lymphoid or myeloid malignancies and about one-quarter of cases occur in patients with AML.311 Bone pain (~80% of patients) and fever (~70% of patients) are the two most common symptoms or signs. Anemia and thrombocytopenia, if not already present, results. White cell counts may be low or high. The blood may contain nucleated red cells and myeloid immaturity (~50% of cases). Lactic dehydrogenase and alkaline phosphatase are elevated in about half the cases. Marrow aspirate is often watery and serosanguineous. An amorphous extracellular eosinophilic background with disintegrating cells that have lost their staining characteristics with indistinct margins and varying degrees of pyknosis and karyorrhexis is characteristic. Rare cases have been described in which the marrow contained Charcot-Leyden crystals without an increase in eosinophils or basophils.312 Boney spicules may also show evidence of necrosis. Destruction of spicule architecture with loss of osteocytes, osteoblasts, and osteocytes may be seen. It is important not to identify these changes as artifact. Usually more than 50 percent of the biopsy is involved. Careful search may identify the underlying hematological disorder in small islands of intact cells. Technetium-99m sulfur colloid scans show little or no uptake. Magnetic resonance imaging (MRI) may not be diagnostic but can show the extent of the necrosis by changes in signal intensity signifying an increase in water content in relation to fat. Both scanning and MRI can point to areas of intact marrow that may be used to make a diagnosis of the underlying disease, if it is unknown. The pathophysiology is uncertain but is thought to be related to marrow vascular injury and or thrombosis secondary to inflammatory or immune factors and cytokines. The prognosis of marrow necrosis is largely related to the underlying disease. Repair of marrow can occur, if the patient enters remission.

Neonatal Myeloproliferation and Leukemia

Four myeloproliferative syndromes related to AML have been identified in the neonate: transient myeloproliferative disorder, transient leukemia, congenital leukemia, and neonatal leukemia. Transient myeloproliferative disorder and transient leukemia are considered to represent the same phenomenon.

Transient myeloproliferative disease (TMD) can be present at birth or occur shortly thereafter in approximately 10 percent of infants with Down syndrome.313–319 The leukocyte count is markedly elevated, blast cells are present in the blood and marrow, and anemia and thrombocytopenia may be present, but the latter are not constant findings. The liver and spleen may be enlarged. Results of cytogenetic studies and marrow cell culture studies are normal, except for trisomy 21, which is characteristic of Down syndrome. The blast cells usually have the immunophenotype of megakaryocytes. In contrast to congenital leukemia, the elevated white cell and blast cell counts disappear in most patients (~80%) over a period of weeks to months. In approximately 20 percent of patients, severe and potentially lethal complications of hydrops fetalis, hepatic fibrosis, or cardiorespiratory failure may occur.

In some cases, an additional cytogenetic abnormality is present, which disappears after regression of the myeloproliferative syndrome, suggesting a reversible clonal disorder (transient leukemia) that is replaced by normal hematopoiesis. The presence of a trisomy of chromosome 21 is essential for the disease as judged by three observations: the trisomy occurs in (1) the TMD clone of patients with constitutional trisomy 21, (2) the TMD clone in patients with Down syndrome with a cell mosaic pattern of trisomy 21, and (3) in the TMD clone of phenotypically normal infants without a constitutional trisomy 21, but with TMD. In the last case, trisomy 21 disappears with resolution of the myeloproliferation.320 Candidate oncogenes on chromosome 21 responsible for the phenomenon include FPDMM, RUNX1 (CBF-), and IFNAR, among others.320 GATA-1 mutations have been found in nearly all patients with TMD and in acute megakaryocytic leukemia in Down patients.321 The TMD syndrome may disappear, only to be followed shortly thereafter by acute leukemia, predominantly AML, but occasionally acute lymphocytic leukemia (ALL).

One hypothesis for TMD is that the disorder originates in a primitive cell of fetal hepatic hematopoiesis. The cell involutes and is replaced with marrow stem cells. Approximately 25 percent of newborns with Down syndrome and transient leukemia develop acute megakaryocytic leukemia in the first 4 years of life.322–324

Very low dose cytarabine has been suggested for those patients with severe hepatic fibrosis, very high white cell counts, or hydrops fetalis.320 TMD cells in these infants are very sensitive to cytarabine.325,326

Children with Down syndrome have a 150-fold risk of AML and about a 40-fold risk of ALL by age five years. A slightly increased risk of acute leukemia persists into older age. Myelogenous leukemia in patients with Down syndrome often has a megakaryoblastic or erythroid phenotype and may have an interstitial deletion of chromosome 21.315,316,327–330 The response rate of infants with Down syndrome and AML to chemotherapy is very high over prolonged followup and better than the response of patients without Down syndrome.322,326,331,332 The response to adjusted-dose anthracycline antibiotic and cytarabine in Down syndrome children with AML is approximately 90 percent and the event-free 5-year survival is approximately 80 percent.329 ALL may occur, and the response to therapy is similar to the response of patients without Down syndrome of the same age. Most solid tumors occur less frequently in Down syndrome patients.325

Congenital or neonatal leukemia, a rare syndrome, occurs less than one-tenth as frequently in infants without Down syndrome than in newborns with Down syndrome.327,328 Leukocytosis, blood and marrow blast cells, hepatosplenomegaly, thrombocytopenia, purpura, anemia, and skin infiltrates are usual. The disease has been diagnosed prenatally. Cytogenetic abnormalities can occur and mark the leukemic clone.328,333,334 Monocytic leukemia and t(4;11) are the most common phenotype and karyotype.334–336 A case of vertical (transplacental) transmission of acute monocytic leukemia from mother to son has been reported.337

Infants who are normal at birth but develop AML in the first few weeks of life (neonatal leukemia) often display pallor, inadequate food intake, insufficient weight gain, diarrhea, and lethargy. The presence of a cytogenetic abnormality on band q23 of chromosome 11 is a very poor prognostic sign. Most infants with congenital or neonatal leukemia do not survive for more than a few weeks or months. Because treatment has been largely ineffective, observation to ascertain if TMD or a transient leukemia is present has been recommended if the clinical picture is unclear.338

Hybrid and Mixed Leukemias

Hybrid Leukemias

Although coincidental myeloid and lymphoid clonal diseases have been reported for more than 50 years, the availability of techniques to identify surface antigens with monoclonal antibodies, immunoglobulin gene, and T-lymphocyte receptor gene rearrangements with molecular methods, and chromosome translocations by chromosome banding cytogenetic techniques has led to the appreciation of several types of hybrid acute leukemia.339–347

In bilineal (interlineal) acute leukemias, a proportion of cells (>10%) have lymphoid and myeloid markers; interlineal here refers to lymphopoietic and myeloid gene expression. Bilineal (biphenotypic) leukemias are heterogeneous. Some patients have cells with both lymphoid and myeloid markers (chimeric), whereas other patients have cells with either lymphoid or myeloid markers but evidence that all the cells are part of the same malignant clone (mosaic). The bilineal leukemias may be synchronous (lymphoid and myeloid cells are present simultaneously) or asynchronous (in which lymphoid cells are succeeded by myeloid cells or vice versa), but evidence exists for their origin from the same clone.

Cases of biphenotypic leukemia that are morphologically or cytochemically indicative of myelogenous leukemia have been referred to as LY+AML; the cases that are more indicative of lymphocytic leukemia are referred to as MY+ALL. As a group, interlineal hybrid leukemias treated with current regimens respond to therapy at approximately the same rate as AML cases without lymphoid markers.339 Some observers suggest altering drug regimens, depending on the balance between lymphoid and myeloid biochemical (drug-response) patterns.348

Acute leukemias may be intralineal hybrids in that the blast cells have markers for two or more myeloid lineages (e.g., erythroid, granulocytic, and megakaryocytic) or, in the case of lymphocytic leukemias, both immunoglobulin gene rearrangement (B-lymphocyte type) and T-cell receptor gene rearrangement (T-lymphocyte type).

Myeloid–Natural Killer Cell Hybrids and T(8;13) Myeloid–Lymphoid Leukemias

Although most hybrid leukemias share myeloid and either B- or T-lymphocyte markers, two notable syndromes are associated with hybrid leukemias: (1) the myeloid leukemia and natural killer cell hybrid (CD56+, CD7+, CD13+, CD33+)349–355 and (2) the lymphoma, eosinophilia, and t(8;13) myeloid leukemia hybrid.356,357 Signs of lymphoma, such as mediastinal or other lymphadenopathy and extranodal lymphoid tumor, are mixed with findings compatible with AML in both syndromes. The morphology of the myeloid–natural killer cell leukemia often simulates APL, with hypergranular cytoplasm present but abnormality of chromosome 17 absent. The hybrids can appear de novo or after relapse of a lymphoma, T-cell leukemia, or blast crisis of CML. The hybrid leukemias usually have a poor prognosis. Myeloid antigens may not be evident at diagnosis in the natural killer cell hybrid but appear later in the course.358 Hematopoietic stem cell transplantation should be considered in an eligible patient.359

Hybrid leukemias may result from either lineage infidelity caused by genetic misprogramming349 or promiscuous gene expression, which occurs transiently in the differentiation of normal pluripotential hematopoietic stem cells. In the case of promiscuity, persistence of the transient normal event is thought to be present because of the block in differentiation that occurs.343,344 Genetic misprogramming (infidelity) could result from rearrangements of the DNA sequences that control the transcription of genes designating differentiation antigens.360

Mixed Leukemias

In these cases, lymphoid and myeloid cells are present simultaneously but are derived from separate clones, or sequential myeloid and lymphoid leukemia are present but the two lineages are derived from separate clones.

Mediastinal Germ Cell Tumors and Acute Myelogenous Leukemia

An unusual but significant concordance has been reported between nonseminomatous mediastinal germ cell tumors and AML, especially the megakaryoblastic variant.361–366 Mediastinal tumors are rare variants of germ cell tumors. The latter ordinarily occur as testicular teratomas and seminomas in men or as ovarian teratomas in women. They are thought to be derived from yolk sac cells that failed to migrate.364,365 AML is a hematopoietic stem cell tumor derived from a cell type that is present in the yolk sac. Cytogenetic studies are compatible with a clonal relationship (identity) of mediastinal germ cells and myelogenous leukemia cells.362,363 Apparently, hematopoietic lineage genes are predisposed to expression in extragonadal (mediastinal) germ cell tumors. Use of etoposide, platinum, and related cytotoxic drugs for treatment of mediastinal germ cell tumors may induce secondary AML in a predisposed cell population.367

Gastrointestinal Tumors and Acute Myelogenous Leukemia

A study of 1892 patients with KIT-positive mesenchymal tumors of the gastrointestinal tract (gastrointestinal stromal tumors or GISTs) found a significant subsequent incidence of AML (9 patients). The standardized incidence ratio was about 3.0 (confidence interval: 1.1–5.8). The patients had not received prior chemotherapy or radiotherapy and the median duration of GIST before onset of AML was 6 years.368

Morphologic Variants of Acute Myelogenous Leukemia

Morphologic variants of AML (Table 89–4) may occur de novo or may be the manifestation of clonal evolution from essential thrombocythemia, idiopathic myelofibrosis, CML, or other chronic clonal myeloid disorders. For example, every phenotypic variant of AML can occur as the blast crisis of CML (see Chap. 90).

Table 89–4. Morphologic Variants of AML
Variant Cytologic Features Special Clinical Features Special Laboratory Features
Acute myeloblastic leukemia (M0,M1,M2) 1. Myeloblasts range from 20 to 90% of marrow cells. Cytoplasm occasionally contains Auer bodies. Nucleus shows fine reticular pattern and distinct nucleolus (1 or 2 usually). 1. Most common in adults, and most frequent variety in infants. 1. Chromosomes +8, –5, –7, del(11q) and complex abnormalities common. RUNX1(AML1) and FLT3 mutations occur in approximately 20–25% of cases.
2. Three morphologic-cytochemical types (M0, M1, M2)
2. Blast cells are sudanophilic. They are positive for myeloperoxidase and chloroacetate esterase, negative for nonspecific esterase, and negative or diffusely positive for PAS (no clumps or blocks). 2. M0 type blast cells positive with antibody to myeloperoxidase and anti-CD34 and CD13 or CD33 coexpression. AML1 mutations in ~25%.
3. M1 expresses CD13 and CD33. Positive for myeloperoxidase by cytochemistry.
3. Electron microscopy shows cytoplasmic primary granules.
4. M2 AML with maturation often associated with t(8;21) karyotype.
5. M2 AML with t(6;9)(p23;q34), an uncommon variant, is associated with marrow basophilia, a high blast count, a high frequency of FLT3-ITD, and a poor outcome.
Acute promyelocytic leukemia (M3, M3v) 1. Leukemic cells resemble promyelocytes. They have large atypical primary granules and a kidney-shaped nucleus. Branched or adherent Auer rods are common. 1. Usually in adults. 1. Cell contains t(15;17) or other translocation involving chromosome 17 (RAR– gene).
2. Hypofibrinogenemia and hemorrhage common.
2. Cells are HLA-DR negative.
3. Leukemic cells mature in response to all-trans-retinoic acid.
2. Peroxidase stain intensely positive.
3. A variant has microgranules (M3v), otherwise the same course and prognosis.
Acute myelomonocytic leukemia (M4, M4Eo) 1. Both myeloblastic and monoblastic leukemic cells in blood and marrow. 1. Similar to myeloblastic leukemia but with more frequent extramedullary disease. 1. Leukemic cells in eosinophilic variant (M4Eo) usually have inversion or translocation of chromosome 16.
2. Peroxidase-, Sudan-, chloroacetate esterase-, and nonspecific esterase-positive cells.
2. Mildly elevated serum and urine lysozyme.
3. M4Eo variant has marrow eosinophilia.
Acute monocytic leukemia (M5) 1. Leukemia cells are large; nuclear cytoplasmic ratio lower than myeloblast. Cytoplasm contains fine granules. Auer rods are rare. Nucleus is convoluted and cell simulates promonocytes (M5a) or may simulate monoblasts (M5b) and contain large nucleoli. 1. Seen in children or young adults. 1. t(4;11) common in infants.
2. Gum, CNS, lymph node, and extramedullary infiltrations are common. 2. Rearrangement of q11;q23 very frequent.
3. DIC occurs.
4. Plasma and urine lysozyme elevated.
5. Hyperleukocytosis common.
2. Nonspecific esterase-positive inhibited by NaF; Sudan-, peroxidase-, and chloroacetate esterase-negative. PAS occurs in granules, blocks.
Acute erythroid leukemia (M6) 1. Abnormal erythroblasts are in abundance initially in marrow and often in blood. Later the morphologic findings may be indistinguishable from those of AML. 1. Pancytopenia common at diagnosis. 1. Cells reactive with antihemoglobin antibody. Erythroblasts usually are strongly PAS and CD71-positive, express ABH blood group antigens, and react with antihemoglobin antibody.
2. Cells reactive with anti–Rc-84 (antihuman erythroleukemia cell-line antigen).
Acute megakaryocytic leukemia (M7) 1. Small blasts with pale agranular cytoplasm and cytoplasmic blebs. May mimic lymphoblasts of medium to larger size. 1. Usually presents with pancytopenia. 1. Antigens of von Willebrand factor, and glycoprotein Ib (CD42), IIb/IIIa (CD41), IIIa (CD61) on blast cells.
2. Markedly elevated serum lactic dehydrogenase levels.
2. Leukemic cells with megakaryocytic morphology may coexist with megakaryoblasts. 3. Marrow aspirates are usually “dry taps” because of the invariable presence of myelofibrosis. 2. Platelet peroxidase positive.
4. Common phenotype in the AML of Down syndrome.
Acute eosinophilic leukemia 1. Mixture of blasts and cells with dysmorphic eosinophilic granules (smaller and less refractile). 1. Hepatomegaly, splenomegaly, lymphadenopathy may be prominent. 1. Cyanide-resistant peroxidase stains eosinophilic granules. TEM shows eosinophilic granules to be smaller and missing central crystalloid.
2. Absence of neurologic, respiratory, or cardiac signs or symptoms characteristic of chronic eosinophilic leukemia (clonal hypereosinophilic syndrome).
2. Biopsy may show Charcot-Leyden crystals in skin, marrow, or other sites of eosinophil accumulation.
Acute basophilic leukemia Mixture of blast cells and cells with basophilic granules in blood and marrow. 1. Often has hepatomegaly and or splenomegaly; symptoms often present. 1. CD9-, CD11b-, CD25-, CD123-positive cells are usually present.
2. Toluidine blue-positive cells.
2. Rash with urticaria, headaches, prominent gastrointestinal symptoms. 3. Hyperhistaminemia and hyperhistaminuria.
4. Cells negative for tryptase but positive for histidine decarboxylase.
Acute mast cell leukemia 1. Mast cells in blood and marrow. Most contain granules but some are agranular and may simulate monocytes. 1. Fever, headache, flushing of face and trunk, pruritus may be present. 1. CD13, CD33, CD68, CD117 often positive.
2. Cells positive for tryptase staining and serum tryptase elevated.
2. Abdominal pain, peptic ulcer, bone pain, diarrhea more common than other AML subtypes.
3. Hyperhistaminemia and hyperhistaminuria.
3. Hepatomegaly, splenomegaly common.
4. Hemorrhagic diathesis may be evident.
DIC, disseminated intravascular coagulation; NaF, sodium fluoride; PAS, periodic acid-Schiff; TEM, transmission electron microscopy.NOTE: Parentheses indicate French-American-British (FAB) designation M0 through M7.

Acute Myeloblastic Leukemia

The designation acute myeloblastic leukemia came into existence in the second decade of the 20th century,4 following the specific description of the myeloblast.6 Approximately 25 percent of AML cases have the features of acute myeloblastic leukemia, a variant in which the leukemic myeloblast is the predominant cell in the marrow. Acute myeloblastic leukemia has been divided into two forms, designated M0 and M1 in the French-American-British (FAB) classification which converts the descriptive term for a leukemic phenotype into a number. In either type, little evidence of maturation of myeloblasts exists, and the marrow is replaced by a monotonous population of blasts. In acute myeloblastic leukemia (M0), the patient’s age distribution, presenting white cell count, and cytogenetic abnormalities are not distinctive. The blasts are nonreactive when stained for myeloperoxidase activity, and Auer rods are not seen. The blasts react with antibodies to myeloperoxidase and antibodies to CD13, CD33, and CD34. Human leukocyte antigen (HLA)-DR is positive in most patients. Occasional cases require in situ hybridization to identify the myeloperoxidase gene369 or genomic profiling for early myeloid-associated genes.370 Abnormal and unfavorable karyotypes (e.g., 5q–,7q–) and higher expression of the multidrug resistance glycoprotein (p170) are more frequent. This phenotypic variant has a poor prognosis.371–374 In the other type of myeloblastic leukemia, designated M1, myeloblasts are present in the blood and compose more than 70 percent of marrow cells. Less than 15 percent of marrow cells are promyelocytes and myelocytes. Auer rods may be present in occasional blasts, but azurophilic granules are not evident in the blasts by light microscopy. At least 3 percent, but usually a much higher percentage, of the blast cells have a positive reaction when stained for peroxidase or with Sudan black or react with monoclonal antibodies specific to myeloblasts, such as CD33. This morphologic subtype is denoted as M1 in the FAB classification. The WHO has divided acute myeloblastic leukemia into three types, designated AML without differentiation, AML without maturation, and AML with maturation. The category without differentiation seems inappropriate as immunophenotypic markers, and often myeloperoxidase assays, unequivocally place it into the acute myeloblastic category, and hence differentiation into myeloblastic leukemia is evident as “differentiation” in the WHO classification implies markers of myeloid or lymphoid lineages. There is no evidence of a clinical distinction in response to therapy or in prognosis within these rarified designations.

In many cases of myeloblastic leukemia, more prominent granulocytic maturation is evident (FAB type M2 or WHO designation AML with maturation). This variant is present in approximately 15 percent of AML cases; thus, approximately 45 percent of cases of AML are myeloblastic leukemia with or without maturation. Blasts usually constitute at least 20 percent of the marrow cells. Auer rods may be present in blast cells. Promyelocytes, myelocytes, and segmented neutrophils, the latter often with the acquired Pelger-Hüet anomaly, may constitute 20 to 60 percent of marrow granulocytes. The anomaly is reflected in bilobed or monolobed neutrophils. Histochemical and surface markers of blast cells are typical of myeloblastic leukemia, and monocytic markers are absent or infrequent. Monocytes represent less than 10 percent of cells. A translocation between chromosomes 8 and 21 t(8;21)(q22; q22), often concomitant with loss of the Y chromosome in men or loss of an X chromosome in women, is associated with the phenotype and occurs in younger patients (average age approximately 30 years).375–377 Patients whose cells contain t(8;21) are more prone to develop myeloid sarcoma.192,195

Acute Myelomonocytic Leukemia

The ability of AML to express cells of the monocytic and granulocytic lineages was first highlighted in the early 1900s by Naegeli. Later, Downey proposed the eponym Naegeli type for myelomonocytic leukemia.378 Approximately 15 percent of patients with AML present with this variant, and they are more likely to have extramedullary infiltrates in gingiva, skin, or CNS than patients with acute myeloblastic leukemia (see “Myeloid [Granulocytic] Sarcoma” above).379 A mixture of myeloblasts and monoblasts is found in the blood and marrow. More than 30 percent of marrow cells are a mixed population of myeloblasts, which react with peroxidase or chloracetate esterase, and monoblasts or promonocytes, which react with fluoride-inhibitable nonspecific esterase (Fig. 89–2F). More than 20 percent of cells are monoblasts or promonocytes in blood and marrow. In some cases, individual cells react with monocytic and granulocytic histochemical stains.380 Serum and urinary lysozyme levels are increased in most cases. This variant of AML is referred to as M4 in the FAB classification and as acute myelomonocytic leukemia in the WHO classification. Translocations involving chromosome 3 have been associated with this phenotype.381

The proportion of marrow eosinophils382 or basophils383 may be increased. A particular variant of myelomonocytic leukemia has increased numbers of marrow eosinophils (10–50%), Auer rods in blast cells, and inversion or rearrangement of chromosome 16 (see Fig. 89–2G).236–239 The eosinophils are abnormally large, and the eosinophilic myelocytes contain large basophilic granules. Macrophages with ingested Charcot-Leyden crystals may be present. This phenotypic variant of AML has been designated M4Eo in the FAB classification. Although this variant has an increased risk of CNS involvement, it carries a more favorable prognosis than the average case of AML. Fluorescence in situ hybridization (FISH) is a more accurate method for detection of cryptic 16q22 gene rearrangements and is useful in conjunction with conventional cytogenetics for patients with M4Eo AML. AML with t(6;9)(p23;q34) is an uncommon variant, occurring in approximately 1 percent of cases, and may express itself as acute myelomonocytic or acute myeloblastic leukemia. Anemia, thrombocytopenia, a variable white cell count, and prevalent myeloblasts are frequent. The myeloblasts often contain Auer rods. Marrow basophilia is present in about half the cases.208,384 The variant occurs at a younger age, has a poor prognosis, and has a tendency to trilineage dysmorphia and ringed sideroblasts.385

Acute Erythroid Leukemia

Prominence of erythroid cell proliferation in AML cases was noted by Copelli386 and DiGuglielmo387 in the early 20th century. Moeschlin388 used the term erythroleukemia. Dameshek389 suggested the name DiGuglielmo syndrome and dissected the disorder into three phases depending on the decreasing prevalence of dysmorphic erythroblasts and the reciprocal increasing prevalence of myeloblasts. Erythroid leukemia makes up approximately 5 percent of AML cases and is referred to as M6 in the FAB classification.390 Familial erythroleukemia has been described.391,392 Erythroid leukemia is arbitrarily divided into three degrees of severity: (1) erythroleukemia in which more than 50 percent of the marrow cells are dysmorphic; (2) erythroblasts admixed with myeloblasts, the latter composing approximately 20 percent of nonerythroid cells or approximately 5 to 10 percent of total marrow cells; and (3) a form in which dysmorphic erythroblasts dominate the marrow, pure erythroid leukemia, in which more than 80 percent of marrow cells are dysmorphic erythroblasts with a trivial granulocytic proportion of cells and very few if any myeloblasts. This last form of the disease may start in as a milder variant, formerly called erythremic myelosis, in which granulopoiesis, and thrombopoiesis may be only mildly abnormal. This phase, dominated morphologically by bizarre dysmorphia of erythroblasts, can be protracted but eventually evolves into a dimorphic phase in which myeloblasts are more prominent, severe neutropenia and thrombocytopenia develop, and the patient progresses to erythroleukemia. The disease may evolve further into polyblastic AML.393–396 In the erythremic myelosis variant, erythropoiesis is ineffective. However, some normal regulation may remain because hypertransfusion decreases both erythropoietin levels and the amount of abnormal erythropoiesis.397 Spontaneous growth of leukemic erythroid clonogenic cells is a feature of the disease.398 Periodic acid-Schiff (PAS)-positive erythroblasts are evident in almost all cases.393,396

The erythroid leukemias are characterized by a striking population of dysmorphic erythroblasts in marrow and red cells in blood (see Fig. 89–2I, 2J, and 2K). Anemia and thrombocytopenia are present in nearly all cases. Some patients may have elevated total leukocyte counts. The red cells show marked anisocytosis, poikilocytosis, anisochromia, and basophilic stippling. Nucleated red cells are present in the blood. The marrow erythroblasts are extremely abnormal, with giant multinucleate forms, nuclear budding, and nuclear fragmentation. Cytogenetic abnormalities are present in approximately two-thirds of patients. The frequency of erythroid leukemia is increased if methods for detecting erythroid differentiation more sensitive than light microscopy are used. These cell features include glycophorin A, spectrin, carbonic anhydrase I, ABH blood group antigens, and other antigens that occur on early erythroid progenitors.399–401 Antihemoglobin antibody and antihuman erythroleukemic cell line antibody often are positive.394

Erythremic myelosis can have an indolent course and may be managed for a time without intensive chemotherapy. Treatment is warranted in patients with erythroleukemia and acute erythroid leukemia, and the results are approximately the same as with other phenotypes in patients of similar age.396 The more predominant the erythroid component and the lower the proportion of myeloblasts, the better the response to therapy.399

Acute Promyelocytic Leukemia

The association of an exaggerated hemorrhagic syndrome with certain leukemias was described by French hematologists in 1949.402 In 1957, Hillstad403 bestowed the appellation promyelocytic leukemia upon this morphologic-clinical subtype of AML. This variant, which is called M3 in the FAB classification and acute promyelocytic leukemia in the WHO classification, occurs at any age and constitutes approximately 10 percent of AML cases.223,224,404,405 This subtype of AML occurs with greater than expected frequency among Latinos from Europe and South and Central America113,114 and among patients with an increased body mass index.406 Unlike all other major variants of AML, which increase in incidence logarithmically with age, the incidence of APL is constant over the human life span.112 Hemorrhagic manifestations are prominent including hemoptysis, hematuria, vaginal bleeding, melena, hematemesis, and pulmonary and intracranial bleeding, as well as the more typical skin and mucous membrane bleeding. In severely leukopenic patients, blasts may not be evident in the blood. Moderately severe thrombocytopenia <50 x 109/L is present in most cases. The marrow contains few agranular blast cells and some blast-like cells with scant granules. The dominant cells are promyelocytes, which comprise 30 to 90 percent of marrow cells (see Fig. 89–2D and 2E). Auer rods and cells with multiple Auer rods (1–10%) are present in nearly every case. Promyelocytes with multiple Auer rods have been referred to as faggot cells. Leukemic promyelocytes stain intensely with myeloperoxidase and Sudan black and express CD 9, CD13, and CD33, but not CD34 or HLA-DR.223,224,404,405

A variant type of promyelocytic leukemia is referred to as microgranular (M3v in the FAB nomenclature).407–410 Microgranular cases represent approximately 20 percent of patients with promyelocytic leukemia. The leukemic cells may mimic promonocytes with convoluted or lobulated nuclei. Auer rods may be present but are less evident. The majority of the leukemic cells contain azurophilic granules that are so small they are not visible by light microscopy, but the peroxidase stain usually is strongly positive. Typical hypergranulated promyelocytes usually are present on careful inspection. The total white cell count often is highly elevated, and severe coagulopathy is prominent in microgranular cases.408 Rarely, the cells contain eosinophilic or basophilic granules, but t(15;17) is present, and the response to all-trans-retinoic acid (ATRA) persists,411–413 although the basophilic variant can be virulent.414

A translocation between chromosome 17 and another chromosome is present in almost all cases of APL and in the acute promyelocytic transformation of CML; it is not found in other AML variants. The t(15;17) is the most frequent (>95%), but variant translocations between chromosome 5 or 11 and 17, isochromosome 17, and other less common variants have been described.106,223,404,415,416 In some cases, cytogenetic analysis is inadequate, and Southern blot analysis is required to identify the rearrangement of the RAR- gene. A functional distinction is that t(15;17), PML-RAR- fusion, and t(5:17), NPM-RAR- fusion, confer retinoid therapy responsiveness, whereas t(11;17), PLZF-RAR- fusion, usually is retinoid resistant. In cells with t(11;17), Auer rods are absent and CD56 expression usually is present, offering some clinical variables to provoke special molecular investigations.417 The retinoid resistance may not always be present.418

The breakpoint on chromosome 17 is within the gene for the RAR-, and the breakpoint on chromosome 15 is within the locus of a gene originally referred to as MYL and renamed PML.223,419 The gene encodes a unique transcription factor. The translocation results in two new chimeric or fusion genes: RAR-PML, which is actively transcribed in APL, and PML-RAR-, which also is transcribed and may account for the aberrancy in hematopoiesis. The PML-RAR- gene has two isoforms that produce a short- and a long-type fusion messenger RNA (mRNA), respectively.420 Patients with the short isoform may have a worse outcome than those with the longer form. Polymerase chain reaction (PCR) for the mRNA of the fusion gene can be used to identify residual cells during remission and may predict relapse. The PML-RAR- transgene can reproduce the disease in mice,421 although in some models a superimposed FLT3 mutation is required to express the disease.107 FLT3 mutations are frequently found in human disease, especially in the hypogranular variant.106

A propensity to hemorrhage is a striking feature of this subtype. The prothrombin and partial thromboplastin times are prolonged, and the plasma fibrinogen level is decreased in most cases. The disturbance in coagulation first was thought to principally result from intravascular coagulation initiated by procoagulant released from the granules of the leukemic promyelocytes. Elevated thrombin–antithrombin complexes, prothrombin fragment 1+2, and fibrinopeptide A plasma levels support that supposition. Increased levels of fibrinogen–fibrin degradation products, D-dimer, and evidence of plasminogen activation indicate fibrinolysis.422–424 Furthermore, decreased levels of plasminogen, increased expression of annexin II on the leukemic cells,425 and reports of responses to tranexamic acid support a role for fibrinolysis in the bleeding in APL.426 Release of nonspecific proteases may further contribute to fibrinogenolysis. Thus, the coagulopathy is now considered tripartite.427

Although APL responded to chemotherapy regimens for AML, especially those containing an anthracycline antibiotic such as daunomycin or rubidazone,428 the cytologic pattern of response in the marrow often was paradoxical.429–432 Persistence of leukemic promyelocytes preceded remission in the absence of further therapy, whereas induction of marrow cell hypoplasia was classically considered a requirement for remission in patients with AML. Generally, if leukemic blast cells persist after therapy for AML, relapse ensues unless hypoplasia is induced by more cytotoxic therapy. The unusual pattern of response in APL was put into context by reports of successful treatment with isomers of retinoic acid, an agent that leads to maturation of leukemic promyelocytes in vitro.432 In 1988, the success of ATRA in remission induction was reported433,434 and confirmed.223,224 Relapse occurs invariably, however, so chemotherapy regimens also are required. Use of ATRA has decreased the risk of early hemorrhagic complications and death and has enhanced the long-term response to chemotherapy. Despite the improvement in therapy, approximately 10 percent of patients die during remission induction, most of hemorrhage, often into the brain. The prolonged remissions of patients with promyelocytic leukemia has been marred in approximately 1 to 5 percent of cases by the later appearance of oligoblastic leukemia with deletions of all or part of chromosome 5 or 7 and no evidence of involvement of chromosome 17, compatible with a myelogenous leukemia secondary to therapy.435,436 The approach to therapy and is discussed in the “Therapy” section below.

Acute Monocytic Leukemia

Monocytic leukemia was first reported by Reschad and Schilling-Torgau437 in 1913. Approximately 8 percent of patients with AML present with monocytic leukemia, which is referred to as M5 in the FAB classification. Patients with monocytic leukemia have a higher prevalence (50%) of extramedullary tumors in the skin, gingiva, eyes, larynx, lung, rectum and anal canal, bladder, lymph nodes, meninges, CNS, and other sites than do other phenotypes (<5%). Hepatomegaly and splenomegaly are more frequent in monocytic leukemia.136,438–440

The proportion of monocytic cells is usually greater than 75 percent. The total leukocyte count is higher in a larger proportion of patients, and hyperleukocytosis occurs more frequently (approximately 35%) than in other variants.441–443 The marrow and blood cells may be largely monoblasts (acute monoblastic leukemia) or more mature-appearing promonocytes and monocytes (acute monocytic leukemia) (see Fig. 89–2H). When the blood contains more mature-appearing monocytic cells, the marrow contains a lower proportion of blast cells, approximately 15 to 50 percent. When the blood monocytes are largely blast cells, the marrow contains approximately 50 to 90 percent blasts. In nearly all cases, 10 to 90 percent of monocytic cells react for nonspecific esterase stains, -naphthyl acetate esterase, and naphthol AS-D-chloroacetate esterase; in a cytochemical or chemoluminescence assay; or with monoclonal antibodies against monocyte surface antigens, especially CD14. Immunoreactivity of cells for lysozyme is characteristic. Serum and urine lysozyme levels are elevated in most patients. Serum lactic dehydrogenase and 2-microglobulin concentrations are increased in greater than 80 percent of patients.444 Plasminogen activator inhibitor-2 is present in the plasma and the cells of a high proportion of patients.445 Auer rods are absent when monoblasts dominate but are present frequently in cases where promonocytes and monocytes are prevalent in blood and marrow. Leukemic monocytes have Fc receptors and can ingest and kill microorganisms in some cases.446,447

There is an association between translocations involving chromosome 11, especially region 11q23, and monocytic leukemia.225–227 In particular, t(9;11) is found in leukemic monocytes.228,229,440,441 In t(9;11) the 1-interferon gene is translocated to chromosome 11, and the protooncogene ETS-1 is translocated to chromosome 9 adjacent to the -interferon gene. The latter juxtaposition may be important in the pathogenesis of monocytic leukemia.448

The expression of FOS is closely correlated with monocytic maturation of cells in myelomonocytic and monocytic leukemia and in normal monocytopoiesis.449,450 Absence or markedly decreased expression of the retinoblastoma gene growth suppressor product (p105) is present in approximately half of patients with monocytic leukemia. Patients express a more dramatic phenotype.451 A variant of acute monocytic leukemia in which the leukemic cells have monocytoid features and are positive for early and late monocytic lineage antigens and for TdT activity often occurs after prior radiotherapy or chemotherapy and is relatively resistant to treatment.452 A syndrome of acute monoblastic leukemia with t(8;16), resulting in MOZ-CBP fusion gene, is characterized by mildly granular promonocytes (simulating hypogranular promyelocytes), intense phagocytosis of red cells, erythroblasts, and sometimes neutrophils and platelets in blood and marrow, simulating macrophagic hemophagocytic syndrome, intravascular coagulation or primary fibrinolysis, and a high frequency of extramedullary disease.453

The management of monocytic leukemia is complicated by a greater incidence of CNS or meningeal disease either at the time of diagnosis or as a form of relapse during remission. Thus, examination of cerebrospinal fluid should be performed even in the absence of symptoms when remission has been achieved.137,440,441 Most therapists recommend prophylactic intrathecal therapy with methotrexate or cytosine arabinoside for patients who enter remission after having presented with hyperleukocytic acute monocytic leukemia because of the risk of subclinical meningeal involvement.

Rare cases of dendritic cell or Langerhans cell phenotype have been described (see Chap. 72).454,455 Uncommon cases of histiocytic sarcoma are the tissue or extramedullary variant of monocytic leukemia (see Chap. 72).456,457 The outcome of treatment, once thought to be less favorable than with other forms of AML, is comparable to the outcome of other subtypes.458

Acute Megakaryoblastic Leukemia

In 1963, Szur and Lewis459 reported patients with pancytopenia, low percentages of blast cells, and intense myelofibrosis but an absence of teardrop red cells, splenomegaly, leukocytosis, and thrombocytosis, the usual features of primary myelofibrosis. They designated the syndrome malignant myelosclerosis.459 Reports of similar cases ensued, with some investigators referring to the syndrome as acute myelofibrosis.460 The development of methods to phenotype megakaryoblasts indicated the cases were variants of AML rather than of primary myelofibrosis and have been designated acute megakaryocytic or acute megakaryoblastic leukemia.326,461,462 This leukemia is referred to as M7 in the FAB classification. The prevalence of this phenotype is approximately 5 percent of all AML cases if appropriate cell markers are used in the diagnosis, and is at least twice that frequency in childhood AML.463,464 The syndrome is an especially prevalent variant of AML that develops in patients with Down syndrome332,465 or in patients with mediastinal germ cell tumors and coincident AML.361–365

Leukemic megakaryoblasts and promegakaryocytes can be difficult to identify by light microscopy using polychrome staining. However, with experience, heightened suspicion can be engendered by blasts in the blood with abundant budding cytoplasm or blasts having a lymphoid appearance, especially if the marrow cannot be aspirated because of intense myelofibrosis, which is evident on the marrow biopsy. Initially high-resolution histochemistry for platelet peroxidase and identification of the demarcation membrane system using transmission electron microscopy were required for diagnosis. Now antibodies to von Willebrand factor or to platelet glycoprotein Ib (CD42), IIb/IIIa (CD41), or IIIa (CD61) can be used to identify very primitive megakaryocytic cells.461,462 A small proportion of megakaryoblasts may be present in other cases of AML, but in megakaryocytic leukemia they are the prominent or the dominant leukemic cells (see Fig. 89–2L through 2O). Moreover, the other key features of the syndrome usually are present, especially severe myelofibrosis.463

Patients usually present with pallor, weakness, excessive bleeding and anemia, and leukopenia. Lymphadenopathy or hepatosplenomegaly is uncommon at the time of diagnosis. High leukocyte and blood blast cell counts may be present initially or may develop later. The platelet count may be normal or elevated in many patients at the time of presentation. Abnormal platelets or megakaryocytic cytoplasmic fragments may be found in the blood. Marrow aspiration often is unsuccessful (“dry tap”) because of extensive marrow fibrosis in most cases, although not all. The marrow biopsy contains small blast cells, large blast cells, or a combination of both. The former have a high nuclear-to-cytoplasmic ratio, have dense chromatin with distinct nucleoli, and resemble lymphoblasts. Cases have been mistaken for ALL. The larger blasts may have some features of maturing megakaryocytes with agranular cytoplasm with cytoplasmic protrusions, clusters of platelet-like structures, or shedding of cytoplasmic blebs. The blast cells are peroxidase negative and tend to aggregate. Confirmation of their megakaryoblastic maturation requires immunocytologic studies for the presence of von Willebrand factor and the immunoreactivity to CD41, CD42, or CD61. The more mature megakaryocytes, which often coexist in the marrow, stain with PAS reagent, contain sodium fluoride-inhibitable nonspecific esterase, and fail to react for -naphthylbutyrate esterase or myeloperoxidase. The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 25 percent of cases of acute megakaryoblastic leukemia.466

The serum lactic acid dehydrogenase level frequently is strikingly increased and has an isomorphic pattern unlike that seen with other acute leukemias. Complex chromosome aberrations are common.467 An association of megakaryoblastic leukemia in infants with t(1;22)(p13;q13) has been reported.467–470 Abnormalities of chromosome 3 have been linked to clonal hemopathies expressing a prominent megakaryocytic phenotype.471,472 Progression of primary myelofibrosis or essential thrombocythemia to AML may have the phenotype of acute megakaryocytic leukemia. Paradoxically, in children with Down syndrome the disease can be treated with modified doses of chemotherapy, with a very high remission rate and long-term event-free survival.473,474 The result is thought to be related to the exquisite sensitivity of the leukemic cells to drug-induced apoptosis,475 whereas the long-term remission rate as a result of chemotherapy in children without Down syndrome or in adults are not as good.476,477

Acute Eosinophilic Leukemia

Acute eosinophilic leukemia is rare. Increased eosinophils in the marrow but not in the blood is a variant of acute myelomonocytic leukemia and inversion 16 or other abnormalities of chromosome 16 but is not considered an acute eosinophilic leukemia.236–239 First described in 1912,478 acute eosinophilic leukemia is a distinct entity that can arise de novo as AML, with 50 to 80 percent of eosinophilic cells in the blood and marrow.479–482 Anemia, thrombocytopenia, and blast cells in blood and marrow are present. There is apparent eosinophilic differentiation in striking proportions. The eosinophilic cells are dysmorphic and the cytoplasm hypogranulated with smaller than normal eosinophilic granules. The granules stain less intensely and are less refractile with polychrome stains. These findings are the result of the loss of the central crystalloid in the eosinophilic granules that can be identified with electron microscopic analysis. Biopsy of skin, marrow, or other sites of eosinophil accumulation often shows Charcot-Leyden crystals. A specific histochemical reaction, cyanide-resistant peroxidase, permits identification of leukemic cells with eosinophilic differentiation and diagnosis of acute eosinoblastic leukemia in some cases of AML with fewer identifiable eosinophils in blood or marrow.483 Eosinophilia, not part of the malignant clone, may be a feature of occasional patients with AML, an uncommon reactive phenomenon. In many cases, idiopathic eosinophilia (hypereosinophilic syndrome) is a monoclonal disorder representing a spectrum of more indolent chronic or subacute eosinophilic leukemia to more progressive acute leukemia (see Chaps. 62 and 90).484 Acute eosinophilic leukemia may develop in patients having the chronic form of a hypereosinophilic syndrome. Overexpression of Wilms tumor gene expression has been proposed as a means of distinguishing acute eosinophilic leukemia from a polyclonal, reactive eosinophilia.485

Patients with acute eosinophilic leukemia do not usually develop bronchospastic signs, neurologic signs, and heart failure from endomyocardial fibrosis as is seen in chronic eosinophilic leukemia, probably because those tissue changes are the result of release of toxins in the granule crystalloid, absent in most eosinophils in acute eosinophilic leukemia and because of the shorter duration of survival in acute eosinophilic leukemia. Hepatomegaly, splenomegaly, and lymphadenopathy are more common than in other variants of AML. The treatment approach is similar to other types of AML. A combination of cytarabine and an anthracycline antibiotic is an appropriate choice for treatment. Response to treatment is approximately the same as in other types of AML.483

Acute Basophilic and Mast Cell Leukemia

First described in 1906,486 basophilic differentiation as a feature of AML is an uncommon event, occurring in about 1 in 100 cases of AML.482 Most cases of acute basophilic leukemia evolve from the chronic phase of CML,487 but de novo acute basophilic leukemia, in which the cells do not contain the Philadelphia chromosome, does occur.482,488–493 The cells stain with toluidine blue, and the basophilic granules can be most striking in myelocytes. In some cases of acute myelomonocytic leukemia associated with t(6;9)(p23;q34), basophils may be increased in the marrow but not in the blood. Because CML with t(9;22)(q34;q11) has the same breakpoint (q34) on chromosome 9 as AML with t(6;9) and both diseases are strongly associated with marrow basophilia, a gene(s) at the breakpoint on chromosome 9 may influence basophilopoiesis.384

Anemia, thrombocytopenia, and blast cells in the blood are present at the time of diagnosis. The blood leukocyte count usually is elevated, and proportions of the cells are basophils. The marrow is cellular with a high proportion of blasts and early and late basophilic myelocytes. Special staining with toluidine blue or Astra blue often is necessary to distinguish basophilic from neutrophilic promyelocytes and myelocytes. Immunophenotyping may show myeloid markers (CD33, CD13) that are not specific. Presence of CD9, CD25, or both is characteristic of basophilic differentiation. Cells may have granules with ultrastructural features of basophils and mast cells.491 Electron microscopy can be useful in identifying basophilic granules in cases where no granules are evident by light microscopy and the phenotype simulates M0.491 Basophilic leukemia can be confused with promyelocytic leukemia if the basophilic early myelocytes are mistaken for promyelocytes.494 On the contrary, promyelocytic leukemia may have basophilic maturation and can be mistaken for basophilic leukemia. However, if the cells contain t(15;17), the disease should respond to ATRA and an anthracycline antibiotic.408,411,412 Prolonged clotting time, intravascular coagulation, and hemorrhage are uncommon presenting features in patients with basophilic leukemia, but are common in patients with promyelocytic leukemia. Coagulopathy can occur after chemotherapy. Cluster headaches, skin rashes, often with an urticarial component, and gastrointestinal symptoms may be present. Elevated blood and urine histamine and urinary methylhistamine levels are characteristic features. Rare cases of a chronic course in BCR-ABL–negative basophilic leukemia preceding the onset of rapid progression have occurred.495 Treatment for acute (Ph-negative) basophilic leukemia is similar to that for other variants of AML.

Mast cell leukemia is a rare manifestation of systemic mast cell disease (see Chap. 63).482,496 It can be related to a mutation of the KIT gene.440 The leukemic mast cells are CD117 positive, naphthol AS-D-chloracetate esterase positive, tryptase positive, myeloperoxidase negative, and CD25 negative.498 Plasma tryptase is elevated. In some cases, electron microscopy of the granule-containing cells, which demonstrates the characteristic scroll-like granules of mast cells, may aid in distinguishing basophils from mast cells (see Chap. 63). Extensive, apparently reactive, mast cell tissue infiltrations may be provoked by cytokines during the course of AML.499,500

The key laboratory distinctions between acute basophilic leukemia and acute mast cell leukemia are that the cells in the former are naphthol AS-D-chloracetate esterase negative, CD11b positive, CD117 negative or weakly positive, CD123 positive, have no increase in cell or plasma tryptase, and have basophilic-like granules on electron microscopy; whereas, the cells in mast cell leukemia are naphthol AS-D-chloracetate esterase positive, CD11b negative, CD117 positive, CD123 negative, have an increase in cell and plasma tryptase, and have mast cell-like granules on electron microscopy.482

Histiocytic and Acute Myeloid Dendritic Cell Leukemia

Chapter 72 discusses histiocytic and myeloid dendritic cell leukemia.

Differential Diagnosis

Acute leukemia in infants with Down syndrome should be differentiated from TMD (see “Neonatal Myeloproliferation and Leukemia” above). In adults, the term pseudoleukemia has been applied to circumstances that mimic the marrow appearance of promyelocytic leukemia. Recovery from drug-induced or Pseudomonas aeruginosa–induced agranulocytosis is characterized by a striking cohort of promyelocytes in the marrow, which upon inspection of the marrow aspirate or biopsy mimics promyelocytic leukemia.501–503

In pseudoleukemia, the platelet count may be normal; the degree of leukopenia often is more profound (<1.0 x 109/L) than usually seen in AML444,445; promyelocytes contain a prominent paranuclear clear (Golgi) zone not covered with granules; and promyelocytes do not have Auer rods.503–505 Similar reactions have been reported after granulocyte colony-stimulating factor (G-CSF) administration.506 In patients suspected of having pseudoleukemia, observation for a few days usually clarifies the significance of the marrow appearance, because progressive maturation to segmented neutrophils normalizes the marrow and leads to an increased blood neutrophil count.

In patients with hypoplastic marrows, careful examination of specimens is required to distinguish among aplastic anemia, hypoplastic acute leukemia,283–285 and hypoplastic oligoblastic leukemia.507 Leukemic blast cells are evident in the marrow in hypoplastic leukemia, and islands of dysmorphic cells, especially megakaryocytes, are present in hypoplastic oligoblastic leukemia.

Leukemoid reactions and nonleukemic pancytopenias can be distinguished from AML by the absence of leukemic blast cells in the blood or marrow.508 In older children and adults, myeloblasts usually do not constitute more than 2 percent of marrow cells except in patients with leukemia, and the proportion of blast cells usually decreases in the marrow with neutrophilic leukemoid reactions.


Overview of Treatment Plan

The usual treatment of AML includes an initial program termed the induction phase. Induction may involve the simultaneous use of multiple agents or a planned sequence of therapy called timed sequential treatment. Once a remission is obtained, further treatment is indicated to preserve the remission state. Remission is defined as elimination of the leukemic cell population in marrow as judged by microscopy and flow cytometry and the restitution of normal or virtually normal white cell, hemoglobin, and platelet concentrations in the blood. The post-induction treatment can consist of cytotoxic chemotherapy, hematopoietic stem cell transplantation, or low-dose maintenance chemotherapy, depending upon patient performance status and risk factors. If relapse occurs, treatment options may include different chemotherapy regimens, allogeneic hematopoietic stem cell transplantation, or other investigational regimens.

Decision to Treat

Most patients with AML should be advised to undergo treatment promptly after diagnosis. Patients younger than 60 years of age have a poorer outcome as the time from diagnosis to treatment lengthens.509 Although remission rates are lower in older patients, a significant proportion enter remission. Occasionally, very elderly patients refuse treatment or are so ill from unrelated illnesses that treatment may be unreasonable. Age per se is not a contraindication to treatment, and septuagenarians and octogenarians who are fit can enter remissions. Treatment can be tailored to the decreased tolerance of older patients, some of whom have a smoldering course (see “Treatment of Older Patients” below). Associated problems, such as hemorrhagic manifestations, severe anemia, or infections, should be treated in parallel.

Preparation of the Patient

Orientation of the patient and the family should provide them with an understanding of the disease, the treatment planned, and the adverse effects of treatment, as well as information about long-term prognosis to the extent this can be provided while awaiting cytogenetic and molecular markers. Socioeconomic status and distance from the treatment center have minimal effects on survival in AML,510 but impaired Karnofsky performance status and instrumental activities of daily living score do impact outcomes.511

Pretreatment laboratory examination should include blood cell counts, cytochemistry analysis and immunophenotyping of leukemic cells from blood or marrow, marrow examination including cytogenetic and molecular analyses to include FLT-3 ITD, NPM-1, and KIT mutation status, if available, blood chemistry studies, chest radiography, electrocardiogram, and determination of partial thromboplastin time, prothrombin time, and fibrinogen level. More extensive evaluation of coagulation factors should be made if (1) clotting times are abnormal, (2) bleeding is exaggerated for the level of the platelet count, or (3) acute promyelocytic or monocytic leukemia is the phenotype. Early HLA typing is useful so that compatible platelet products can be provided if alloimmunization (see Chap. 141) occurs and for patients who will become marrow transplantation candidates (see Chap. 21). Herpes simplex virus and cytomegalovirus serotyping may be helpful, especially if transplantation is a consideration. HIV and hepatitis serology is indicated in patients with appropriate risk factors, and patients should have a baseline cardiac scan to determine ejection fraction prior to administration of an anthracycline antibiotic.

A tunneled central venous catheter should be placed. This access to the circulation facilitates administration of chemotherapy, blood components, antibiotics, and other intravenous fluids and medications. It also permits sampling blood for analysis without patient discomfort or concern about venous access. Meticulous skin care at the catheter exit site is required to minimize tunnel infections. Central venous catheters have become a major source of infection during neutropenia, especially with Gram-positive organisms.512

Therapy for hyperuricemia is required if (1) the pretreatment uric acid level is greater than 7 mg/dL (0.4 mmol/L), (2) the marrow is packed with blast cells, or (3) the blood blast cell count is moderately or markedly elevated. Allopurinol 300 mg/day orally should be given. Allopurinol can cause allergic dermatitis and should not be used if the uric acid level is less than 7 mg/dL and the total white cell count is less than approximately 20,000/L (20 x 109/L), as long as hydration is adequate and urine flow is high (>150 mL/h). The dermatitis may appear when antibiotics are instituted. This concurrence may confound the decision to continue antibiotics. Thus, allopurinol should be discontinued after the risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to 7 days). Recombinant urate oxidase (rasburicase) can be used to prevent urate-induced nephropathy. This preparation, although costly, can reduce plasma urate levels by approximately 80 percent within 4 hours of the first drug dose. It is well tolerated, and the recommended dose of rasburicase is 0.2 mg/kg daily for 5 to 7 days, although shorter courses are usually effective.513

Attention to decreasing pathogen exposure by assiduous hand washing and meticulous care of catheter and intravenous sites is important, especially when the total neutrophil count is less than 500/L (0.5 x 109/L). Care of the patient in a single room is advisable to provide privacy during periods of intensive care and to help decrease the risk of exogenously acquired infection until the neutrophil count recovers.

Remission-Induction Therapy


The cytotoxic therapy of AML rests on two tenets: (1) two competing populations of cells are present in marrow—a normal polyclonal and a leukemic monoclonal population; and (2) profound suppression of the leukemic cells to the point they are inapparent in the marrow aspirate and biopsy is required to permit restoration of polyclonal hematopoiesis.514,515 Although these two principles hold in most cases, two deviations from these guidelines are (1) the predisposition of patients with APL to enter remission despite cellular posttherapy marrow516 and (2) the occasional presence of monoclonal hematopoiesis in some cases of AML during remission (see “Results of Treatment” below). AML is a heterogeneous disease, and subgroups with different prognosis can be identified. In the future, incorporation of knowledge about the biology of the particular AML subtype may be utilized for adapted therapies, but at present, all subtypes of AML classified by cytogenetics or molecular changes with the exception of acute promyelocytic leukemia are approached similarly.517

The goal of induction therapy in AML is achievement of complete remission (<2% blasts in the marrow), a neutrophil count greater than 1000/L, and a platelet count greater than 100,000/L. An International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards has redefined outcomes in an effort to standardize reporting and comparison of data.518 Other treatment guidelines have been published.519,520 Most adults enter remission with standard induction therapy, but for patients with high-risk disease, consideration can be given to an experimental approach. How durable a complete remission will be attained in an individual patient often is difficult to predict at diagnosis. Gene expression profiling can separate some patients into prognostic groups that may indicate patients with a high risk of not responding to standard approaches.123,124

Cytotoxic Regimens

Anthracycline Antibiotic or Anthraquinone and Cytarabine

Current standard induction treatment for AML involves drug regimens with two or more agents that include an anthracycline antibiotic or an anthraquinone and cytarabine 521,522 Remission rates in the studies cited range from approximately 55 to 90 percent in adult subjects, depending on the composition of the population treated (Table 89–5). The two most important variables are the age of the patients and the proportion of patients with therapy-induced leukemia or an antecedent clonal myeloid disease. In the studies listed in Table 89–5, the median age of the patient populations was much younger (~50 years) than the median age of the population of AML patients at large (~70 years); thus the results cannot be generalized (see “Treatment of Older Patients” below). A combination of anthracycline and cytarabine has been the standard induction therapy since 1973.11 A now classic standard induction regimen is cytarabine 100 mg/m2 daily by continuous infusion on days 1 through 7 and daunorubicin at 45 to 60 mg/m2 on days 1 through 3, the so-called 7-and-3 regimen. Dose or schedule modulation of the anthracycline or cytarabine, addition of other agents such as etoposide, in various schedules of administration, represent attempts to improve upon results obtained with “7-and-3” therapy.

Table 89–5. Remission Induction for AML: Examples of Cytosine Arabinoside and Anthracycline Antibiotic Combinations
Cytarabine Anthracycline Antibiotic ± Another Agent No. of Patients Age Range in Years (Median) Complete Remissions (%) Year of Report Reference
100 mg/m2, days 1-7 DNR 45 mg/m2, days 1-3 330 17–60 (47) 57 2009 525
100 mg/m2, days 1-7 DNR 90 mg/m2, days 1-3 327 18–60 (48) 71 2009 525
200 mg/m2, days 1–7 DNR 60 mg/m2, days 1–3 200 16–60 (45) 72 2004 537
200 mg/m2, days 1–7 DNR 60 mg/m2, days 1–3 200 16–60 (45) 69 2004 537
Cladribine 5 mg/m2, days 1–5
200 mg/m2 twice per day for 10 days (some in this report received FLAG-Ida vs. H-DAT) DNR 50 mg/m2, days 1, 3, 5 64 18–59 (46.5) 91 2003 535
Thioguanine 100 mg/m2 twice per day, days 10–20
Gemtuzumab ozogamicin 3 mg/m2, day 1
3 g/m2 every 12 h for 8 doses 60 mg/m2 DNR daily for 2 days 122 Adults 80 2000 529
100 mg/m2 daily for 7 days (2 courses always given) IDA 12 mg/m2 daily for 3 days 153 NR 63 2000 522
500 mg/m2 by continuous infusion, days 1–3, 8–10 Mitoxantrone 12 mg/m2 for 3 days 133 15–70 (43) 60 1996 532
Etoposide 200 mg/m2 IV, days 8–10
100 mg/m2 daily for 7 days DNR 45 mg/m2 for 3 days 113 NR (55) 59 1992 521
100 mg/m2 daily for 7 days IDA 13 mg/m2 for 3 days 101 NR (56) 70 1992 521
DNR, daunorubicin; FLAG, fludarabine, cytarabine, and granulocyte colony-stimulating factor; H-DAT, hydroxydaunorubicin, cytarabine, and thioguanine; IDA, idarubicin; NR, not reported.NOTE: The reader is advised to consult the original reports for details of induction and ancillary therapy and consolidation or continuation therapy, which may vary from protocol to protocol.

Choice of Anthracycline

Development of drug resistance is reduced with idarubicin relative to other anthracyclines. Idarubicin does not induce P-glycoprotein expression, but daunorubicin, doxorubicin, and epirubicin do.523 Idarubicin 12 mg/m2 gives better complete remission rates in younger adults than does daunorubicin 45 mg/m2, each given for 3 days. Amsacrine, aclarubicin, and mitoxantrone give improved results over standard-dose daunorubicin. In older adults, mitoxantrone may reduce cardiotoxicity, but this is controversial.524 In two randomized studies, high dose daunorubicin (90 mg per square meter) for 3 days resulted in superior complete remission rates as compared to 45 mg per square meter for 3 days when combined with cytarabine.525,526 Dexrazoxane may be given during induction to reduce the risk of cardiotoxicity in patients at higher than usual risk because of a history of coronary artery disease or congestive heart failure.527

High-Dose versus Standard-Dose Cytarabine

High-dose cytarabine does not increase complete remission rates and increases toxicity compared to conventional doses, especially in older patients (for doses of these regimens, see “Intensive Consolidation Therapy” below). Patients receiving high-dose cytarabine have more leukopenia, thrombocytopenia, gastrointestinal distress, and eye toxicity. Disease-free survival and overall survival may be better than that achieved with standard therapy, leading some investigators to suggest use of high-dose therapy for induction in patients younger than age 50 years, but this approach is not a standard one, and these studies do not take into account the role of high-dose cytarabine in postremission therapy.528 Complete remission rates of greater than 60 percent have been noted with high-dose cytarabine in patients with poor-risk cytogenetics.529,530

Timed Sequential Therapy and Other Drugs

Timed sequential therapy, which uses agents in a scheduled sequence rather than concurrently, may prolong remission duration.531–533 Timed sequential chemotherapy combining mitoxantrone on days 1 to 3, etoposide on days 8 to 10, and cytarabine on days 1 to 3 and 8 to 10 resulted in a complete remission in 60 percent of patients, but treatment-related death in 9 percent of patients. Median disease-free survival was 9 months.531

Adding ATRA,534 gemtuzumab ozogamicin,535 fludarabine,536 cladribine537 or topotecan538 to induction regimens has not improved results significantly. There are preliminary reports suggesting that the addition of gemtuzumab ozogamicin to standard induction chemotherapy may increase disease-free survival in patients with low- and standard-risk cytogenetic abnormalities,539 and inhibitors of FLT-3 ITD are now being examined in this setting, as well in those patients who express the mutation, but no data are available regarding utility of this approach.540 Thus, the practice guideline for AML, other than promyelocytic leukemia, recommends standard-dose cytarabine plus an anthracycline antibiotic as treatment.520

Hematopoietic Cytokines to Enhance Chemotherapy

G-CSF and granulocyte-monocyte colony-stimulating factor (GM-CSF), when used in untreated leukemia, can increase the percentage of leukemic cells in the DNA synthetic phase, resulting in blast population expansion during short-term administration. This process could render the cells more sensitive to simultaneous chemotherapy, but clinical benefit from growth-factor priming has not been observed541,542 despite an increased ratio of intracellular cytosine arabinoside triphosphate to deoxycytidine-5′-triphosphate and enhanced cytarabine incorporation into the DNA of AML blasts.542 Remission rates or overall survival did not differ among adult patients who received cytarabine plus idarubicin or cytarabine plus amsacrine with or without G-CSF given concurrently, but relapse rates decreased in patients who received G-CSF.543 GM-CSF priming in a younger patient group treated with timed-sequential therapy increased complete remission rates but did not impact overall survival.544 Thus, these growth factors are not generally considered useful as enhancers of chemotherapy. However, complete remissions have occurred in hypoplastic AML after G-CSF treatment without chemotherapy.545

Duration of Induction Therapy

Patients who have persistent leukemia after the first course of induction chemotherapy generally are given a second course of the same drugs. The patient’s long-term outcome is worse if two courses of treatment are required even if a complete remission is achieved. Approximately 40 percent of patients with persistent AML after one course of induction therapy have a complete remission after a second course,546 and disease-free survival at 5 years is approximately 10 percent. In some European centers, two courses of induction chemotherapy are given routinely, but impact on remission rates or overall survival is uncertain.547 The longer the time to remission after the first induction therapy, the shorter the duration of disease-free survival.548 High-risk cytogenetic abnormalities, antecedent hematologic disorders, and other poor prognostic factors can be used to assign nonresponders to an experimental chemotherapy regimen designed to treat refractory disease, rather than repeating induction therapy. In one study, overall response to reinduction was 53 percent. Those patients with poor risk cytogenetics and those with marrow blast percentage ≥60 percent following the 7-and-3 regimen induction treatment were found to have a low probability of achieving a complete remission with reinduction.549 Mortality during induction therapy is correlated with age550 and, perhaps, leukocyte count.551 The effect of polymorphisms of detoxification genes and DNA repair enzymes, such as the glutathione-S-transferase gene on the response to antileukemic therapies is under study.552,553

Special Considerations during Induction Therapy


Patients with blast counts greater than 100,000/L (100 x 109/L) require prompt treatment to prevent the most serious complications of hyperleukocytosis: intracranial hemorrhage or pulmonary insufficiency. Hydration should be administered promptly to maintain urine flow greater than 100 mL/hour per m2. Cytoreduction therapy can be initiated with hydroxyurea 1.5 to 2.5 g orally every 6 hours (total dose 6 to 10 g/day) for approximately 36 hours. Appropriate remission-induction therapy should be initiated as soon as possible after the leukocyte count has been decreased significantly. Simultaneous leukapheresis can decrease blast cell concentration by approximately 30 percent within several hours,264,554,555 without contributing to uric acid or cellular phosphate release. Leukapheresis may improve acute disturbances resulting from the vascular effects of blast cells, but the procedure may not alter the long-term outcome with current therapeutic programs272,273,554 Inhaled nitric oxide reportedly improves hypoxemia related to hyperleukocytosis.555

Antibiotic Therapy

Pancytopenia is worsened or induced shortly after treatment is instituted. Absolute neutrophil counts less than 100/L (0.1 x 109/L) are expected and are a sign of effective drug action. The patient usually becomes febrile (>38°C), often with associated rigors. Cultures of urine, blood, nasopharynx, and, if available, sputum should be obtained. Because the inflammatory response is blunted by severe neutropenia and monocytopenia, evidence of exudates on physical examination or imaging studies may be minimal or absent. Antibiotics should be started immediately after cultures are obtained.556 Chapter 22 describes antibiotic usage in the setting of intensive chemotherapy. Infections remain a major cause of therapy-associated morbidity and mortality.557,558 Gram-positive bacterial isolates now outnumber Gram-negative organisms.558 Cultures are often negative but if fever and other signs are present, antibiotic therapy should be continued.

Some centers use prophylactic antibacterial, antifungal, and/or antiviral antibiotics, whereas other centers do not. Antifungal prophylaxis can consist of low-dose amphotericin, fluconazole, itraconazole, posaconazole, or voriconazole.559,560 Acyclovir, valacyclovir, or famciclovir prophylaxis during remission-induction therapy of patients with AML does not affect the duration of fever or the need for antibiotics. The incidence of bacteremia is not reduced, but acute oral infections are less severe.561 The caspofungins and azoles are available for treatment of established fungal infections.562 Some centers use outpatient supportive therapy immediately after induction therapy in adult AML. One approach is use of cotrimoxazole, itraconazole, or fluconazole administered orally until the granulocyte count is greater than 1000/L, and every-other-day platelet transfusions until the platelet count is greater than 20,000/L.563

Hematopoietic Growth Factors to Treat Cytopenias

Cytokine therapy as an adjunctive treatment for AML remains controversial.564 Although GM-CSF and G-CSF accelerate neutrophil recovery, neither GM-CSF nor G-CSF reproducibly decreases major morbidity or mortality. However, one study has shown decreased mortality from fungal infections in older patients.565 Use of cytokines during periods of cytopenia following induction therapy is safe, and nearly all trials have shown a modestly reduced duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and duration of hospital stays. Although no increase in relapse has been noted when growth factors are started after completion of chemotherapy, no consistent enhancement of remission, event-free survival, or overall survival has been noted.566 Therefore, the cost-effectiveness of growth factor usage is doubtful.

Component Transfusion Therapy

Red cell transfusions should be used to keep the hemoglobin level greater than 8.0 g/dL, or higher in special cases (e.g., symptomatic coronary artery disease; see Chap. 140). Platelet transfusions should be used for hemorrhagic manifestations related to thrombocytopenia and prophylactically if necessary to maintain the platelet count between 5000/L (5 x 109/L) and 10,000/L (10 x 109/L).567 Patients without coagulation abnormalities, anticoagulant use, sepsis, or other complications usually can maintain hemostasis with platelet counts of 5000 to 10,000/L (5–10 x 109/L). Initially, random donor platelets can be used, although single-donor platelets or HLA-matched platelets may be preferable products and should be tried if random-donor platelets do not raise the platelet count significantly. Family members may be effective donors, if allogeneic transplantation is not being considered (see Chap. 141). There are data that fever should result in increasing the platelet count used as a transfusion threshold, and there is some suggestion that higher hemoglobin values protect against bleeding related to thrombocytopenia.568

All red cell and platelet products should be depleted of leukocytes, and all products, including granulocytes for transfusions, should be irradiated to prevent transfusion-associated graft-versus-host disease (GVHD) in this immunosuppressed population (see Chap. 141).

Granulocyte transfusion should not be used prophylactically for neutropenia but can be used in patients with high fever, rigors, and bacteremia unresponsive to antibiotics, with blood fungal infections, or with septic shock. G-CSF administration to a volunteer donor increases neutrophil yield fourfold and results in posttransfusion blood neutrophil increments for more than 24 hours after transfusion.569 GM-CSF administration may be warranted for treatment of major fungal infections (see Chap. 22).

Jehovah’s Witnesses and others who refuse blood product support can survive tailored chemotherapy.570 In general, phlebotomy is minimized, and antifibrinolytics, hematinics, and growth factors are used to support such patients during severe cytopenias.

Therapy for Hypofibrinogenemic Hemorrhage

Patients with evidence of intravascular coagulation (see Chap. 130) or exaggerated primary fibrinolysis (see Chap. 136) should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started. If the findings are equivocal, patients should be monitored closely with measurements of fibrinogen levels, fibrin(ogen) degradation products, D-dimer assay, and coagulation times. Intravascular coagulation or primary fibrinolysis may occur in patients with APL and acute monocytic leukemia, but also may occur in occasional patients with other AML subtypes.

Management of Central Nervous System Disease

CNS disease occurs in approximately 1 in 50 cases at presentation.571 Prophylactic therapy usually is not indicated, but examination of the spinal fluid after remission should be considered in (1) monocytic subtypes,441 (2) cases with extramedullary disease, (3) cases with inversion 16183 and t(8;21)192,195 cytogenetics, (4) CD7- and CD56-positive (neural-cell adhesion molecule) immunophenotypes,572 and (5) patients who present with very high blood blast cell counts. In these situations, the risk of meningeal leukemia or a brain myeloid sarcoma is heightened, but prophylactic intrathecal chemotherapy is not recommended if high dose cytarabine is used for consolidation. Treatment of meningeal leukemia can include high-dose intravenous cytarabine (which penetrates the blood–brain barrier), intrathecal methotrexate, intrathecal cytarabine, cranial radiation, or chemotherapy and radiation in combination.571 Systemic relapse commonly follows relapse in the meninges, and concurrent systemic treatment usually is indicated. Long-term success is unusual unless allogeneic hematopoietic stem cell transplantation is possible. Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared. No consensus exists on a trigger for platelet transfusion in adults with AML undergoing lumbar puncture, but a platelet count less than 20,000/L (20 x 109/L) has been proposed as such a trigger.573

Management of Nonleukemic Myeloid Sarcoma

Some patients present with myeloid (granulocytic) sarcomas without evidence of leukemia in the blood or marrow (see “Myeloid [Granulocytic] Sarcoma” above). Myeloid sarcoma may be the presenting finding in approximately 2 percent of patients with AML. Such patients should receive intensive AML induction therapy.191 Intensive therapy results in a longer nonleukemic period than patients who have undergone surgical resection or resection followed by local irradiation.179 Median relapse-free survival is about 12 months after AML-type chemotherapy.191 Patients with trisomy 8 have poorer survival rates.189

Postremission Therapy

Cytotoxic Therapy

General Considerations

Postremission therapy is intended to prolong remission duration and overall survival, but no consensus exists regarding the best approach. Postremission chemotherapy that does not produce profound prolonged cytopenias, closely simulating intensive induction therapy, has produced on average only slight prolongation of remission or life. Regimens that fall between these intensities have been used, with equivocal results. Intensive consolidation therapy after remission results in a somewhat longer remission duration and, more significantly, a subset of patients who have a remission of more than 3 years. The issue of postremission therapy and its impact is complicated by the large proportion of patients with AML who are older than 60 years of age and have limited tolerance for intensive therapy in the later decades of life. In addition, a very small pool of leukemic stem cells may sustain the process, and elimination of these cells may require approaches other than intensive chemotherapy, especially in adults.

Several randomized trials have studied whether AML patients in first remission should receive consolidation chemotherapy alone, autologous transplantation, or allogeneic marrow transplantation, without reaching a consensus. Allogeneic transplantation was compared to autologous transplantation using unpurged marrow and two courses of intensive chemotherapy in 623 patients who had a complete remission after induction chemotherapy.574 Disease-free survival was 53 percent at 4 years for those receiving allogeneic transplantation, 48 percent for those receiving autologous transplantation, and 30 percent for patients receiving intensive chemotherapy. Overall survival after complete remission was similar in all three groups because patients who relapsed after chemotherapy could be rescued with stem cell transplantation. No significant difference in the 4-year disease-free survival between allogeneic stem cell transplantation (42%) and other types of intensive postremission therapy (40%) has been found.575 In another study, only patients younger than 15 to 35 years of age with poor-risk cytogenetics had improved disease-free survival if they had a sibling donor and underwent allogeneic transplantation (43.5% vs. 18.5% at 4 years).576 Thus, in several studies, the early mortality after allogeneic transplantation and the chemotherapy-induced remissions in patients who relapse following autologous transplantation or chemotherapy have led to comparable overall survival rates. However, leukemia-free survival was greater after allogeneic transplantation.577 When quality of life was measured for patients in complete remission for 1 to 7 years, those treated with chemotherapy had the highest quality of life whereas those who underwent allogeneic stem cell transplantation had the lowest.578

The decision to utilize autologous or allogeneic stem cell transplantation or high-dose cytarabine alone for consolidation is individualized based on the patient’s age and other prognostic factors, such as high-risk cytogenetic findings and antecedent hematologic disease. Patients with good-risk cytogenetics should receive up to four cycles of high-dose cytarabine. Patients with poor-risk cytogenetics should be considered for allogeneic or autologous stem cell transplantation after one or two cycles of high-dose cytarabine. A meta analysis has shown that compared with non-allogeneic therapies, allogeneic hematopoietic stem cell transplant has superior relapse-free survival and overall survival for cases of AML classified intermediate and poor-risk but not for cases considered good-risk AML in first remission.579

Intensive Consolidation Therapy

For patients who do not receive high-dose chemotherapy with autologous or allogeneic transplantation in first remission, consolidation chemotherapy regimens containing high-dose cytarabine provide better results than intermediate-dose cytarabine,580,581 but these regimens are not universally accepted.582 Patients who have ablative allogeneic hematopoietic stem cell transplantation do not require four cycles of high-dose cytarabine.583 RAS mutations have been associated with benefit from high-dose cytarabine therapy.584 Patients with t(8;21) also have particularly favorable responses to repetitive cycles of high-dose cytarabine. In patients who received three or more cycles, a relapse rate of 19 percent was reported.585

Other regimens, such as those containing gemtuzumab ozogamicin and fludarabine, have been used in postremission therapy, but whether they provide benefit over use of high-dose cytarabine has not been studied.586 Long-term disease-free survival at 5 years generally is approximately 30 percent when two to four cytarabine-containing regimens are administered.587,588 Most centers use four cycles of therapy. A cycle is 3 g/m2 twice daily on days 1, 3, and 5, providing six doses per cycle, with cycle durations dependent on normal blood count recovery. The optimal number of cycles for this therapy is not known.589 High-dose cytarabine can be administered at a dose of 3 g/m2 in a 1- to 3-hour intravenous infusion every 12 hours for up to 6 days (12 doses), but this schedule is almost never used because of its toxicity. High-dose cytarabine frequently causes conjunctivitis and photophobia, and glucocorticoid eye drops are usually used every 6 hours until 24 hours after the last dose of the drug.590 Cerebellar function abnormalities also may occur, and these require cessation of drug administration. A 1-hour duration infusion of high-dose or reduced-dose (e.g., 2 g/m2) cytarabine may decrease the likelihood of severe cerebellar toxicity.590 Older patients and patients with renal insufficiency require dose attenuation (i.e., to 1–2 g/m2).591

Additional Maintenance Therapy

Various forms of less-intensive maintenance chemotherapy have been attempted after completion of intensive consolidation chemotherapy. Many of the regimens consist of monthly chemotherapy, for example, low-dose 6-thioguanine or cytarabine. Although improved disease-free survival was noted in some studies, no improvement in overall survival has been demonstrated in most studies.592 Some groups are examining the role of demethylating agents (e.g., 5-azacytidine) as maintenance therapy.

Autologous Stem Cell Infusion after Ablative Chemotherapy or Chemoradiotherapy for Consolidation

Removal and cryopreservation of postremission marrow or collection of mobilized blood stem cells from patients with AML and reinfusion of these products following intensive chemotherapy and/or radiotherapy is a form of postremission therapy (see Chap. 21).593 Autologous marrow or blood stem cell rescue can be used in patients with AML who achieve a remission, do not have a compatible stem cell donor, and are as old as 70 years.

Various preparative regimens for autologous transplantation in AML have been utilized,594 such as busulfan-cyclophosphamide, busulfan-etoposide-cytarabine, high-dose cytarabine-mitoxantrone plus total-body irradiation, melphalan plus total-body irradiation, and cyclophosphamide plus total-body irradiation. A disease-free survival rate of approximately 40 percent at 3 years is average after such regimens in the age-range treated.595,596 Long-term disease-free survival can occur in patients who undergo this treatment for AML in second remission.597 Patients older than age 50 years have inferior outcomes, but no strict upper-age limit for this procedure has been determined.598 Administration of two or more courses of consolidation chemotherapy prior to harvest and transplant is associated with decreased relapse rates and improved disease-free survival. A marrow nucleated cell dose greater than 2 x 108/kg improves disease-free survival.599 Chemotherapy agents such as 4-hydroperoxycyclophosphamide have been utilized for purging residual leukemic cells,600,601 and antisense agents reportedly diminish leukemic cell contamination.602 Use of marrow grafts purged of residual leukemia cells has not significantly improved the results obtained with unpurged marrow in many studies, suggesting that low proportions of leukemic stem cells may not transplant easily or that they do not survive the freeze–thaw cycle to which autologous marrow is subjected as well as do normal stem cells.603 In addition, residual leukemia in the patient may contribute to relapse. For these reasons, marrow purging is rarely utilized in AML autografting (see Chap. 21). In long-term cultures from patients newly diagnosed with AML, normal progenitors can be detected, and their numbers are increased by in vitro culture with cytokines.604 In oligoblastic leukemia (myelodysplasia), secondary AML, and therapy-related AML, leukapheresis products obtained after chemotherapy and growth factor treatment contain normal progenitors,605 indicating mobilized stem cells may be relatively free of leukemic counterparts even in the absence of ex vivo purging.606 Early mortality may be decreased using blood stem cells because they engraft more rapidly, but relapse rates may be higher.607 The Center for International Bone Marrow Transplantation reported that in 2007 the majority of autologous stem cell transplantations in AML used blood stem cell collections. Mobilized stem cells can be collected after high-dose cytarabine plus G-CSF or after G-CSF alone.608 There is a plateau in the survival curve after autologous stem cell transplantation at about 2.2 years,609 and there is evidence that autologous transplantations improve disease-free survival but not overall survival.610 The total number of CD34+ cells infused influences early engraftment, but durable engraftment is associated more closely with the CD34+/CD38– subset in the graft.611 Myeloablative chemotherapy followed by autologous stem cell rescue may overcome the adverse prognosis associated with FLT3 mutations.612

Chemoradiotherapy Plus Allogeneic Stem Cell Transplantation for Consolidation Therapy

General Considerations

Utilization of allogeneic hematopoietic stem cell transplantation for AML is increasing in Europe and the United States.613 No strict upper-age limit for transplantation exists,614 but many centers use age 60 or 65 years for transplants following ablation of hematopoiesis and 70 years for transplants not preceded by ablation of hematopoiesis (nonmyeloablative transplants). Decisions to proceed to allogeneic transplantation should be individualized, and feasibility depends on (1) the availability of a suitable donor, (2) the recipient’s age and health status, and (3) whether AML is in remission.

For ablative transplantations, the patient is prepared with a regimen that includes total-body irradiation and/or high-dose chemotherapy, after which the donor stem cells are infused by vein. Patients given allogeneic blood stem cells have more rapid hematopoietic reconstitution than patients given marrow stem cells.615 Chapter 21 describes the indications, procedure, and preparative regimens for stem cell transplantation. For standard-risk leukemia, blood and marrow appear to be equivalent sources for allografting.616 Engraftment is faster, but chronic GVHD may be more frequent when blood stem cells are used, and longer followup is needed to determine the ultimate effects of blood versus marrow allografts when the donor is a matched sibling.617 G-CSF–primed donor-marrow stem cells may result in less GVHD compared with G-CSF–mobilized blood stem cells.618 In general, no single preparative regimen is superior for patients with AML in first remission.619 In one study, cyclophosphamide and total-body irradiation lowered relapse risk, but overall results were comparable to conditioning with chemotherapy alone.620 Postremission consolidation with cytarabine before allogeneic transplantation for AML in first remission does not improve outcome compared with immediate transplant after successful induction.621 It is unclear that this result will also hold in the setting of reduced-intensity transplants or for transplants performed beyond first remission.622

Related Donors

When matched-sibling transplantation is performed for AML in first remission, approximately half of patients have a disease-free survival of 4 years. Small series using T-cell depletion have reported 4-year disease-free survival of 65 percent.623 Leukemia relapses occur in approximately 20 percent of patients who receive an allogeneic transplant.618 Patients who are alive with good performance status 3 years after transplantation have excellent prospects of long-term survival.623 In the posttransplantation period, approximately one-third of patients die of severe GVHD, opportunistic infection, or interstitial pneumonitis. Marrow transplantation therapy is superior to chemotherapy in that the proportion of subjects who have leukemia relapse is lower, but whether marrow transplantation provides an advantage in overall survival at 3 years is uncertain.624 The outlook for long-term survival is improved if (1) the AML is in remission prior to transplantation, (2) grade III to IV acute GVHD does not occur, and (3) chronic GVHD is low grade.625,626 For patients with unfavorable cytogenetics, an allogeneic sibling transplantation in first remission is often recommended.627 Patients with FLT3/ITD-positive AML may also benefit from stem cell transplantation in first remission.628 When AML patients in first remission were compared on a donor versus no donor basis, and more than 80 percent of patients with a donor went on to transplantation, patients with a donor had a significantly better disease-free survival, although treatment-related mortality was higher.629 For patients with intermediate-risk cytogenetics, where the decision is made to delay transplantation until first relapse, physicians should identify a source of a hematopoietic stem cell graft and ensure that careful monitoring of the patient occurs so that transplantation can be instituted as quickly as possible.630

In an attempt to decrease the relapse rate after stem cell transplantation for advanced acute leukemia, 131I-labeled anti-CD45 antibody to deliver radiation to leukemic cells, followed by a standard transplant preparative regimen, has been used. Nine of 13 patients with AML were disease free 8 to 41 months after transplantation. With this regimen, more radiation can be delivered to hematopoietic tissues compared with liver, lung, or kidney, which may improve the efficacy of the transplantation.631

Unrelated Donors

Approximately 70 percent of all patients with AML are older than 50 years of age, and the current mean family size in the United States is slightly more than two children per family. Thus, only approximately 10 to 15 percent of subjects with AML are within the age range and have a sibling donor for marrow transplantation. The ability to extend the proportion of patients who can be transplanted has led to histocompatible, unrelated donors or HLA type-mismatched sibling or parent (haploidentical) donor transplants.632 Molecular matching of class I and II HLA alleles adds to the clinical success of unrelated donor transplantations but makes finding a donor more difficult.633 Treatment of high-risk acute leukemia with T-cell–depleted stem cells from related donors with one mismatched HLA haplotype with standard conditioning regimens has been successful, with an acceptable incidence of GVHD. However, infectious complications were high.634 HLA-matched or HLA-mismatched cord blood stem cells can be used in adults with acute leukemia but generally not for patients in first remission.635,636 In adults, the numbers of stem cells available in a single cord product may not result in engraftment, which has led to the use of two-cord blood units for grafting (see Chap. 21).637

Nonmyeloablative Transplantation

Patients who, based upon comorbidities or performance status, are deemed too old or too ill to undergo a myeloablative stem cell transplantation may be offered a reduced-intensity transplantation procedure, provided a suitable donor is available. This type of transplantation relies upon the graft versus leukemia effect as primary therapy.638 Use of this approach, specific to AML and a variety of hematologic malignancies, has been described.639,640 These regimens have moderate hematologic and nonhematologic toxicity, and often can be performed on an outpatient basis. Engraftment and establishment of complete donor chimerism are successful in most patients. GVHD rates have been variable, and the ultimate risk of acute and chronic GVHD with these regimens is unclear. A variety of low-intensity regimens have been proposed.641 In AML in first remission, the 1-year progression-free survival is approximately 55 percent.642,643 The role of this approach in the treatment of AML remains to be defined, and comparative trials with longer followup are needed. Nonmyeloablative conditioning with unrelated donors has been used successfully.644,645 Although randomized trials of ablative versus reduced-dose-intensity conditioning regimens for transplantation of AML patients in first remission have not been done, there is evidence that reduced-dose intensity is an inferior option for disease control, but that disadvantage is offset by the decreased treatment-related mortality.646 In one retrospective study, stratified outcomes based on comorbidity and disease status did not differ significantly between reduced-dose and full-dose conditioning of patients, with the exception of lessened nonrelapse mortality in the high-risk group.647 In a multivariate analysis, active disease at transplant and development of grades II to IV GVHD after transplantation had a negative impact on survival in reduced-dose-intensity transplantations.648 Reduced-dose-intensity transplantations are feasible in elderly patients, but donor availability and coexisting medical problems often limit its use.649

Use of Transplantation in Relapsed Patients

Some form of allograft usually is recommended for patients in early first relapse or second remission, because long-term survival with chemotherapy alone is improbable, whereas histocompatible sibling transplants have a 25 percent survival rate. For patients who lack a sibling donor, matched-unrelated donor transplants can be effective, but treatment-related mortality is high, suggesting that patients with unfavorable cytogenetics should undergo a matched-unrelated donor transplant in first complete remission, if an acceptable donor can be found.650 However, when transplantation was compared to chemotherapy for AML in second remission, the 3-year probability of event-free survival was 17 percent with chemotherapy and 16 percent with transplant. Patients younger than 30 years of age who were in remission for at least 1 year fared best.651 Development of chronic GVHD, an unrelated donor, a young age of donor, and blast cell count <30 percent at transplant were found in another series to be favorable predictors of survival for transplants performed in leukemia relapse.652 Patients with extramedullary sites of leukemia are more likely to relapse after allogeneic marrow transplantation.653

Patients with AML who relapse after allogeneic stem cell transplantation can have a long-term remission if they undergo retransplantation.654 The mechanism of benefit of stem cell transplantation was thought to result from high-dose ablative chemoradiotherapy followed by marrow “rescue.” The increased relapse rate of AML in patients transplanted with marrow from identical twins, compared to nonidentical siblings, or transplanted with T-lymphocyte–depleted marrow has indicated an immunologic effect of donor lymphocytes may determine the results of transplantation. This immunologic response, referred to as graft-versus-leukemia effect, may play a role in preventing leukemia relapses.655

Donor Leukocyte Infusion

In an attempt to enhance graft-versus-leukemia effects, adoptive immunotherapy with donor mononuclear cell infusions is sometimes used to treat relapse of leukemia after allografting.656,657 These infusions have been successful in only a minority of patients with AML, but given the high mortality associated with alternative procedures such as second transplantations, the infusions are a reasonable approach for patients who relapse after allogeneic transplantation.658 GVHD and marrow aplasia are the major complications of this form of treatment.659 The graft-versus-leukemia reaction is thought to be directed against minor histocompatibility antigens on the cell surface of hematopoietic cells, but reactions against leukemia-specific antigens are possible. Relapses after donor leukocyte infusions for recurring acute leukemia have a higher probability of being extramedullary.660 Donor lymphocyte infusions are most effective in early relapses and in the absence of extensive of chronic GVHD.661 Some patients also enter a new remission upon withdrawal of immune suppression. Patients who enter remission by donor lymphocyte infusion or cessation of immune suppressive agents have a better survival than those who entered remission with chemotherapy alone or after a second transplant.662 Unrelated-donor leukocyte infusions can be used to treat relapsed leukemia after unrelated donor stem cell transplantation.663 Approximately 40 percent of AML patients enter remission with this treatment. G-CSF has been used as an alternative to donor leukocyte infusions after AML relapse posttransplant.664 Donor blood stem cells can be combined with chemotherapy for early relapse of AML after allogeneic stem cell transplantation.665 Strategies with donor leukocyte infusions are anticipated to become more effective once the effector cells are identified and the tumor target antigens better understood.666

Adjunct Therapy with Interleukin-2 and Vaccines

Interleukin-2 has been used to modulate natural killer cell and T-cell activity after both autologous and allogeneic transplantation. The efficacy of this approach has not yet been determined.667 Minor histocompatibility antigens restricted to hematopoietic cells are an ideal target for antileukemic immune responses. Modification of leukemic cells to express costimulatory molecules identical to professional antigen-presenting cells to generate cytotoxic T lymphocyte responses against myeloid leukemia cells may be possible.668 Dendritic cells derived in vitro from AML cells also can be used to stimulate leukemia-specific cytolytic activity in autologous or allogeneic lymphocytes.669

Recurrent Leukemia in Donor Cells or New Leukemia in Recipient Cells

Recurrence of AML in donor cells has been reported in patients who received stem cell transplants from healthy siblings. These recurrences in donor cells occurred in approximately 1 in 18 relapsed patients who received marrow from a donor of the opposite sex.670 A similar frequency of relapsed AML is observed in recipient cells but with a different clonal cytogenetic abnormality, suggesting a “new” leukemia.670 The frequencies are dependent on the sensitivity and specificity of cytogenetic techniques, which have been challenged. AML developing in a stem cell recipient but of donor cell origin long after transplantation has been documented in rare cases.671

Treatment of Relapsed or Refractory Patients


Patients who relapse after remission-induction and postinduction therapy have a decreased probability of entering a subsequent remission, and the duration of any remission that occurs is usually shorter. In patients who relapse more than 1 year after the first remission, the original remission-induction regimen can be readministered or a combination salvage chemotherapy regimen can be administered.

Refractory leukemia is defined as leukemia that does not respond to initial induction chemotherapy with cytarabine and an anthracycline antibiotic or anthraquinone. Patients with refractory disease are more likely to have disease with adverse cytogenetic findings, a history of antecedent clonal myeloid disease, adverse immunophenotypic features, and expression of multidrug resistance (MDR).672

Relapsed leukemia is leukemia that recurs following a remission. The duration of remission greatly affects the patient’s prognosis and response to additional treatment. The wide range of response rates may not only reflect the regimen used but may also reflect variability in patient selection, age, and other prognostic factors.672,673

Chemotherapy regimens can be divided into cytarabine-based, noncytarabine-based, and timed sequential therapy with growth factors and cytotoxic drugs. Table 89–6 lists the response rates; the duration of response usually is measured in months. The duration of response is difficult to define because many patients go on to other therapies, including stem cell transplantation.

Table 89–6. Examples of Chemotherapy Used for Relapsed or Refractory Patients
Regimen No. of Patients % of Patients Entering a Complete Remission (Median Duration) Year Reference
Gemtuzumab ozogamicin 6 mg/m2 IV, days 1 and 13 15 21 (27 weeks) 2003 679
Idarubicin 12 mg/m2, days 2–4
Cytarabine 1.5 g/m2, days 2–5
Mitoxantrone 12 mg/m2, days 1–3 66 36 (5 months) 2003 680
Cytarabine 500 mg/m2, days 1–3
Followed (at count recovery) by
Etoposide 200 mg/m2, days 1–3
Cytarabine 500 mg/m2, days 1–3
Cladribine 5 mg/m2, days 1–5 58 50 (29% disease-free at 1 year) 2003 681
Cytarabine 2 g/m2, days 1–5 2 h after 2-CdA
G-CSF 10 mcg/kg/day, days 1–5
Fludarabine 30 mg/m2, days 1–5 46 52 (13 months) 2003 682
Cytarabine 2 g/m2, days 1–5
Idarubicin 10/m2 days 1–3
G-CSF 5 mcg/kg per day, day +6 until neutrophil recovery
Gemtuzumab ozogamicin 9 mg/m2, days 1 and 15 43 9 2002 683
Mitoxantrone 4 mg/m2, days 1–3 37