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CHAPTER 93 ACUTE MYELOGENOUS LEUKEMIA

CHAPTER 93 ACUTE MYELOGENOUS LEUKEMIA
Williams Hematology

CHAPTER 93 ACUTE MYELOGENOUS LEUKEMIA

MARSHALL A. LICHTMAN
JANE L. LIESVELD

Definition and History
Etiology and Pathogenesis

Environmental Factors

Evolution From a Chronic Clonal Hemopathy

Predisposing Diseases

Pathogenesis

Mode of Inheritance

Epidemiology

Classification
Clinical Features

Signs and Symptoms
Laboratory Features

Blood Cell Findings

Marrow Findings

Plasma Chemical Findings

Special Clinical Features
Morphologic Variants of Acute Myelogenous Leukemia

Myeloblastic Leukemia

Myelomonocytic Leukemia

Erythroleukemia

Promyelocytic (Progranulocytic) Leukemia

Monocytic Leukemia

Megakaryoblastic Leukemia

Eosinophilic Leukemia

Basophilic and Mast Cell Leukemia
Differential Diagnosis
Therapy, Course, and Prognosis

Decision to Treat

Preparation of the Patient

Remission-Induction Therapy

Remission-Maintenance Therapy

Treatment of Relapsed or Refractory Patients

New Treatment Modalities

Special Therapeutic Considerations

Nonhematopoietic Adverse Effects of Treatment

Course and Prognosis
Chapter References

Acute myelogenous leukemia (AML) is the result of a somatic mutation in a pluripotential stem cell or a slightly more differentiated progenitor cell. Exposure to very high doses of radiation or chronic exposure to benzene increases the incidence of the disease. A small but increasing proportion of cases develop after the exposure of a patient with lymphoma or a nonhematologic cancer to intensive chemotherapy. The mutant cell gains a growth and/or survival advantage in relationship to the normal pool of stem cells. As the progeny of the mutant cell proliferates to form about ten billion cells or more, 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 for lack of treatment or if chemotherapy-induced impairment of neutrophil and monocyte blood cell levels is superimposed. The diagnosis is made by measurement of the blood cell counts and examination of blood and marrow cells and is based on the identification of blast cells in the marrow and blood. The diagnosis of AML is enhanced in some cases by identification of myeloperoxidase activity in blast cells by cytochemistry or a specific antibody test and by identifying characteristic CD antigens on the blast cells (e.g., CD13, CD33). The leukemic stem cell is capable of imperfect differentiation and maturation, and the clone may contain cells that have the morphologic or immunophenotypic features of erythroblasts, megakaryocytes, monocytes, eosinophils, or rarely basophils in addition to myeloblasts or promyelocytes. When one cell line is sufficiently dominant, the leukemia may be referred to as acute erythroblastic, acute megakaryocytic, acute monocytic, and so on. Certain cytogenetic alterations are very frequent. These include t(8;21), t(15;17), inversion 16, trisomy 8, and deletions of all or part of chromosome 5 or 7; t(15;17) 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. High-dose chemotherapy and either autologous stem cell infusion or allogeneic stem cell transplantation may be used in an effort to treat relapse or those at high risk to relapse after chemotherapy alone. The probability of remission ranges from about 75 percent in children to less than 25 percent in octagenarians. The probability for cure decreases from about 35 percent in children to virtually zero in octagenarians.

Acronyms and abbreviations that appear in this chapter include: ACTH, adrenocorticotropic hormone; ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; ATRA, all-trans-retinoic acid; CML, chronic myelogenous leukemia; FISH, fluorescence in situ hybridization; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-monocyte colony stimulating factor; PCR, polymerase chain reaction; TAM, transient abnormal myeloproliferation.

DEFINITION AND HISTORY
AML is a clonal, malignant disease of hematopoietic tissue that is characterized by (1) the proliferation 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 it was Epstein who used the term acute leukämie in 1889,2 and this led to the general appreciation of the clinical distinctions between AML and chronic myelogenous leukemia (CML).3 In 1878, Neumann, 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.4 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 of our current understanding of the disease.
ETIOLOGY AND PATHOGENESIS
ENVIRONMENTAL FACTORS
Table 93-1 lists the major conditions that predispose to subsequent development of AML. Only three well-documented environmental factors are established causal agents: high-dose external low-linear energy transfer radiation exposure,8,9 chronic benzene exposure,10,11,12 and 13 and chemotherapeutic agents.14,15,16,17,18 and 19 Most patients have not been exposed to an antecedent causative factor. Exposure to high linear energy transfer radiation from alpha-emitting radioisotopes such as thorium dioxide increases the risk of AML.20 Case control studies have sometimes found a relationship between AML and organic solvents, petroleum products, radon exposure, pesticides, and herbicides, but these data have not reached the level of the strong association that exists for benzene or high-dose external irradiation or certain chemotherapeutic agents.21 The aggregate of studies has suggested an association between cigarette smoking and AML.22,23 Maternal alcohol use has been associated with AML in infancy.24

TABLE 93-1 CONDITIONS PREDISPOSING TO THE DEVELOPMENT OF ACUTE MYELOGENOUS LEUKEMIA

EVOLUTION FROM A CHRONIC CLONAL HEMOPATHY
AML may develop from the progression of other clonal disorders of hematopoietic stem cells including CML, polycythemia vera, idiopathic myelofibrosis, primary thrombocythemia, and certain preleukemic clonal syndromes such as acquired sideroblastic anemias (Table 93-1). This clonal progression can occur spontaneously, although with a different probability of occurrence in each disorder. The frequency of clonal progression to AML is enhanced by radiation or chemotherapy in patients with polycythemia vera (see Chap. 61) or essential thromobocythemia (see Chap. 118).18,25
PREDISPOSING DISEASES
Patients who develop AML may have an antecedent predisposing disease, such as aplastic anemia, myeloma,26 or, rarely, AIDS.27 A number of inherited conditions, for example, Down syndrome, Fanconi anemia, Bloom syndrome, and others carry an increased risk of AML28,29,30,31,32,33,34,35,36,37,38,39,40 and 41 (Table 93-1).
PATHOGENESIS
AML results from a somatic mutation in either a hematopoietic stem cell or a somewhat more differentiated cell.51 Some cases of monocytic leukemia, of promyelocytic leukemia, and acute myelogenous leukemia in younger individuals are more likely to arise in a progenitor cell with lineage restrictions (progenitor cell leukemia).51,52,53,54 and 55 Other morphologic phenotypes and older patients are likely to have the disease originate in a primitive multipotential cell.51 In the latter case, all blood cell lineages can be derived from the leukemic stem cell, since it retains the ability for some degree of differentiation and maturation.
The somatic mutation results from a chromosomal translocation in nearly 80 percent of patients.57 The translocations result in rearrangment of a critical region of a protooncogene. The fusion of portions of two genes usually does not prevent the process of transcription, and thus the fusion gene encodes a fusion protein that, because of its abnormal structure, disrupts a normal cell pathway and leads to a malignant transformation of the cell. This protein product is often a transcription factor that disrupts the regulatory sequences that control differentiation, growth rate, or survival of blood cell progenitors.57,58 and 59 Since 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. Other genetic changes occur in leukemic cells involving RAS, FES, MYC, FOS, MPL, KIT, p53, RB, WT1, and other genes.60,61,62,63,64,65,66,67,68,69,70,71,72 and 73 In some cases, deletions of all or part of a chromosome, 5- or 7- for example, or additional chromosomes such as trisomy 4, 8, or 13 are the principal cytogenetic abnormalities (see Chap. 10), although the specific causative “oncogenes” in these latter circumstances have not been defined.
MODE OF INHERITANCE
In most cases there is little evidence for a strong influence of genetic factors. The identical twin of a child with leukemia has a greatly heightened risk (1 in 5) of developing the disease. This risk drops to that of a nonidentical sibling (1 in 800) within about 6 months of age, as compared to a risk of 1 in 3000 in American children of European descent under 15 years of age.74 This propensity of identical twins to develop leukemia is related to parabiotic metastasis from one twin to another and not an inherent common mutation. This phenomenon explains the rapid attenuation of risk after 6 months of age. Clusters of AML cases in families have been documented, but their frequency is rare.42,43,44,45 and 46 Clusters of AML in unrelated persons in a community are very rare and usually appear to be a chance occurrence.
EPIDEMIOLOGY
AML is the predominant form of leukemia during the neonatal period, but it represents a small proportion of cases during childhood and adolescence. The mortality rate from AML is about 0.5 per 100,000 persons under age 10 years and increases progressively until it reaches about 20 per 100,000 persons in the ninth decade of life.24 AML accounts for 15 to 20 percent of the acute leukemias in children and 80 percent of the acute leukemias in adults.27,29,70 It is slightly more common in males, and there is little difference in incidence between those of African or European descent at any age. There is an increase in the frequency of AML in Jews, especially of Eastern European descent.
CLASSIFICATION
Variants of AML can be identified by morphologic features of blood films using polychromatic stains and histochemical reactions,75 monoclonal antibodies against surface markers,76,77,78,79 and 80 or by the presence of specific chromosome translocations.81 There is overlap in the epitopes on the progenitor cells of several phenotypic variants, and several monoclonal antibodies are required to make specific distinctions among cell types (Table 93-2). See also the section “Morphologic Variants of AML” and Table 93-4 later in the chapter. There is a poor correlation between morphologic and immunologic phenotyping of AML as would be expected, since 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.82 Chapter 91, “Classification and Clinical Manifestations of Clonal Myeloid Diseases,” contains the classification of morphologic variants of AML (Fig. 91-2). A need to include functional markers for drug resistance, such as MDR expression, has also been proposed to separate more responsive from less responsive AML.83

TABLE 93-2 IMMUNOLOGIC PHENOTYPES OF AML

TABLE 93-4 MORPHOLOGIC VARIANTS OF AML

CLINICAL FEATURES
SIGNS AND SYMPTOMS
GENERAL
Signs and symptoms that signal the onset of AML include pallor, fatigue, weakness, palpitations, and dyspnea on exertion. They reflect the development of anemia; however, weakness, loss of sense of well being, and fatigue on exertion can be out of proportion to the severity of anemia.84,85,86,87 and 88
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 bleeding can occur at the onset of the 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 as presenting features of the disease, in part because absolute neutrophil counts under 500/µl (0.5 × 109/liter) are uncommon until chemotherapy is begun. With intensification of neutropenia after chemotherapy, major bacterial, fungal, or viral infections become frequent. Anorexia and weight loss are frequent findings. Fever is present in many patients at the time of diagnosis.87,88,89,90 and 91 Palpable splenomegaly or hepatomegaly occurs in about one-third of patients.84,85,88 Lymphadenopathy is extremely uncommon,88,92,93 except in the monocytic variant of AML.94
SPECIFIC ORGAN SYSTEM INVOLVEMENT
Leukemic blast cells circulate and enter most tissues in small numbers.95 Occasionally biopsy or autopsy will uncover marked aggregates or infiltrates of leukemic cells, and less frequently collections of such cells may cause functional disturbances. Extramedullary involvement is most common in monocytic or myelomonocytic leukemia.
Skin involvement may be of three types: nonspecific lesions, leukemia cutis, or granulocytic sarcoma of skin and subcutis.96,97,98,99,100 and 101 Nonspecific lesions include macules, papules, vesicles, pyoderma gangrenosum, or vasculitis,102,103 and 104 neutrophilic dermatitis (Sweet’s syndrome),105 cutis vertices gyrata,106 or erythema multiforme or nodosum.96,97 Skin involvement preceding marrow and blood involvement is rare.101,107
Sensory organ involvement is very unusual, but retinal, choroidal, iridial, and optic nerve infiltration can occur.108 Otitis externa and interna, inner ear hemorrhage, and mastoid tumors with seventh nerve involvement may be presenting signs.109,110 and 111
The gastrointestinal tract may be involved at any point, but functional disturbances are unusual.112,113 The mouth, colon, and anal canal are sites of involvement that most commonly lead to symptoms. Oral manifestations may bring the patient to the dentist; gingival or periodontal infiltration and dental abscesses may lead to an extraction followed by prolonged bleeding or an infected tooth socket.114 Iliotyphlitis (enterocolitis), a necrotizing inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a presenting syndrome or occur during treatment.115,116 and 117 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 are often associated with a fatal outcome. Isolated involvement of the gastrointestinal tract is rare.118,119 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.112
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.120,121,122,123 and 124
Cardiac involvement is frequent but rarely causes symptoms. Symptomatic pericardial infiltrates, transmural ventricular infiltrates with hemorrhage, and endocardial foci with associated intracavitary thrombi can, on occasion, cause heart failure, arrhythmia, and death.125 Infiltration of the conducting system or valve leaflets or myocardial infarction has occurred.126
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, however.127,128 Cases of vulvar, bladder neck, prostatic, or testicular involvement have been described.129,130 and 131
Osteoarticular symptoms are infrequent. Bone pain, joint pain, and bone necrosis can occur, and rarely arthritis with effusion may be present.132 Crystal-induced arthritis of either calcium pyrophosphate dihydrate (pseudogout) or monosodium urate (gout) may be responsible for the synovitis in some cases.133
Central or peripheral nervous system involvement by infiltration of leukemic cells is very uncommon, although in the monocytic type of AML meningeal involvement is an important consideration in treatment.134,135 There is an association of central nervous system involvement and diabetes insipidus in AML with monosomy 7136 and inversion of chromosome 16.137,138
GRANULOCYTIC SARCOMA
Granulocytic sarcoma is a tumor composed of myeloblasts or monoblasts. It may be found in virtually any location, especially the skin; orbit; paranasal sinuses; bone; chest wall; breast; gastrointestinal, respiratory, or genitourinary tract; central or peripheral nervous system; or lymph nodes.139,140 These tumors were originally called chloromas because of the green color imparted by the high concentration of the enzyme myeloperoxidase present in myelogenous leukemic cells. Chloracetate esterase histochemical stains or antilysozyme immunoperoxidase reaction is positive when biopsy specimens are studied. Granulocytic sarcomas may be the initial manifestation of AML, and the appearance of the disease in the blood and marrow may follow weeks or months later if intensive therapy is not administered.139,140 AML with the t(8;21) has a propensity to extramedullary leukemia,141 and patients with granulocytic sarcomas have a poorer outcome with treatment.142
LABORATORY FEATURES
BLOOD CELL FINDINGS
Anemia is a constant feature.84,85,86,87 and 88 Red cell life span may be mildly shortened, but the principal cause of anemia is inadequate production of red cells. The reticulocyte count is usually between 0.5 and 2.0 percent. Occasionally patients may 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 relating to circulating immune complexes or as a result of an anti-I antibody. 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 may occur, but these changes are more often seen in oligoblastic leukemia (see Chap. 92).
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, and over half the patients have a platelet count less than 50,000/µl (50 × 109/liter) at the time of diagnosis.143 Giant platelets and poorly granulated platelets with functional abnormalities can occur.144 Defects in platelet aggregation and 5-hydroxytryptamine release are frequent.144
The total leukocyte count is less than 5000/µl (5 × 109/liter) in about half the patients at the time of diagnosis.84,88 The absolute neutrophil count is less than 1000/µl (1 × 109/liter) in over half the cases at diagnosis.84,88 Patients with elevated leukocyte counts have a low proportion of mature neutrophils but may have a normal or slightly elevated 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.145 Defects in phagocytosis or microbial killing are also common.146
Myeloblasts are almost always present in the blood, but in leukopenic patients they may be infrequent. Diligent search may uncover them or examination of a white cell concentrate (buffy coat) may permit their identification. Blood myeloblasts range from 3 to 95 percent of total leukocytes (see Plate XVI and Plate XVII). Classic leukemic blast cells are agranular, but mixtures of immature cells can occur including agranular and slightly granular cells ranging up to overt progranulocytes. Auer rods are elliptical cytoplasmic inclusions about 1.5 µm long and 0.5 µm wide that are derived from azurophilic granules (see Chap. 64). These inclusions are present in the blast cells of about one-quarter of cases, and when present are found in only a small percent of blast cells.75,147
MARROW FINDINGS
MORPHOLOGY
The marrow always contains leukemic blast cells. Three to 95 percent of marrow cells are blasts at the time of diagnosis or relapse.84,85,86,87 and 88,147 Myeloblasts are distinguished from lymphoblasts by any of three pathognomonic features: reactivity with specific histochemical stains; Auer rods in the cells; or reactivity with specific monoclonal antibodies against epitopes present on myeloblasts (for example, CD11, CD13). 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 about one-quarter of cases. Blast cells express granulocytic or monocytic 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 also, “Hybrid and Mixed Leukemias”). In a proportion of otherwise typical cases of AML, the cells may contain terminal deoxynucleotidyl transferase.148,149 Variations in marrow findings are discussed further in “Morphologic Variants of Acute Myelogenous Leukemia,” below. Normal erythropoiesis, megakaryocytopoiesis, and granulopoiesis are decreased or absent in the marrow aspirate. The biopsy may contain residual islands of erythroblasts or megakaryocytes. Dyshematopoietic changes, 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 percent to 50 percent of patients with de novo AML.150 Marrow reticulin fibrosis is common but is usually slight to moderate except in cases of megakaryoblastic leukemia, in which intense fibrosis is the rule.151 Increased blood vessel density (angiogenesis) has been demonstrated in the marrow of patients with AML compared to normal subjects.56
MARROW CELL CULTURE
Progenitor cells for granulocytes, for monocytes and macrophages, or for 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. About 85 percent of patients do not have colony-forming cells in their marrow, but the marrow of 60 percent of patients does have cells capable of forming small clusters in vitro (4 to 40 cells in size). About 15 percent of patients retain colony-forming cells but often in reduced numbers and with abnormal maturation patterns.152,153 Restoration of colony-forming cells in the marrow of treated patients often precedes morphologic evidence of remission.154 The correlation of pretreatment marrow colonial growth pattern in vitro with the outcome of intensive chemotherapy is not sufficiently strong to use growth pattern as a prognostic variable.155
CYTOGENETIC FEATURES
An abnormal number (aneuploidy) or structure (pseudodiploidy) of chromosomes or both are readily evident in about 75 percent of cases.156,157 and 158 The most prevalent abnormalities are trisomy 8, monosomy 7, monosomy 21, trisomy 21, and loss of an X or Y chromosome, but virtually any chromosome may be rearranged, added, or lost. In cases of AML that occur following chemotherapy or radiotherapy, loss of part or all of chromosome 5 is a common feature,159,160 and 161 as are the cytogenetic findings noted above for AML, occurring de novo. The major abnormalities and translocations seen in AML are presented in Table 93-3 (see Chap. 10). The translocations 8;21, 15;17, and inv 16 confer a more favorable outcome on average; deletion of all or part of chromosomes 5 and 7 or the presence of complex changes confer a less favorable prognosis. Other abnormalities generally confer an intermediate prognosis.156,157

TABLE 93-3 CLINICAL CORRELATES OF FREQUENT CYTOGENETIC ABNORMALITIES OBSERVED IN AML

PLASMA CHEMICAL FINDINGS
Prior to treatment, mild to moderate increases in serum uric acid and lactic dehydrogenase levels are frequent, and both levels are higher in myelomonocytic and monocytic AML than in other AML phenotypes.87,88 Occasional patients may have very elevated uric acid levels, but usually this occurs after chemotherapy if proper precautions are not taken (e.g., allopurinol and hydration therapy).168 Abnormalities of sodium, potassium, calcium, or hydrogen ion concentration are infrequent and usually mild.169,170 Severe hyponatremia associated with inappropriate antidiuretic hormone secretion has occurred at presentation,169,170 and severe hypernatremia as a consequence of diabetes insipidus can be an initial event.171 Hypokalemia is a somewhat more frequent finding at presentation and is related to kaliuresis, although the reason for the proximal renal tubular dysfunction is unclear.169,170,172 The hypokalemia can be severe, occasionally, and is often worsened by the effects of treatment, especially the use of kaliuretic antibiotics.172 Factitious elevations in serum potassium levels have been reported in patients with hyperleukocytosis as a result of leakage from white cells in vitro.173,174 Factitious hypoglycemia and spurious hypoxia from the effects of high blast cell counts also can occur.173,175
Hypercalcemia can occur. The pathogenesis is probably multifactorial,176 but cases with increased ectopic parathormone-like activity in the plasma have been described.177 Severe lactic acidosis prior to treatment has been reported.170,178,179 Hypophosphatemia as a result of phosphate uptake by leukemic cells can occur.180 Ectopic adrenocorticotropic hormone (ACTH) secretion181; circulating immune complexes182; and abnormal concentrations of coagulation factors or their inhibitors183 may be present.
Although prothrombin and partial thromboplastin times are usually normal or near normal, abnormalities in the concentration of coagulation factors are frequent. Elevation of platelet factor 4 and thromboxane-B2 occur often.184 A decrease in alpha2-antiplasmin, protein C, and antithrombin III levels are also frequent184 and may be associated with venous thrombosis.185 Acute promyelocytic and acute monocytic leukemia are associated with hypofibrinogenemia and other indicators of activation of coagulation or fibrinolysis.186 See “Morphologic Variants of AML.”
The levels of the shed form of L-selectin187 and anticardiolipin antibodies188 are frequently elevated in plasma.
SPECIAL CLINICAL FEATURES
HYPERLEUKOCYTOSIS
About 5 percent of patients with AML develop signs or symptoms attributable to a markedly elevated blood blast cell count, usually in excess of 100,000/µl (100 × 109/liter)189 (see Chap. 91). The circulation of the central nervous system, lungs, and penis is most sensitive to the effects of leukostasis. Intracerebral hemorrhage from vascular occlusion, invasion, and disruption, and pulmonary insufficiency, sometimes with hemorrhage, are the most virulent manifestations of the syndrome. Dizziness, stupor, dyspnea, and priapism may also occur.189,190,191 and 192 Diabetes insipidus has been another rare association.193 A high early mortality in patients with AML is correlated with hyperleukocytosis, greater than 100,000/µl (>100 × 109/liter).190,191 and 192 Chemotherapy in hyperleukocytic patients may also lead to a pulmonary leukostatic syndrome, presumably from the effects of rigid, effete blast cells or the effect of the discharge of large amounts of cell contents and resultant cell aggregation.194,195 Larger-vessel vascular occlusion as a result of white thrombi or masses of leukemic cells is very rare.196,197,198 and 199
HYPOPLASTIC LEUKEMIA
About 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.200,201 and 202 About 75 percent of these patients are men over age 50 years. Marrow biopsy is hypocellular, which is the unusual feature of the syndrome, but leukemic blast cells are evident and in a proportion of 15 to 90 percent of marrow cells. Response to intensive chemotherapeutic treatment has been favorable in some patients.
OLIGOBLASTIC (SMOLDERING) LEUKEMIA
In about 10 percent of cases, usually in patients over age 50, 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 to 15 percent) and marrow (3 to 30 percent). Such cases have been termed oligoblastic leukemia or smoldering leukemia203,204 and 205 or classified as a specific syndrome, especially refractory anemia with excess blasts. The clinical course of the untreated disease can be protracted, but the disease has a high morbidity and mortality from infection and hemorrhage and can evolve into overt (polyblastic) AML. The smoldering or oligoblastic leukemias have historically been grouped with the clonal refractory cytopenias as part of the myelodysplastic syndromes (refractory anemia with excess blasts). For that reason the diagnosis and treatment of these variants are discussed in Chap. 92. Biologically and clinically, this subset of the myelodysplastic syndrome with blast cell proportions in the marrow above normal are leukemias, not dysplasias, but with a slower rate of progression than that of polyblastic myelogenous leukemia. Dysmorphogenesis of red cells, neutrophils, and platelets are more frequent and more striking than in the average case of polyblastic AML (see Chap. 92), but such dysmorphogenesis occurs in polyblastic leukemia as well.150
NEONATAL MYELOPROLIFERATION AND LEUKEMIA
Four myeloproliferative syndromes related to AML have been identified in the neonate: transient abnormal myeloproliferation, transient leukemia, congenital leukemia, and neonatal leukemia.
Transient abnormal myeloproliferation (referred to by the acronym TAM) can be present at birth or occur shortly thereafter, principally in infants with Down syndrome.206,207,208,209 and 210 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. Cytogenetic studies and marrow cell culture studies are often normal, except for trisomy 21, characteristic of Down syndrome. The blast cells usually have the phenotype of megakaryocytes. The elevated white cell and blast cell counts disappear over a period of weeks to months. 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 transient abnormal myeloproliferative syndrome may disappear only to be followed shortly thereafter by acute leukemia. About 25 percent of newborns with Down syndrome and transient leukemia will develop acute megakaryocytic leukemia in the first 4 years of life.211,212 and 213 The response rate of infants with Down syndrome and AML to chemotherapy has been very high over several years of follow-up.211,214,215 The leukemic blast cells in patients with Down syndrome often have a megakaryoblastic and an erythroid phenotype and may have an interstitial deletion of chromosome 21.208,209,216,217
Congenital or neonatal leukemia can occur in apparently normal infants, but this rare syndrome is over 10 times more frequent in newborns with Down syndrome.215,216 Leukocytosis, blood and marrow blast cells, hepatosplenomegaly, thrombocytopenia, purpura, anemia, and skin infiltrates are usual. Cytogenetic abnormalities can occur and mark the leukemic clone.217,218 and 219 Monocytic leukemia and t(4;11) are the most common phenotype and karyotype.219,220 A case of vertical (transplacental) transmission of acute monocytic leukemia from mother to son has been reported.221
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 of band q23 on chromosome 11 is a very poor prognostic sign. Infants with congenital or neonatal leukemia rarely survive for more than a few weeks. Since treatment has been largely ineffective, observation to ascertain if a transient myeloproliferative syndrome or a transient leukemia is present has been recommended if the clinical picture is unclear.222
HYBRID AND MIXED LEUKEMIAS
Hybrid Leukemias Although coincidental myeloid and lymphoid clonal diseases have been reported for over 30 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.223,224,225,226,227,228,229,230,231,232,233 and 234,237
Bilineal (interlineal) acute leukemias are cases in which a significant proportion of cells (over 10 percent) have lymphoid and myeloid markers, interlineal here referring to lymphocytic and hematopoietic gene expression. Bilineal (biphenotypic) leukemias are heterogeneous in that some cases have cells with both lymphoid and myeloid markers (chimeric) and other cases 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 (that is, lymphoid and myeloid cells are present simultaneously) or asynchronous (in which lymphoid cells are succeeded by myeloid cells or vice versa), but there is evidence 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, and those more indicative of lymphocytic leukemia MY+ ALL.225 Interlineal hybrid leukemias, as a group, treated with current regimens, respond to therapy at about the same rate as AML cases without lymphoid markers.224 Some observers suggest altering drug regimens depending on the balance between lymphoid and myeloid biochemical (drug-response) patterns.236
Acute myelogenous leukemias may be intralineal hybrids in that the blast cells have markers for two or more myeloid lineages, for example, 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 Two notable syndromes have been associated with hybrid leukemias: the myeloid leukemia and natural killer cell hybrid238,239 and 240 and the lymphoma, eosinophilia, and myeloid, t(8;13), leukemia hybrid.241,242 In both syndromes signs of lymphoma such as mediastinal or other lymphadenopathy and extranodal lymphoid tumor are mixed with findings compatible with acute myeloid leukemia. The morphology of the myeloid leukemia simulates acute promyelocytic leukemia.
Hybrid leukemias may result from either lineage infidelity as a result of genetic misprogramming237 or from promiscuous gene expression, which occurs transiently in the differentiation of normal multipotential hematopoietic stem cells. In the latter case (promiscuity), a persistence of this transient normal event is thought to be present because of the block in differentiation that occurs in these cases.230 Genetic misprogramming (infidelity) could result from DNA rearrangements of the sequences that control the transcription of genes that designate differentiation antigens.243
Mixed Leukemias In these cases lymphoid and myeloid cells are present simultaneously but are derived from separate clones or there is sequential myeloid and lymphoid leukemia but the two lineages are derived from separate clones.
MEDIASTINAL GERM CELL TUMORS AND AML
An unusual but significant concordance has been reported between mediastinal germ cell tumors and AML, especially the megakaryoblastic variant.244,245,246,247 and 248 The 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 and are thought to be derived from yolk sac cells that failed to migrate.247,248 AML is a hematopoietic stem cell tumor derived from a cell type that is present in the yolk sac also. Cytogenetic studies are compatible with a clonal relationship (identity) of the mediastinal germ cells and the myelogenous leukemia cells.244,245 Apparently, hematopoietic lineage genes are predisposed to expression in extragonadal (mediastinal) germ cell tumors.
MORPHOLOGIC VARIANTS OF ACUTE MYELOGENOUS LEUKEMIA
Morphologic variants of AML (Table 93-4) may occur de novo or may be the manifestation of clonal evolution from essential thrombocythemia, idiopathic myelofibrosis, chronic myelogenous leukemia, or other nonacute clonal stem cell disorders. For example, every phenotypic variant of AML can occur as the blast crisis of CML (see Chap. 94).
MYELOBLASTIC LEUKEMIA
The designation acute myeloblastic leukemia came into being in the second decade of the twentieth century,6,7 following the specific description of the myeloblast.6 About 30 percent of cases of AML 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, there is little evidence of maturation of myeloblasts, and the marrow is replaced by a monotonous population of blasts. In the former type, 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 do react with antibodies to myeloperoxidase and antibodies to CD13, CD33, and CD34. There is a more frequent presence of abnormal and unfavorable karyotypes (e.g., 5q-,7q-) and higher expression of the multidrug resistance glycoprotein (p170). This phenotypic variant has a poor prognosis.249,250 and 251 In the other type of myeloblastic leukemia, designated M1, myeloblasts are present in the blood and comprise over 70 percent of the marrow cells. Fewer 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 5 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.
In many cases of myeloblastic leukemia, more prominent granulocytic maturation is evident (FAB type M2). This variant is present in about 25 percent of cases of AML; thus myeloblastic leukemia with or without maturation makes up over 50 percent of cases of AML. Blasts usually constitute at least 30 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 30 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. A translocation between chromosomes 8 and 21 t(8;21)(q22;q22), often concomitant with the loss of the Y chromosome in men or an X chromosome in women, has been associated with this phenotype and occurs in younger patients (average age about 30).252,253 and 254 Patients whose cells contain t(8;21) are prone to granulocytic sarcoma.141,142
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.256 About 20 percent of patients with AML present with this variant, and they are more likely to have extramedullary infiltrates in gingiva, skin, or central nervous system than those with acute myeloblastic leukemia.257 A mixture of myeloblasts and monoblasts is found in the blood and marrow. Over 30 percent of marrow cells are myeloblasts, which react with peroxidase or chloracetate esterase, and monoblasts, which react with fluoride-inhibitable nonspecific esterase. Over 20 percent of cells are monoblasts or promonocytes in blood and marrow. In some cases, individual cells react with both monocytic and granulocytic histochemical stains.258 Serum and urinary lysozyme levels are increased in most cases. This variant of AML is referred to as M4 in the FAB classification. The proportion of marrow eosinophils259 or basophils260 may be increased.
Translocations involving chromosome 3 have been associated with this phenotype.261 A special variant of myelomonocytic leukemia has increased numbers of marrow eosinophils (10 to 50 percent), Auer rods, and inversion or rearrangement of chromosome 16.262,263,264 and 265 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. A variant of acute myelomonocytic leukemia has an increased number of marrow basophils and a translocation involving chromosomes 6 and 9, t(6;9)(p23;q34).266 This variant occurs at a younger age, has a poor prognosis, and has a tendancy to trilineage dysmorphogenesis and ringed sideroblasts.267
ERYTHROLEUKEMIA
Prominence of erythroid cell proliferation in cases of AML was noted by Copelli268 and DiGuglielmo269 in the early twentieth century. Erythroleukemia makes up about 5 percent of cases of AML and is referred to as M6 in the FAB classification. Familial erythroleukemia has been described.43,44
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 about two-thirds of patients. In the earlier stage or less severe form of the disease, so-called erythremic myelosis, granulopoiesis and thrombopoiesis may be only mildly abnormal. This severe dyserythropoietic phase can be protracted but evolves, sooner or later, into one 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.270,271,272 and 273
During the erythremic myelosis and erythroleukemia stages, erythropoiesis is markedly ineffective but some normal influences remain, since hypertransfusion decreases both erythropoietin levels and the amount of abnormal erythropoiesis.274 Spontaneous growth of leukemic erythroid clonogenic cells is a feature of the disease.275 Periodic acid–Schiff-positive erythroblasts are evident in virutally all cases.270,273 The frequency of erythroblastic leukemia is increased if methods of detecting erythroid differentiation more sensitive than light microscopy are used. These cell features include glycophorin A, spectrin, carbonic anhydrase I, ABH blood group antigens, or other antigens that occur on early erythroid progenitors.276,277 and 278 Anti-hemoglobin antibody and anti-human erythroleukemic cell-line antibody are often positive.271
Erythremic myelosis can have an indolent course and may be managed for a time without intensive chemotherapy. In patients with erythroleukemia, treatment is warranted, and the results are approximately those of other phenotypes in patients of similar age.273 The more predominant the erythroid component and the less the proportion of myeloblasts, the better the response to therapy.276
PROMYELOCYTIC (PROGRANULOCYTIC) LEUKEMIA
The association of an exaggerated hemorrhagic syndrome with certain leukemias was described by French hematologists in 1949,279 and in 1957 Hillstad bestowed the appellation promyelocytic leukemia upon this morphologic-clinical subtype of AML.280 This variant, which is called M3 in the FAB classification, occurs at any age and constitutes about 10 percent of cases of AML.281,282,283 and 284 This subtype of AML occurs with greater frequency than expected among Latinos from Europe and South and Central America285,286 and among patients with an increased body mass index.287
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 [<50,000/µl (<50 × 109/liter)] is present in most cases. The marrow contains few agranular blast cells and some blastlike cells with scant granules. The dominant cells are promyelocytes, which comprise 30 to 90 percent of marrow cells. Auer rods and cells with multiple Auer rods (1 to 10 percent) are present in nearly every case. Promyelocytes with bundles of 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.281,282,283 and 284
A variant type of promyelocytic leukemia is referred to as microgranular (M3v in the FAB nomenclature).288,289,290 and 291 Microgranular cases represent about 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 such small azurophilic granules that they are not visible by light microscopy, but the peroxidase stain is usually strongly positive. Typical hypergranulated promyelocytes are usually present on careful inspection. The total white cell count is often very elevated, and severe coagulopathy is prominent in microgranular cases.289 Rarely the cells may contain eosinophilic or basophilic granules, but the t(15;17) is present, and the response to all-trans-retinoic acid persists.292,293 and 294
A translocation between chromosome 17 and another chromosome is present in virtually all cases of acute promyelocytic leukemia and in the acute promyelocytic transformation of CML and is not found in other AML variants. The t(15;17) is the most frequent (over 95 percent), but variant translocations between chromosomes 5 or 11 and 17, isochromosome 17, and other less common variants have also been described.281,283,295,296 In some cases, cytogenetic analysis is inadequate, and Southern blot analysis is required to identify the rearrangement of the RARa gene.
The breakpoint on chromosome 17 is within the gene for the retinoic acid receptor-a, and the breakpoint on chromosome 15 is within the locus of a gene originally referred to as MYL and renamed PML.297,298,299 and 300 The gene may encode a unique transcription factor. The translocation results in two new chimeric or fusion genes, RARa-PML that is actively transcribed in acute promyelocytic leukemia, and PML-RARa that is also transcribed and may account for the aberrancy in hematopoiesis. The PML-RARa gene has two isoforms that produce a short and a long type fusion mRNA, respectively.301 Patients with the short isoform may have a worse outcome than those with the longer form. Polymerase chain reaction for the mRNA of the fusion gene can be used to identify residual cells during remission and may predict for relapse. The PML-RARa transgene can reproduce the disease in mice.302 The specific transforming effects of the protein product are uncertain.283
A propensity to hemorrhage is a striking feature of this subtype. The prothrombin and partial thromboplastin times are prolonged and the plasma fibrinogen level decreased in most cases. The disturbance in coagulation was initially thought to be principally the result of 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 plasminogen activiation indicate fibrinolysis.303,304 and 305 Decreased levels of plasminogen, increased expression of annexin II on the leukemic cells, and reports of responses to tranexamic acid support an important role for fibrinolysis.306 Release of nonspecific proteases may further contribute to fibrinogenolysis.
Although acute promyelocytic leukemia responds to chemotherapy regimens for AML, especially those containing an anthracycline antibiotic like daunomycin or rubidazone,307 the cytologic pattern of response in the marrow was often paradoxical.308,309 and 310 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 of AML, relapse ensued unless hypoplasia is induced by more cytotoxic therapy. The unusual pattern of response in acute promyelocytic leukemia was put into context by reports of successful treatment with isomers of retinoic acid, an agent that was known to lead to maturation of leukemic promyelocytes in vitro.311 In 1988 the success of all-trans-retinoic acid in remission induction was reported312,313 and confirmed.283,284 Relapse occurs invariably, however, and thus chemotherapy regimens are required as well. The use of all-trans-retinoic acid has decreased the risk of early hemorrhagic complications and death and enhanced the long-term response to chemotherapy. The approach to therapy and outcome is discussed in the section “Therapy, Course, and Prognosis.”
MONOCYTIC LEUKEMIA
Monocytic leukemia was first reported by Reschad and Schilling-Torgau in 1913.314 About 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 percent) of extramedullary tumors in the skin, gingiva, eyes, larynx, lung, rectum and anal canal, bladder, lymph nodes, meninges, central nervous system, or other sites than do other phenotypes (<5 percent). Hepatomegaly and splenomegaly also are more frequent in monocytic leukemia.94,315,316 and 317
The total leukocyte count is higher in a larger proportion of patients, and hyperleukocytosis occurs more frequently (about 35 percent) than in other variants.318,319 and 320 The blood cells may be largely monoblasts or more mature-appearing promonocytes and monocytes. When the blood contains more mature monocytic cells, the marrow contains a lower proportion of blast cells, about 25 to 50 percent, and when the blood monocytes are largely blast cells, the marrow contains about 50 to 90 percent blasts. In nearly all cases 10 to 90 percent of monocytic cells react with nonspecific esterase stains, a-naphthyl acetate esterase, and naphthol AS-D acetate esterase, or with monoclonal antibodies against monocyte surface antigens, especially CD-14. Immunoreactivity of cells for lysozyme is also characteristic. Serum and urine lysozyme levels are elevated in most patients. Serum lactic dehydrogenase and beta-2 microglobulin concentrations are increased in over 80 percent of patients.321 Plasminogen activator inhibitor-2 is present in the plasma and the cells of a high proportion of patients.322 Auer rods are absent when monoblasts dominate but are present frequently in cases in which promonocytes and monocytes are prevalent in blood and marrow. Leukemic monocytes have Fc receptors and can ingest and kill microorganisms in some cases.323,324
An association between translocations involving chromosome 11, especially region 11q23, and monocytic leukemia is present.163 In particular, t(9;11) and t(11;17) are found in leukemic monocytes.317,318,325 In t(9;11) the b1-interferon gene is translocated to chromosome 11, and the protooncogene ETS-1 is translocated to chromosome 9 adjacent to the a-interferon gene. The latter juxtaposition may be important in the pathogenesis of monocytic leukemia.164
The expression of FOS is closely correlated with monocytic maturation of cells in myelomonocytic and monocytic leukemia and in normal monocytopoiesis.326,327 Absence or markedly decreased expression of the retinoblastoma gene growth suppressor product (p105) is present in about half the patients with monocytic leukemia. These patients express a more dramatic phenotype.328 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 terminal deoxynucleotidyl transferase activity often occurs after prior radio- or chemotherapy and is relatively resistant to treatment.329
The management of monocytic leukemia is complicated by a greater incidence of central nervous system or meningeal disease either at the time of diagnosis or as a form of relapse during remission. Thus, an examination of cerebrospinal fluid should be performed even in the absence of symptoms.94,317,318,319 and 320 Some therapists recommend prophylactic intrathecal therapy with methotrexate or cytosine arabinoside for patients who enter remission.
Rare cases of dendritic cell or Langerhans’ cell phenotype have been described330,331 (see Chap. 78). Very uncommon cases of histiocytic sarcoma are the tissue or extramedullary variant of monocytic leukemia332,333 (see Chap. 78).
MEGAKARYOBLASTIC LEUKEMIA
In 1963 Szur and Lewis reported patients with pancytopenia, low percentages of blast cells, and intense myelofibrosis but absence of teardrop red cells, splenomegaly, leukocytosis, and thrombocytosis, the usual features of idiopathic myelofibrosis. They designated the syndrome malignant myelosclerosis.334 Reports of similar cases ensued, some referring to the syndrome as acute myelofibrosis.335 The development of methods to phenotype megakaryoblasts indicated that these cases were variants of AML rather than of myelofibrosis and have been designated acute megakaryocytic or acute megakaryoblastic leukemia.336,337 This leukemia is referred to as M7 in the FAB classification. The prevalence of this phenotype is about 5 percent of all cases of AML and is at least twice that frequency in childhood AML.338 It is an especially prevalent variant of AML that develops in patients with Down syndrome339,340 or mediastinal germ cell tumors.244,245,246,247 and 248
The leukemic megakaryoblasts and promegakaryocytes can be very difficult to identify by light microscopy using polychrome staining, although with experience heightened suspicion can be engendered by blasts with abundant budding cytoplasm or blasts that have 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 glycoprotein Ib (CD42), IIb/IIIa (CD41), or IIIa (CD61) can be used to identify very primitive megakaryocytic cells.336,337 A small proportion of megakaryoblasts may be present in other cases of AML, but in megakaryocytic leukemia they are prominent (>10 percent) or the dominant leukemic cells; moreover, the other key features of the syndrome are usually present, especially severe myelofibrosis.338
Patients usually present with pallor, weakness, excessive bleeding and anemia, and leukopenia. Lymphadenopathy or hepatosplenomegaly is very uncommon at the time of diagnosis. High leukocyte and blood blast cell counts may be present initially or develop later. The platelet count may be normal or elevated in many patients at the time of their presentation. Marrow aspiration is often unsuccessful (“dry tap”) because of the extensive marrow fibrosis in most cases. The marrow biopsy contains either small or large blast cells or some combination of both. The former have a high nuclear/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 plateletlike structures, or shedding of cytoplasmic blebs. The blast cells are peroxidase-negative and tend to aggregate. Confirmation of their megakaryoblastic maturation requires immunocytologic studies of the presence of von Willebrand factor and the immunoreactivity to CD41, CD42, or CD61. The more mature megakaryocytes stain with periodic acid–Schiff reagent, contain sodium fluoride-inhibitable nonspecific esterase, and fail to react for a-naphthylbutyrate esterase.
The serum lactic acid dehydrogenase is frequently strikingly increased and has an isomorphic pattern unlike that seen with other myeloproliferative disorders. An association of megakaryoblastic leukemia in infants with t(1;22)(p13;q13) has been reported.341 Abnormalities of chromosome 3 have been linked to clonal hemopathies expressing a prominent megakaryocytic phenotype.342,343 The progression to AML of idiopathic myelofibrosis or essential thrombocythemia may have the phenotype of acute megakaryocytic leukemia.
EOSINOPHILIC LEUKEMIA
Acute eosinophilic leukemia is rare. Increased eosinophils in the marrow but not the blood is seen as a variant of acute myelomonocytic leukemia and inv 16 or other abnormalities of chromosome 16 but is not considered an acute eosinophilic leukemia.262,263,264 and 265 First described in 1912,344 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. 345,346 and 347 A specific histochemical reaction, cyanide-resistant peroxidase, permits the identification of leukemic blast cells with eosinophilic differentiation and the diagnosis of acute eosinoblastic leukemia in some cases of AML with few identifiable eosinophils in blood or marrow.348 Eosinophilia, not part of the malignant clone, may be a feature of occasional patients with AML. Idiopathic eosinophilia (hypereosinophilic syndrome) is, in some cases, a monoclonal disorder and represents a spectrum of more indolent chronic or subacute eosinophilic leukemia to more progressive acute leukemia349 (see Chap. 68). Acute eosinophilic leukemia may also evolve in patients who have the chronic form of a hypereosinophilic syndrome. The overexpression of Wilms’ tumor gene expression has been proposed as a means of distinguishing acute eosinophilic leukemia from a polyclonal, reactive eosinophilia.350
Patients with acute eosinophilic leukemia have a propensity for developing bronchospastic signs and heart failure from endomyocardial fibrosis. Hepatomegaly and splenomegaly are more common than in other variants of AML.
Response to treatment is about the same as in other types of AML.348
BASOPHILIC AND MAST CELL LEUKEMIA
First described in 1906,351 basophilic differentiation as a feature of AML is a very rare event. Most cases of basophilic leukemia evolve from the chronic phase of CML,352 but de novo acute basophilic leukemia, in which the cells do not contain the Philadelphia chromosome, does occur.353,354,355 and 356 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. Since 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 or genes at the breakpoint on chromosome 9 may influence basophilopoiesis.266
The blood leukocyte count is usually 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 is often necessary to distinguish basophilic from neutrophilic promyelocytes and myelocytes. Immunophenotyping may show myeloid markers and CD9 or CD25. Cells may have granules with ultrastructural features of basophils and mast cells.354 Electron microscopy can be useful in identifying basophilic granules in cases in which none are evident by light microscopy and simulate M0 phenotype. Basophilic leukemia can be confused with promyelocytic leukemia if the basophilic early myelocytes are mistaken for promyelocytes.357 Prolonged clotting time, intravascular coagulation, and hemorrhage are uncommon presenting features in patients with basophilic leukemia, whereas they are very common in promyelocytic leukemia. Urticaria and elevated blood histamine levels occur in patients with basophilic leukemia. 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 disease358 (see Chap. 69). It can be related to a mutation of the C-KIT gene.359 Extensive, apparently, reactive mast cell tissue infiltrations may be provoked by cytokines during the course of acute myelogenous leukemia.360
DIFFERENTIAL DIAGNOSIS
Acute leukemia in infants with Down syndrome should be differentiated from transient myeloproliferative disease (see “Neonatal Myeloproliferation and Leukemia,” above). In adults pseudoleukemia is the term that 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 on inspection of the marrow aspirate or biopsy mimics promyelocytic leukemia.361,362 and 363
In pseudoleukemia the platelet count may be normal; the degree of leukopenia is often more profound [<1000/µl (<1.0 × 109/liter)] than usually seen in AML361,362; promyelocytes contain a prominent paranuclear clear (Golgi) zone not covered with granules; and promyelocytes do not have Auer rods.365,366,367 and 368 Similar reactions have been reported after G-CSF administration.364 In patients suspected of pseudoleukemia, observation for a few days will usually clarify the significance of the marrow appearance, since progressive maturation to segmented neutrophils will normalize the marrow and lead to an increasing blood neutrophil count.
In patients with hypoplastic marrows, careful examination of specimens is required to distinguish among aplastic anemia, hypoplastic acute leukemia,200,201 and 202 and hypoplastic oligoblastic leukemia.369 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. 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.
THERAPY, COURSE, AND PROGNOSIS
DECISION TO TREAT
Most patients with AML should be advised to undergo treatment promptly after diagnosis. Although remission rates are lower in aged 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 can enter sustained remissions. Treatment can be tailored to the decreased tolerance of elderly patients (see “Treatment of Older Patients,” below). Associated problems such as hemorrhagic manifestations, severe anemia, or infections should be treated in parallel. Since remission is necessary to eliminate these associated problems, delays in induction chemotherapy treatments are usually detrimental in the long run.
PREPARATION OF THE PATIENT
Orientation of the patient and the family should give them an understanding of the disease, the treatment planned, and the adverse effects of treatment. For example, the likelihood of alopecia and its duration should be discussed and advice about hair pieces provided. While most patients and their families will be focused upon their new diagnosis of leukemia and the induction chemotherapy treatment phase, most will also want information about prognosis and long-term treatment plans. Because most patients will enter a complete remission, and because some patients can expect to have long-term disease-free survival after completion of their treatment regimen, cautious optimism is appropriate.
Pretreatment laboratory examination should include blood cell counts, cytochemistry, immunophenotyping of leukemic cells, and marrow examination, including cytogenetic analysis, blood chemistry studies, chest x-ray films, electrocardiogram, and determination of partial thromboplastin and prothrombin times. More extensive evaluation of coagulation factors should be made if clotting times are abnormal, if bleeding is exaggerated for the level of the platelet count, or if acute promyelocytic or monocytic leukemia is the phenotype. Early HLA typing is useful so that compatible platelet products can be provided if alloimmunization occurs and for patients who will become marrow transplant candidates. It can also be helpful to perform Herpes simplex virus and cytomegalovirus serotyping. HIV and hepatitis serology is indicated in certain patients, and patients should have a baseline cardiac scan to determine ejection fraction prior to administration of an anthracycline agent.
A tunneled central venous catheter should be placed (see Chap. 20). This access to the circulation facilitates administration of chemotherapy, blood components, antibiotics, and other intravenous fluids and medications and permits sampling blood for analysis without patient discomfort or concern about venous access.375 Meticulous skin care at the catheter exit site is required to minimize tunnel infections.376
Therapy for hyperuricemia is required if (1) the pretreatment uric acid level is greater than 7.0 mg/dl (0.4 mmol/liter), (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 used. Allopurinol can cause allergic dermatitis, and it should not be used if uric acid is under 7 mg/dl, and the total white cell count is under about 20,000/µl (20 × 109/liter), as long as hydration is adequate and urine flow is high (>150 ml/h). The dermatitis appears at a time when antibiotics may be instituted. This concurrence may make it unclear whether the antibiotics can be continued. Thus, allopurinol use should stop after the risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to 7 days).
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 under 500/µl (0.5 × 109/liter). Care of the patient in a single room is advisable to provide privacy during periods of intensive care and severe discomfort and to help decrease the risk of exogenously acquired infection until recovery of the neutrophil count occurs. Unwashed fruits and vegetables and marijuana are also thought to be sources of pathogenic microorganisms and should be prohibited during the neutropenic period [<500/µl (<0.5 × 109/liter)].
REMISSION-INDUCTION THERAPY
PRINCIPLES
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; (2) profound suppression of the leukemic cells to the point that they are inapparent in the marrow aspirate and biopsy is required to permit the restoration of polyclonal hematopoiesis.377
Although these two principles hold in most cases, two deviations from these guidelines are the predisposition of patients with acute promyelocytic leukemia to enter remission despite cellular posttherapy marrows378,379 and the observation that monoclonal hematopoiesis may be present in some cases of AML during remission (see “Results of Treatment”).
CYTOTOXIC REGIMENS
Current standard induction treatment for AML involves drug regimens with two or more agents,380,381 which include an anthracycline or anthraquinone and cytarabine.382,383 and 384 The remission rates with such treatment vary from about 50 to 90 percent in adult subjects (Table 93-5) depending on the composition of the population treated. The two most important variables are age of the patients and the proportion of patients with therapy-induced leukemia or an antecedent clonal hemopathy. A combination of an anthracycline and cytarabine has been the standard induction therapy since the 1960s. A current standard induction regimen is daunorubicin at 45 mg/m2 for 3 days and cytarabine at 100 mg/m2 by continuous infusion for 7 days. Dose or schedule modulation of the anthracycline or cytarabine, addition of other agents such as etoposide, and timed-sequential therapy have represented attempts to improve results above those obtained with standard therapy.385

TABLE 93-5 REMISSION INDUCTION FOR AML—COMBINATION OF CYTOSINE ARABINOSIDE AND ANTHRACYCLINE ANTIBIOTIC

Development of drug resistance is reduced with idarubicin relative to other anthracyclines. Idarubicin does not induce P-glycoprotein expression whereas daunorubicin, doxorubicin, and epirubicin do.386 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 also give improved results over standard-dose daunorubicin. In older adults, mitoxantrone may reduce cardiotoxicity.390 Higher doses of daunorubicin may yield higher complete response rates.387 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.388
High-dose cytarabine does not increase complete remission rates and increases toxicity when compared to conventional doses, especially in older patients. Patients receiving high-dose cytarabine have more leukopenia, thrombocytopenia, gastrointestinal distress, and eye toxicity. Disease-free survival is better, however, than that achieved with standard therapy, leading some to suggest that high-dose therapy be utilized for induction in patients less than 50 years of age.389
Timed, sequential therapy with addition of etoposide may also lead to prolongation of remission duration.391,392,393 and 394 Timed, sequential chemotherapy combining mitoxantrone on days 1 to 3, etoposide on day 8 to 10, and cytarabine on days 1 to 3 and 8 to 10 resulted in a complete remission in 60 percent, but a toxic death in 9 percent of patients so treated. Median disease-free survival was 9 months.393 Other studies have not found benefit after addition of high-dose cytarabine to induction regimens. Because many of the studies of various induction regimens differ in age of patients, inclusion criteria, supportive care, and different doses and scheduling of chemotherapy agents, conclusions regarding superiority of any of these regimens compared with standard regimens is difficult. For these reasons, the practice guidelines for AML, other than promyelocytic leukemia, recommend standard-dose cytarabine plus anthracycline treatment.395 Hematopoietic growth factors used with induction therapy have generally shown no additional benefit.396
Patients who have persistent leukemia after the first course of induction chemotherapy are generally given a second similar course. The outcome is worse if two courses of treatment are required even if a complete remission is achieved. About 40 percent of patients with persistent AML after one course of induction therapy have a complete remission after a second course397 and disease-free survival at 5 years is about 10 percent. The longer the time to remission after the first induction therapy, the shorter the duration of disease-free survival.235,371 High-risk cytogenetic abnormalities, antecedent hematologic disorders, and other poor prognostic factors can be used to assign nonresponders to a “salvage” chemotherapy regimen rather than repeating induction therapy.
SPECIAL CONSIDERATIONS DURING INDUCTION THERAPY
Hyperleukocytosis Patients with blast counts greater than 100,000/µl (100 × 109/liter) require prompt treatment to prevent the most serious complication of hyperleukocytosis, intracranial hemorrhage. Cytoreduction therapy can be initiated with hydroxyurea, 1.5 to 2.5 g, orally, every 6 h (total dose of 6 to 10 g/day) for about 36 h. Simultaneous leukapheresis can decrease blast cell concentration within several hours without contributing to the release of uric acid. Each leukapheresis will decrease the blast concentration by about 30 percent.189 During the first few days of therapy, hydration should be administered to maintain urine flow over 100 ml/h per m2. Furosemide administration can be helpful in enhancing urine flow.
Antibiotic Therapy Pancytopenia is worsened or induced shortly after treatment is instituted. Absolute neutrophil counts under 200/µl (0.2 × 109/liter) are to be expected and are a sign of effective drug action. The patient usually becomes febrile [t > 38°C (100.4°F)], often with associated rigors. Cultures of urine, blood, nasopharynx, and if available, sputum should be obtained. Since the inflammatory response is blunted by severe neutropenia and monocytopenia, evidence of exudates on physical examination or in radiographic studies may be minimal or absent. Antibiotics should be started immediately after cultures are obtained.398 Antibiotic usage in the setting of induction chemotherapy is described in Chap. 17.
Some centers use prophylactic antibacterial, antifungal, and/or antiviral antibiotics whereas others do not. Antifungal prophylaxis can take the form of low-dose amphotericin, fluconazole, or itraconazole.399,400 Acyclovir 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.401 Liposomal amphotericin has less infusion-related toxicity and less nephrotoxicity when used in patients with fever and neutropenia402 but is more expensive to administer than is conventional amphotericin. Some centers are utilizing outpatient supportive therapy immediately after induction therapy in adult AML. Cotrimoxazole, and itraconazole orally until the granulocyte count is over 1,000/µl, and the use of every-other-day platelet transfusions until the count is over 20,000/µl is one approach used.403
HEMATOPOIETIC GROWTH FACTORS
Cytokine therapy as an adjunctive treatment for AML remains controversial.404,405 and 406 While accelerating neutrophil recovery, neither GM-CSF nor G-CSF reproducibly decrease major morbidity or mortality,407 although one study has shown a decrease in mortality from fungal infections in older patients.408 G-CSF and 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 of G-CSF. This can render the cells more sensitive to simultaneous chemotherapy, but clinical benefit from growth factor priming has not been observed408,409 despite an increase of intracellular cytosine arabinoside triphosphate:deoxycytidine-5′-triphosphate ratios and an enhanced cytarabine incorporation into the DNA of AML blasts.409
Use of cytokines during periods of cytopenia following induction therapy is safe, and nearly all trials have shown a modest reduction in the duration of severe neutropenia with a variable effect on the incidence of severe infections, antibiotic usage, and the duration of hospital stays.405 While no increase in relapse has been noted when growth factors are begun after the completion of chemotherapy, there is no consistent enhancement of remission, event-free survival, or overall survival.410 The cost-effectiveness of growth factor usage has therefore come into question.405
The role of megakaryocyte-stimulating cytokines such as thrombopoietin411 or interleukin-11412 is being investigated in AML treatment. Interleukin-11 or keratinocyte growth factor might provide gastrointestinal mucosal protection during AML treatment.413
COMPONENT TRANSFUSION THERAPY
Red cell packs should be used to keep the hematocrit above 25 ml/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 keep the platelet count between 5000/µl (5 × 109/liter) and 10,000/µl (10 × 109/liter).414,415,416 and 417 Patients without complicating coagulation abnormalities, anticoagulant use, sepsis, or other complications usually can maintain hemostasis with platelet counts of 5000 to 10,000/µl (5 to 10 × 109/liter). Initially, random donor platelets can be used, although single-donor platelets or HLA-matched platelets are sometimes preferable products and should be tried if random-donor platelets do not raise the platelet count significantly. Platelets from siblings, parents, or offspring can be tried if available but should be avoided if allogeneic marrow transplantation is contemplated (see Chap. 142).
In patients who are platelet-refractory, platelets should be used sparingly unless bleeding occurs. Use of autologous platelet transfusions that are stored in 5% DMSO in liquid nitrogen and transfused during subsequent marrow aplasia can be used in alloimmunized patients, but this approach is obviously not helpful if needed during remission induction regimens.418 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 in this immunosuppressed population. This step is particularly important if allogeneic marrow transplantation is to be considered. The benefit of using cytomegalovirus-negative blood products as compared to leukodepletion to prevent virus transmission in patients who are not virus carriers is unsettled.419
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 fungal infections, or with septic shock (see Chap. 141). G-CSF administration to a volunteer donor increases neutrophil yield fourfold and results in posttransfusion blood neutrophil increments for more than 24 h after transfusion.420 This may be warranted in the treatment of major fungal infections (see Chap. 17).
Jehovah’s Witnesses or others who refuse blood product support can survive tailored chemotherapy.421 In general, phlebotomy is minimized, and antifibrinolytics, hematinics, and growth factors are utilized to support such patients during severe cytopenias.
THERAPY FOR HYPOFIBRINOGENEMIC HEMORRHAGE
Patients with evidence of intravascular coagulation (see Chap. 126) or exaggerated primary fibrinolysis (see Chap. 136) should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started, or if the findings are equivocal they 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 acute promyelocytic leukemia and acute monocytic leukemia but may also occur in occasional patients with acute myeloblastic leukemia with Auer rods.
MANAGEMENT OF CENTRAL NERVOUS SYSTEM DISEASE
Central nervous system disease occurs in about 1 in 50 cases at presentation.785 Prophylactic therapy is usually not indicated, but examination of the spinal fluid after remission in monocytic subtypes317,318,319 and 320; cases with extramedullary disease; the inv 16,137,138 the t (8;21)141,142 genotypes, CD7- and CD56-positive (neural cell adhesion molecule) immunophenotypes786; or in patients who present with very high blast counts, should be considered. These are situations in which the risk of meningeal leukemia or a brain myeloblastoma is heightened. The treatment of meningeal leukemia can include high-dose cytarabine (which penetrates the blood-brain barrier), intrathecal methotrexate, and cranial radiation in combination.785 Systemic relapse commonly follows relapse in the meninges, and concurrent systemic treatment is usually indicated. Long-term success is unusual unless allogeneic stem cell transplantation can be used.
REMISSION-MAINTENANCE THERAPY
CYTOTOXIC THERAPY
Some form of postremission therapy is necessary to prolong remission duration and overall survival, but there is no consensus on which is best. 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.422 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 prolonged remission (more than 3 years).
Whether AML patients in first remission should receive consolidation chemotherapy alone, autologous transplantation, or allogeneic marrow transplantation has now been studied in several randomized trials with no consensus emerging. 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.423 Disease-free survival was 53 percent at 4 years for those receiving allogeneic marrow; 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 since patients who relapsed after chemotherapy could be rescued with marrow transplantation. No significant difference in the 4-year disease-free survival between allogeneic marrow transplant (42 percent) and other types of intensive postremission therapy (40 percent) has been found.424 A reduction of relapse rate in patients receiving autografts was found in another study, but there was no benefit in disease-free or overall survival.425 In this trial, only 45 percent of patients received the randomly assigned treatments. Thus, in several studies, the early mortality after allogeneic transplantation and the salvageable relapses after autologous marrow transplantation have led to comparable overall survival rates. Autologous transplantation results might be improved by the use of blood stem cells. The mortality after allogeneic transplant in first remission was 43 versus 7 percent for chemotherapy, whereas relapse was less for transplants (24 percent as compared to 63 percent after chemotherapy). Survival was comparable between the groups, but leukemia-free survival was greater after transplantation.426 When quality of life was measured for patients in complete remission for 1 to 7 years, those treated with chemotherapy had the highest perceived quality and those undergoing allogeneic BMT the lowest.427
For patients who do not receive high-dose chemotherapy with autologous or allogeneic transplantation in first remission, consolidation chemotherapy regimens containing high-dose cytarabine provides better results than intermediate-dose cytarabine.428,429 Long-term disease-free survival at 5 years is generally around 30 percent when two to four such cytarabine-containing regimens are administered.430,431 and 432 Most centers utilize four cycles of 3 g/m2 twice daily on days 1, 3, and 5, providing 6 total doses per cycle.432 The optimal number of cycles for this therapy is not known.433 High-dose cytarabine can be administered at a dose of 3 g/m2 in a 1-h intravenous infusion every 12 h for periods up to 6 days (12 doses). High-dose cytarabine frequently causes conjunctivitis and photophobia, and glucocorticoid eye drops are usually used every 6 h until 24 h after the last dose of the drug.434 Cerebellar function abnormalities also may occur, and these require cessation of drug administration. A 1-h duration of infusion of high-dose cytarabine may decrease the likelihood of severe cerebellar toxicity, as may a reduced dose (e.g., 2 g/m2).435 Older patients and patients with renal insufficiency require dose attenuation, e.g., to 2 g/m2.436
Once intensive consolidation chemotherapy has been completed, various forms of less intensive maintenance chemotherapy have been utilized. Many of these regimens consist of monthly chemotherapy; e.g., low-dose 6-thioguanine or cytarabine. While improved disease-free survival is noted in some studies, no improvement in overall survival has been demonstrated in most studies.437 Other forms of maintenance therapy, such as interleukin-2,438,439 interleukin-2 plus histamine,440,441 and 442 and induction chemotherapy drugs used at lower doses443 have also been examined with no definitive benefits on survival reported. Low-dose interleukin-2 alone has not been found beneficial.444 Leukemic dendritic cells generated ex vivo from myelomonocytic AML cells may have a role in maintenance therapy.445,446
The decision to utilize autologous or allogeneic stem cell transplantation or high-dose cytarabine alone for consolidation can be individualized based on patient age and on other prognostic factors such as high-risk cytogenetic findings or antecedent hematologic disease.395 Patients with good-risk cytogenetics should receive four cycles of high-dose cytarabine. Patients with poor-risk cytogenetics should be considered for allogeneic or autologous stem cell transplantation after 1 or 2 cycles of high-dose cytarabine as discussed below.
CHEMORADIOTHERAPY PLUS AUTOLOGOUS STEM CELL INFUSION
Removal and cryopreservation of postremission marrow or collection of mobilized blood stem cells from patients with AML and reinfusion of these following intensive chemotherapy and/or radiotherapy is a form of postremission therapy447,448,449 and 450 (see Chap. 18). Autologous marrow rescue can be used in patients with AML who achieve a remission, do not have a compatible stem cell donor, and are up to 70 years of age, potentially tripling the proportion of patients amenable to this from of treatment, as compared to those patients who meet the donor and age requirements for allogeneic marrow transplantation.
Various preparative regimens for autologous transplantation in AML have been utilized451 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 at 3 years of approximately 40 percent is average after such regimens.452,453,454 and 455 Long-term disease-free survival can occur in patients who undergo this treatment for AML in second remission.456 Patients greater than 50 years of age have inferior outcomes, but no strict upper age limit for this procedure has been determined.457 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 × 108/kg improves disease-free survival.458 Use of marrow grafts purged of residual leukemia cells has not resulted in significantly better results than unpurged marrow in many studies, suggesting that low proportions of leukemic stem cells are extremely difficult to transplant or that they do not survive the freeze-thaw cycle to which autologous marrow is subjected as well as normal stem cells do.459 The possible benefits of marrow purging thus remain controversial (see Chap. 18). Chemotherapy agents such as 4-hydroperoxycyclophosphamide have been utilized for purging, and various antisense agents have also been reported to diminish leukemic cell contamination.460
In long-term cultures from newly diagnosed patients with AML, normal progenitors can be detected and their numbers increased by in vitro culture with cytokines.461 In oligoblastic leukemia (myelodysplasia), secondary AML, and therapy-related AML, leukapheresis products obtained after chemotherapy and growth factor treatments contain normal progenitors,462 indicating that mobilized stem cells may be relatively free of leukemic counterparts even in the absence of ex vivo purging.463 Whether use of mobilized blood versus marrow stem cells will improve long-term outcomes has not been determined.463
CHEMORADIOTHERAPY PLUS ALLOGENEIC STEM CELL TRANSPLANTATION
Patients between ages of approximately 1 to 60 years who have AML and are in remission and who have a histocompatible sibling donor are candidates for stem cell transplantation therapy. The patient is prepared with a regimen that includes total-body irradiation and/or high-dose chemotherapy and thereafter is given the donor stem cells by intravenous infusion. Patients given allogeneic blood stem cells have more rapid hematopoietic reconstitution than those given marrow stem cells.464 Chapter 18 describes the indications, procedure, and preparative regimens for stem cell transplantation.
Disease-free remission after 4 years is about 53 percent.465 Small series utilizing T-cell depletion have reported 4-year disease-free survival of 65 percent.466 Leukemia relapses occur in about 20 percent of patients who receive an allogeneic transplant.465,467 Patients who are alive with good performance status 3 to 4 years after transplant have excellent prospects of long-term survival.468 In the posttransplant period about one-third of patients die of severe graft-versus-host disease, 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 it is uncertain whether marrow transplantation provides an advantage in overall survival at 3 years.464,465,466,467,468,469,470 and 471
About 65 percent of all patients with AML are over 50 years of age, and the current mean family size in the United States is slightly over two children per family. Thus, only about 10 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 by using histocompatible, unrelated donors or HLA-type-mismatched sibling or parent donors is being studied.472,473 Molecular matching of class I and class II HLA alleles adds to the clinical success of unrelated donor transplants but makes finding a donor more difficult.474 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 graft-versus-host disease. Infectious complications were high, however.473 HLA-matched or -mismatched cord blood stem cells can be used in adults with acute leukemia, but generally not for those in first remission.475
Some form of allograft is usually recommended for patients in early first relapse or second remission, since long-term survival with chemotherapy alone is improbable, whereas histocompatible sibling transplants have a 25 percent survival rate.476 However, in one study, 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 less than 30 years of age and in remission for at least 1 year fared best.477 Patients with extramedullary sites of leukemia are more likely to have extramedullary sites of relapse after allogeneic bone marrow transplantation.478
In an attempt to decrease the relapse rate after marrow 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 utilized. Nine out of 13 patients with AML were disease-free at 8 to 41 months after transplant. With this regimen, more radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.479
Patients with AML who relapse after allogeneic marrow transplantation can have a long-term remission if retransplanted.480,481,482 and 483 The mechanism of benefit of marrow transplantation was thought to be the result of high-dose ablative chemoradiotherapy preparatory to marrow “rescue.” The increased relapse rate of AML in patients transplanted with marrow from identical twins, as compared to nonidentical siblings, or transplanted with T-lymphocyte-depleted marrow has indicated that an immunologic effect of donor lymphocytes may determine the results of transplantation. This immunologic reaction, referred to as graft-versus-leukemia, may play a role in preventing leukemia relapses.470,484
In an attempt to enhance graft-versus-leukemia effects, adoptive immunotherapy with donor mononuclear cell infusions is sometimes utilized to treat relapse of leukemia after allografting.485 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 transplants, these infusions are a reasonable approach for relapsed AML after allogeneic transplant. Graft-versus-host disease and marrow aplasia are the major complications of this form of treatment.486 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.487 Donor blood stem cells can also be combined with chemotherapy for early relapse of AML after allogeneic stem cell transplantation.488
Interleukin-2 has been used to modulate natural killer and T-cell activity after both autologous and allogeneic transplantation. It is too early to determine efficacy of this approach.489 Minor histocompatibility antigens restricted to hematopoietic cells are an ideal target for antileukemic immune responses. It may be possible to modify leukemic cells to express costimulatory molecules identical to professional antigen-presenting cells to generate cytotoxic T-lymphocyte responses against myeloid leukemia cells.490 Irradiated B7.1-transduced primary AML cells can be used as therapeutic vaccines in murine AML.491 B7.1 is the ligand for the T-cell costimulatory molecules CD28 and CTLA-4. Dendritic cells derived in vitro from AML cells may also be utilized to stimulate leukemia-specific cytolytic activity in autologous or allogeneic lymphocytes.446
The recurrence of AML in donor cells has been reported in patients who have received marrow transplants from healthy siblings. These recurrences in donor cells occurred in about 1 in 18 relapsed patients who received marrow from a donor of the opposite sex.491 There is a similar frequency of relapsed AML in recipient cells but with a different clonal cytogenetic abnormality, suggesting a “new” leukemia.491 These frequencies are dependent on the sensitivity and specificity of cytogenetic techniques, which have been challenged.492 AML developing in a stem cell recipient but of donor cell origin long after transplant has been documented in rare cases.372
TREATMENT OF RELAPSED OR REFRACTORY PATIENTS
Patients who relapse after remission-induction and remission-maintenance therapy have a decreased probability of entering a subsequent remission, and the duration of remission is shorter if it occurs. 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. One regimen includes high-dose cytosine arabinoside without or with another agent such as mitoxantrone,494 amsacrine,495 or etoposide.496 Other salvage chemotherapy regimens are illustrated in Table 93-6.

TABLE 93-6 EXAMPLES OF CHEMOTHERAPY USED FOR RELAPSED OR REFRACTORY PATIENTS

Refractory disease is defined as that which does not respond to initial induction chemotherapy with cytarabine and an anthracycline antibiotic. Patients with refractory disease are more likely to have disease with adverse cytogenetic findings, a history of antecedent hematologic disturbance, adverse immunophenotypic features, and expression of multidrug resistance.508,509 Relapsed leukemia is that which recurs following a remission. The duration of remission greatly affects the patient’s prognosis and response to additional treatment. The wide range in response rates noted may not only reflect the regimen used but may also reflect variability in patient selection, age, and other prognostic factors.510,511 and 512 Chemotherapy regimens can be divided into cytarabine-based, non-cytarabine-based, and timed, sequential therapy with growth factors and cytotoxic drugs. Despite the response rates shown in Table 93-6, the duration of response is usually only 3 to 6 months. Chemomodulation with drugs designed to overcome multidrug resistance, such as the cyclosporine analog PSC-833, is under study; the use of the latter agent necessitates a two-thirds reduction in mitoxantrone and etoposide doses.513
Homoharringtonine, an alkaloid derived from the bark of the Chinese evergreen tree and administered by continuous infusion daily for up to 9 days in a dose of 5 mg/m2, has shown effectiveness in de novo, relapsed, or refractory AML.514,515 Aclacinomycin, an anthracycline antibiotic, has been used successfully in patients with AML516; 2-chlorodeoxyadenosine has been found to be active against AML blast cells but is generally not an improvement over existing modalities.517 Interleukin-2 has been effective in decreasing leukemia cells in the marrow when given in a relatively high dose (e.g., 6 to 8 million units/m2 intravenously for 5 days). Occasional complete remissions after IL-2 alone have been observed in refractory patients.518,519 These successes have occurred in cases of early limited relapsed disease (greater than 5 but less than 30 percent blast cells).520
Results from second remission-induction therapy are better in younger patients, those with longer remissions, longer durations since last chemotherapy, and better general health. The probability of a second remission is about 50 percent in younger subjects (15 to 60 years of age) and about 25 percent in older patients (60 to 80 years of age), but the duration of remission is nearly always much shorter than the first remission, and an eventual fatal outcome is nearly certain. Rare patients may have a third (or more) relapse followed by a remission when treated with cytotoxic drugs, but each remission is shorter than the preceding one and is usually measured in weeks.
Marrow transplantation may be the only means to induce a sustained remission in patients with AML who do not enter remission with cytotoxic drug therapy or who relapse after a first remission. About 25 percent of patients with refractory or relapsed AML have a sustained remission of at least 3 years.521,522 and 523 Transplant-related mortality at 3 years is about 50 percent, and relapse rates are higher after sibling than matched unrelated transplantation.524 If a histocompatible donor is available and the patient is under 50 years of age, marrow transplantation can be as successful if performed at the time of early relapse.521,522
NEW TREATMENT MODALITIES
CHEMOTHERAPY
Oral idarubicin can be used in AML when intravenous anthracycline treatment is precluded. Myelosuppression, nausea, vomiting, diarrhea, and mucositis have occurred, but cardiotoxicity has been minimal.525
Decitabine, a potent hypomethylating agent, can result in maturation and growth arrest of AML cells. It may have synergism with interferons and retinoids. It has effects as a single salvage agent and has resulted in response rates of 30 to 50 percent in combination with anthracyclines.526
GROWTH FACTORS AND RECEPTOR TARGETS
GM-CSF, G-CSF, and IL-3 have been used concurrently with chemotherapy regimens. GM-CSF increases white blood count and blast cell percentage with no constant increase in cells in S-phase. No correlation with in vivo treatment results is usually noted.527 A ricin fusion toxin attached to human GM-CSF has been found to be selectively toxic to AML cells.528 A diphtheria toxin and GM-CSF fusion protein is toxic to AML progenitors.529 GM-CSF can alter the cellular metabolism of cytarabine and fludarabine in AML patients.530
Transforming growth factor beta and dexamethasone enhance c-JUN gene expression and inhibit the growth of human monocytic leukemia cells.531 Recombinant human interferons may induce the differentiation of acute megakaryoblastic leukemia blast cells.532 Interleukin-1 and its inhibitors have also been found to have anti-leukemic effects.533 Interleukin-6 can induce improvement in smoldering relapsed AML.534
ANTIBODIES TO CD33
Antibodies to the myeloid differentiation antigen, CD33, may have a role in treatment after tumor burden has been reduced by chemotherapy.535 CD33 antibodies have been conjugated to calicheamicin or have been labeled with 131I. Humanized CD33 antibodies have been infused in relapsed or refractory AML patients and some antileukemic activity observed, and no immune neutralization of the CD33 antibodies has been observed.536,537 and 538
MATURATION THERAPIES
A stable benzoic derivative of retinoic acid has been found to induce maturation of promyelocytic leukemic cells. It is 10- to 100-fold more potent than all-trans-retinoic acid (ATRA).539 Several analogs of vitamin D inhibit AML cells by inducing inhibition of cyclin-dependent kinases.540 WAF-1 is also induced by vitamin D analogs, and, when combined with retinoids, maturation of leukemic cells is observed.541 In general, AML cells have not responded to retinoids. Single-strand conformational polymorphism analysis and DNA sequencing of leukemic cells from nonpromyelocytic AML did not find mutations of RARa.542 Combinations of retinoids, growth factors, and chemotherapeutic agents are being examined for therapeutic potential in AML.543 Leukemias with 11q, -5, and -7 chromosome abnormalities have high telomerase activity, and this activity can be inhibited by maturation-inducing agents.544
OTHER APPROACHES
Phosphorothioate antisense oligonucleotides against multidrug resistance genes545; anti-Fas antibodies to mediate apoptosis546,547; and 67-gallium548 inhibit AML cells in vitro. Other antileukemic vaccine strategies have also been proposed.373,549 In addition, other surface antigen550 or transcription signal transduction molecules may serve as therapeutic targets.551,552 and 553
SPECIAL THERAPEUTIC CONSIDERATIONS
ACUTE PROMYELOCYTIC LEUKEMIA
All-trans-Retinoic Acid ATRA, an analogue of vitamin A, has been used to initiate the therapy of acute promyelocytic leukemia since 1987. The drug is administered in a total dose of 25 mg/m2 to 45 mg/m2 per day given in two doses orally, with the lower doses equally as effective and less toxic.554 This drug induces complete remissions in about 80 percent of previously untreated patients.555,556,557,558 and 559 In vitro, ATRA is ten times more potent in inducing maturation of leukemic promyelocytes to neutrophils than 13-cis-retinoic acid, the other naturally occurring isomer.560 ATRA induces maturation of the leukemic cells and the suppression of the malignant clone, resulting in a switch in most cases to polyclonal hematopoiesis and a remission.555,561,562 and 563 ATRA may induce synthesis of a protein that selectively degrades PML-RARa, and interferons may regulate PML-RARa expression.564 Signal transducer and activator of transcription factor STAT-1 is induced and activated by ATRA. As a consequence of elevated amounts of corresponding transcripts, ATRA is capable of modulating the amounts and the state of activation of some of the components of the IFN intracellular signaling pathways.563 Promyelocytic leukemia cells with PML-RARa break/fusion sites in PML exon 6 have decreased in vitro responsiveness to ATRA. The t(11;17) variant of APML in which the promyelocytic leukemia zinc finger (PLZF) gene is fused to RARa566 does not respond to ATRA but does mature in the presence of G-CSF.567 Other types of AML have not been responsive to ATRA therapy.
Toxic Effects of ATRA ATRA therapy is associated with dryness of the skin and lips, occasionally leading to mild exfoliation, nausea, headache, arthralgias, and bone pain. The white cell count may rise dramatically in the first week or two of therapy. Serum glutamic-pyruvate transaminase and triglyceride concentrations often increase. Leukemic promyelocytes disappear from the blood in 2 to 4 weeks, and a normal marrow aspirate may be obtained in from 4 to 10 weeks. Anemia improves gradually. The majority of patients become PML-RARa negative by PCR after the second consolidation therapy in conjunction with ATRA.568 ATRA has been used successfully to treat promyelocytic leukemia diagnosed during pregnancy.569
A rapid increase in the total blood leukocyte count to as high as 80,000/µl (80 × 109/liter) in the first several weeks of therapy, referred to as the “retinoic acid syndrome,” is a potential cause of early death during therapy.374 Two approaches have been suggested to treat this phenomenon: early use of cytotoxic chemotherapy570 and glucocorticoid administration.571 The syndrome consists of fever, weight gain, dependent edema, pleural or pericardial effusion, and bouts of hypotension. Respiratory distress is the key feature, and in fatal cases pulmonary interstitial infiltration with maturing granulocytes is prominent. Once respiratory distress is evident, the patient should receive dexamethasone, 10 mg, intravenously every 12 h for several days.571 Since the syndrome may occur at relatively low total white cell counts and its onset is unpredictable, high-dose glucocorticoid therapy should be instituted if respiratory symptoms develop even in the absence of pulmonary infiltrates or an elevated white cell count.572
Treatment of the Coagulopathy The risk of early death from hemorrhage as a result of the coagulopathy that accompanies acute promyelocytic leukemia requires use of fresh-frozen plasma and platelet replacement and antifibrinolytic agents.303,304 Heparin treatment was often utilized during induction chemotherapy in the past to prevent onset of disseminated intravascular coagulopathy during treatments, but this is now rarely used.573 ATRA may have some corrective effect on coagulation disorders in promyelocytic leukemia. The coagulation abnormalities are due either to release of procoagulant activity, primary fibrinogenolysis, or both mediated by the release of leukocyte proteases. Increased thrombin-antithrombin III complexes, prothrombin fragments 1+2, and D-dimer complexes are seen, but no factor V, AT III, or protein C consumption occurs. With ATRA treatment, more pronounced procoagulant effects versus lytic effects303,574 may be seen. Abnormally high levels of expression of annexin II on leukemic cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications. Expression of RNA for annexin II disappears after treatment with ATRA.575 Paradoxcially, hypercoagulable clotting tendency may occur in patients during the first months of ATRA therapy.561
Chemotherapy Induction of remission with ATRA is followed by relapse in weeks to months unless intensive chemotherapy is used.378,557,558 At relapse, cells show high levels of a cytosolic retinoic-acid-binding protein not detected prior to ATRA therapy.564 Mechanisms of retinoid resistance in leukemic cells may also involve cytochrome P450 and P glycoprotein due to induction of various P450 enzymes which may alter ATRA metabolism.576 Chemotherapy with daunorubicin plus cytarabine has produced relatively good results when used as remission-induction therapy. Remission induction with mitoxantrone and high-dose cytarabine or mitoxantrone, etoposide, and high-dose cytarabine may be more effective.556 Treatment without cytarabine permits administration of more anthracycline antibiotic.577 Idarubicin, 12 mg/m2, for 4 days with 45 mg/m2 of ATRA followed by two more courses of idarubicin for 3 days achieved a remission rate of 77 percent, comparable to standard regimens.577 Patients randomized to receive ATRA alone or conventional daunorubicin and cytarabine as induction therapy followed by two cycles of consolidation chemotherapy with a later randomization either to ATRA maintenance or no further treatment had equivalent results and equivalent treatment mortality rates.578 ATRA, whether administered as part of induction therapy or as maintenance therapy appeared to confer a disease-free survival advantage; more than 70 percent of patients receiving ATRA at any point were in continuous remission at 2.5 years versus less than 20 percent of patients who never received ATRA.578 Cure rates have increased from 30 percent to above 50 percent since introduction of the use of ATRA. Acquired in vivo resistance to ATRA requires consolidation of ATRA-induced complete remission with intensive chemotherapy. Maintenance therapy has not been tested in randomized trials.
Age, hemorrhagic diathesis, and initial leukocyte count are prognostic factors for patients treated with ATRA followed by intensive chemotherapy.581 Secondary cytogenetic changes do not confer a poor prognosis in patients treated with an anthracycline and cytarabine. There is a relationship between PML-RARa S isoform and secondary cytogenetic changes. These secondary chromosome changes have been seen in 30 percent to 85 percent of newly diagnosed patients.582
Arsenic Trioxide For patients who relapse, arsenic trioxide (AsO3) can be useful (see ref. 787). AsO3 can trigger apoptosis of promyelocytic leukemia cells at high concentrations and maturation at low concentrations. The presence of PML-RARa is important for the response.579 The apoptosis effect may occur through induction of the expression of proenzymes of caspases 2 and 3 and activation of caspases 1 and 3.580 AsO3, 0.06 to 0.12 mg/kg body weight per day until leukemic cells were eliminated from the marrow, induced remission of 12 to 89 days in 11 of 12 patients.580 Marrow depression did not occur. Rash, lightheadedness, fatigue, and musculoskeletal pain were the main side effects. Conventional chemotherapy is effective after relapse, and patients under age 60 should be considered for allogeneic or autologous transplantation after achieving a second remission or for allogeneic transplantation if a second remission cannot be induced. Transplantation is generally not recommended in first remission for patients with promyelocytic leukemia.
SECONDARY LEUKEMIA
Secondary leukemias arise after a myelodysplastic syndrome or after previous diagnosis and treatment of another malignancy with cytotoxic chemotherapy or radiation. In general, secondary AML has a poorer prognosis than does de novo AML and responds more poorly to chemotherapy and transplantation. Secondary AML accounts for about 15 percent of all AML cases, and this percentage is probably increasing.583,584 Exposure to topoisomerase II inhibitors can lead to AML with 11q32 rearrangement. Ten of 12 patients with 11q32 rearrangements with secondary leukemia had topoisomerase II exposure, and 9 of those were found to have MLL gene rearrangements on chromosome 11 as seen in de novo AML with 11q32 rearrangement.585 Patients with secondary leukemia without topoisomerase II inhibitor exposure do not have MLL rearrangements. Inversion 16 is an uncommon aberration in secondary AML and, like balanced translocations of chromosome bands 11q32, 21q22, and t(15;17), is associated with prior chemotherapy with topoisomerase II inhibitors when they are seen in the setting of treatment-induced leukemias. Breakpoints within the MYH11 gene involved in inversion 16 may vary between therapy-induced AML and AML de novo.586 The latency period with topoisomerase II inhibitors is about 2 years. No relationship with higher cumulative dose or a genetic predisposition has been identified.587 Even the use of low-dose or oral etoposide can be associated with the development of secondary AML.
Alkylating agents cause secondary AML characterized by antecedent myelodysplasia, after a mean latency period of about 6 years and usually with deletion of all or part of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline aberrancies of NF-1 and p53 may increase the risk. Cisplatin used in the treatment of ovarian cancer also increases the risk of secondary leukemia.588
Secondary leukemia is also seen after autologous marrow or blood stem cell transplants which involve high-dose chemotherapy and/or radiotherapy. In a study of 83 patients after autografting, 12 had nonclonal cytogenetic abnormalities and 10 had clonal abnormalities, 5 of whom developed secondary AML. Onset was 12 to 48 months after autografting. The relative contribution of the underlying disease and conditioning therapy is uncertain.589 Analysis of the human androgen receptor locus in cell samples in patients with lymphoma after autologous transplantation found a clonal marrow cell population 6 months after transplant at a time when there was no morphologic or clinical evidence of AML; AML appeared later in some patients.590
Secondary leukemia is generally treated akin to de novo leukemia, but given its lower response rates and remission durations, patients can be treated in clinical trials examining new therapies or treated initially with alternative salvage chemotherapy regimens.591,592,593 and 594
TREATMENT OF OLDER PATIENTS
About 60 percent of patients with AML are over 60 years of age at the time of diagnosis.595 The disease in this age group is less responsive to therapy, and this age group has a higher proportion of patients who have oligoblastic leukemia (myelodysplasia); an antecedent clonal myeloid disease; prior chemotherapy for cancer of the breast, ovary, or another site and comorbid conditions, which decrease the tolerance to intensive chemotherapy programs. The AML cells of elderly patients often have more CD34+ expression, suggesting origin from a more primitive multipotential stem cell. This is thought to contribute to longer duration of postchemotherapy aplasia and to the increased risk of induction deaths in this age group.596 Patients over 55 years of age also have a high frequency of unfavorable cytogenetic findings (32 percent) and higher MDR1 expression (71 percent) and functional drug efflux (58 percent).597
The therapist and patient determine whether a standard regimen, a standard regimen with dose reductions, or a special regimen is used.598,599,600 and 601 In patients over 60 years of age who are fit and are otherwise considered to be good candidates, standard two-drug therapy can be used. Remission rates of approximately 30 percent can be achieved, whereas in those who are chronically ill or have other reasons for being intolerant to standard therapy, low-dose cytarabine, 10 mg/m2, subcutaneously or as a short infusion every 12 h daily for 14 to 28 days, can be used.602,603,604,605,606 and 607 If necessary the cycle can be repeated after about 3 weeks or an attenuated standard regimen can be used. An example of an attenuated regimen is cytarabine, 100 mg/m2, subcutaneously every 12 h for 10 doses on days 1 through 5, daunorubicin, 30 mg/m2, intravenously on days 1 through 3 of treatment. In previously untreated elderly patients with AML, mitoxantrone induction therapy produces a slightly higher remission rate than does daunorubicin, but it has no significant effect on remission duration and survival.608,609 In a prospective randomized trial of idarubicin compared to daunorubicin in combination chemotherapy for AML in those 55 to 65, idarubicin resulted in higher remission rates.610 Oral idarubicin alone has also been used with success.604
There is no consensus about the best regimen or the number of treatment cycles for postremission therapy in older adults. Regardless of the consolidation regimen, the duration of the leukemia-free survival is longer with high-dose cytarabine and autologous stem cell transplantation just as it is in other patients,611 but the percentage of patients able to tolerate this therapy is less. High-dose cytarabine can be used in older adults with AML, but usually at a reduced dose.612 Older patients treated with attenuated high-dose cytarabine at 750 mg/m2 intravenously for 12 doses and then consolidated with 4 to 6 doses had about a 50 percent remission rate with a median duration of remission of 326 days.613 Fifty-one percent of 110 patients greater than 60 years old had a 9-month median remission duration when consolidated with high-dose cytarabine.614 The elderly are at higher risk of relapse despite successfully completing intensive consolidation therapy, regardless of whether other adverse prognostic features were present. Others have reported that cytarabine in maintenance therapy may prolong disease-free survival, but it does not improve overall survival.615
Patients over 80 years of age do not tolerate treatments well; remission rates are about 30 percent, but the median survival of treated patients is about 1 month. Less than 10 percent survive for 1 year.616
Treatment options in the elderly range therefore from no treatment to supportive care to palliative low-dose chemotherapy to attentuated induction chemotherapy designed for older patients to high-dose chemotherapy regimens used in younger patients. AML in the elderly generally has an adverse karyotypic and phenotypic presentation in a patient who has a reduced ability to withstand aggressive chemotherapy regimens. The Medical Research Council of the United Kingdom observed remission rates of 80 percent in children, 70 percent in adults under 50, 68 percent in those 50 to 59, 53 percent in those 60 to 69, 39 percent in those 70 to 75, and 22 percent in those over 75 years old.617 Remissions, therefore, occur in elderly patients and can occassionally be longer than 12 months. Lower-dose regimens are toxic, also, and can lead to severe cytopenias. The use of colony-stimulating factors permit more elderly patients to tolerate full-dose induction therapy.408,618,619 In the 15 percent of older patients who remain free of leukemia beyond a year, quality of life is usually good.620
TREATMENT OF PREGNANT PATIENTS
Leukemia (AML, ALL, CML) is the second most common malignancy of women in the childbearing age group621 and can be expected to occur in about 1 in 75,000 pregnancies.622 There has been no systematic study of the effects of leukemia on pregnancy or delivery, the effects of the leukemia or its treatment on the fetus, or the postnatal development of the offspring exposed in utero to maternal chemotherapy. Folic acid inhibitors, purine analogues, or pyrimidine analogues given during the first trimester of pregnancy will increase the probability of major congenital malformations.623 Interruption of the pregnancy may be required to provide the patient with intensive therapy. Intensive chemotherapy given to women in the second and third trimesters of pregnancy does not present an inordinate risk to fetal or neonatal development,624,625,626,627,628,629,630 and 631 although there is an increase in premature delivery, a higher perinatal mortality, and a lower birth weight for gestational age, especially if the fetus is exposed to chemotherapy. Development of the newborn seems to be normal, however.628,630 Newborn infants may be cytopenic transiently if the mother is receiving chemotherapy at the time of delivery. Vaginal delivery should be used whenever possible. Although pregnant women with AML who enter remission have little difficulty with childbirth or postparturition, relapse of AML and maternal death are usual. Leukemic infiltrates can be found on the maternal side of the placenta but usually not in the villi.632 One case of maternal-to-fetal transmission of AML has been documented.633 Leukapheresis has been employed to treat AML during pregnancy and might be useful in the first trimester,634 when chemotherapy poses a high risk to the embryo. ATRA has been used successfully to treat promyelocytic leukemia during pregnancy.635
TREATMENT OF CHILDREN
Intensive treatment of patients less than 17 years of age—including remission-induction therapy with cytarabine and daunomycin or doxorubicin, followed by intensive multidrug consolidation and continuation therapy including daunorubicin, cytarabine, 6-thioguanine, etoposide, and intrathecal cytosine arabinoside—has resulted in remission in about 75 percent of children and 3-year relapse-free remissions in about 35 percent of treated children.636,637,638,639 and 640 Somewhat better long-term results have also been reported.641 As in adults, duration of first remission predicts remission rate and long-term survival in children with relapse.642 Monocytic leukemia and hyperleukocytic [>100,000/µl (>100 × 109/liter)] myelogenous leukemia account for most of the 15 percent of children who either have early deaths from hemorrhage or other causes or present with extramedullary disease and relapse after induction therapy.636,637,643 Children under the age of 2 years have a poor prognosis when treated with chemotherapy and should be considered for marrow transplantation, if an appropriate donor is available.644 Relapse rates have been found to be high when children are transplanted at less than 2 years of age. Growth failure and endocrine deficiences are common.645 Long-term remission in infants can occur after marrow transplantation.646
NONHEMATOPOIETIC ADVERSE EFFECTS OF TREATMENT
SKIN RASHES
Over 50 percent of patients with AML develop skin lesions during remission-induction or remission-consolidation therapy. The rash may be on the trunk and extremities and is usually maculopapular initially but can become hemorrhagic in the patient who has thrombocytopenia. Allopurinol, trimethoprim-sulfamethoxazole, and other beta-lactam antibiotics are commonly implicated causes. The use of multiple drugs enhances the reactivity of patients.647 Cytostatic therapy coupled with the effects of leukemia predisposes patients to an increased frequency of allergic dermatitis.
CARDIAC TOXICITY
Cardiomyopathy occurs in some patients after exposure to the anthracycline antibiotics, daunorubicin, or doxorubicin and is discussed further in Chap. 16. The frequency is a function of the dose used and can reach 10 to 20 percent if between 550 mg/m2 and 700 mg/m2 of doxorubicin is administered.648,649 and 650 Measurement of the ejection fraction can assist in assessing the risk of proceeding with anthracycline treatment.650 Since most patients receive total doses of anthracycline below toxic levels, cardiac toxicity has become infrequent. Dexrazoxane may reduce the cardiotoxicity when combined with anthracycline antibiotics.388
HEPATITIS
Persistent elevation in serum transaminases occurring after initiation of chemotherapy in patients with AML is usually the result of blood transfusion-transmitted hepatitis C. Hepatitis caused by type A virus is nearly nonexistent early in the course of AML. Cases of type B can occur infrequently. Hepatitis may occur in multiply transfused patients and is usually mild, but persistent hepatitis can develop. Liver biopsy findings do not show fibrosis or bridging necrosis.651 Screening blood for hepatitis virus C has markedly decreased this risk.
SYSTEMIC CANDIDIASIS SYNDROME
Although microbial sepsis is a common complication of the treatment of AML, the chronic systemic candidiasis syndrome has become of special concern.652,653 and 654 The syndrome is manifested by fever, abdominal pain, and hepatomegaly. Neutrophilia and increased serum alkaline phosphatase activity are often noted. Abdominal computed tomography shows characteristic hepatic lesions: circular areas of decreased attenuation of liver and often spleen, kidney, lung, or paraspinal muscles. Ultrasound reveals multiple hypoechogenic areas with a bull’s-eye appearance. Laparoscopic-guided liver biopsy reveals yellow nodules on the liver surface, which on microscopic examination are large granulomas with Candida and pseudohyphae. Cure of this infection is possible with long-term (2 to 10 months) amphotericin B, supplemented by fluconazole or itraconazole.654,655
NEUTROPENIC TYPHLITIS
Necrotizing inflammation of the cecum with secondary infection can occur in patients with acute leukemia on intensive chemotherapy. The diagnosis can be confirmed by sonography in which a characteristic mucosal thickening and polypoid appearance is evident.656 Management includes bowel rest, nasogastric suction, parenteral nutrition, and antibiotics. In the absence of resolution, surgical excision should be considered.657
THROMBOTIC THROMBOCYTOPENIC PURPURA
This syndrome has been reported in patients with solid tumors treated with cisplatin, bleomycin, vinca alkaloids, or mitomycin C and has been reported in patients in remission of AML during consolidation chemotherapy658 (see Chap. 51).
FERTILITY AND GONADAL FUNCTION
Women in remission following treatment for AML can be fertile and can become pregnant and deliver healthy infants.659,660 and 661 Histologic studies of the testes show marked suppression of spermatogenesis as a function of duration of treatment for AML and not of the specific agents used or the age of the patient. Residual spermatogenesis in intensively treated patients makes possible the recovery of reproductive function in males.662 Males receiving intensive daunorubicin, cytosine arabinoside, or 6-thioguanine treatment for AML have conceived children during their therapy.663 Banking of sperm can be attempted before institution of cytotoxic therapy but is often not logistically possible or successful in males with AML who are often febrile and acutely ill at presentation.
COURSE AND PROGNOSIS
RESULTS OF TREATMENT
Prior to the introduction of chemotherapy for AML 40 years ago, the median survival of patients was about 6 weeks,664 the 1-year survival was about 3 percent, and longer survival occurred in less than 1 percent of patients. Initial remission rates now approach 90 percent in children, 70 percent in young adults, 50 percent in middle-aged subjects, and 25 percent in the elderly.665,666,667,668,669,670 and 671 Median survival time has increased to about 12 months, and of those patients who enter remission, about 30 percent are alive at 24 months and about 10 percent 60 months after remission induction.665,666,667,668,669,670,671,672 and 673 Somewhat better survival has been reported for patients who have received allogeneic marrow transplantation in first remission, but the confidence limits for remission duration and survival are widely overlapping for drug-treated and drug- and transplantation-treated groups.674,675,676,677 and 678
CLONAL REMISSIONS
A small proportion of patients who enter remission have their apparently normal hematopoiesis supported by a single clone rather than the expected polyclonal hematopoiesis.679,680,681,682,683 and 684 Evidence points to this clone being a preleukemic cell rather than a normal stem cell.679,680,681,682,683,684 and 685 This finding is in keeping with previous hypotheses about the possible patterns of remission and relapse in AML686,687 and 688 and has implications for minimal residual disease detection (see below).
SPONTANEOUS REMISSIONS
Spontaneous disappearance of AML has been reported for over 100 years, although most cases before 1960 had poor documentation of the diagnosis. Bona fide cases of AML that entered complete remission, usually after or concurrent with an infection, do occur but are very rare.689,690 and 691 The occurrence of spontaneous remission with infection is consistent with the observation that the antibody response to Pseudomonas vaccine692 has been correlated with improved probability of chemotherapy-induced remission. Spontaneous remissions are often short-lived but have lasted up to 3 years in adults and over 9 years in children.693 A particularly notable case of remission of over 60 years has been documented following “treatment” prior to the introduction of chemotherapeutic drugs. The regimen included arsenic.694
LONG-TERM SURVIVAL
About 10 percent of adults treated with chemotherapy between the ages of 15 and 60 remain in sustained remission for over 5 years.692,693 Five-year survival in childhood AML with intensive chemotherapy is projected to be over 60 percent of those treated with intensive chemotherapy and about 70 percent of those who enter remission.695 Studies of the full age range (0 to over 80 years) have reported about a 20 percent 5-year relapse-free survival.696
Relapse (or a new leukemic event) in long-term survivors has been reported as late as 8 years after remission in adults693,694 and over 16 years in children.695 Relapse in long-term survivors is nearly always in the marrow in adults and usually in the marrow in children, with occasional childhood cases of central nervous system or gonadal relapses initially, followed by relapse in the marrow.696 Studies of long-term survivors of AML have shown that most are able to return to work and that at a median follow-up of 9 years, no increased risk of secondary invasive cancer has occurred.697,698
FEATURES INFLUENCING OUTCOME OF THERAPY IN ACUTE MYELOGENOUS LEUKEMIA
Numerous features have been found to relate to outcome of treatment in AML.699 It is often difficult, even with multivariate analysis, to dissect which features are themselves important or are associations that segregate with another prognostic factor (see Table 93-7).

TABLE 93-7 PROGNOSTIC FACTORS IN ACUTE MYELOGENOUS LEUKEMIA

Determining useful prognostic variables in patients with AML is imprecise because negative prognostic factors are being eliminated by better treatment protocols. Moreover, several prognostic factors are significant only when AML is stratified by age or by morphologic phenotype. Conflicting findings are common among studies. In addition, although a prognostic variable may be correlated significantly with a more or less favorable outcome, the lack of a very strong statistical correlation with the outcome of treatment makes its presence or absence of little prognostic value in an individual patient. If a stem cell donor is available, unfavorable prognostic factors could influence the therapist to use allogeneic stem cell transplantation as a means of remission maintenance in patients who enter remission.753 The impact of prognostic factors may change in relationship to treatment with allogeneic stem cell transplantation.754,755
DETECTION OF MINIMAL RESIDUAL DISEASE
General Considerations The tumor cell burden in acute leukemia is about 1 trillion (1012) cells. Apparent marrow aplasia can be induced following chemotherapy with a 2- to 3-log reduction in cell number, which represents a residual tumor cell burden of 1 to 10 billion cells. Intensification therapy is intended to decrease the residual cell numbers further. With the advent of specific monoclonal antibodies for leukemic cell antigens and fluorescent in situ hybridization coupled with flow cytometry and DNA amplification by polymerase chain reaction, residual cell populations below the 10 billion cells detectable by light microscopy of stained marrow films can be quantified.756,757 Sampling remains an important problem, since a marrow aspiration contains about one ten-thousandth of the marrow cell population, and variation among sites of aspiration is well-documented. In addition the markers of the leukemic cell used for detection can change over time during the disease. Persistence of circulating cells containing t(8;21) in patients with AML in long-term remission, for example, has been established using PCR.758
Routine marrow examinations are not needed in the great majority of AML patients in first complete remission.759 Routine cytogenetic follow-up is also not usually helpful. Emergence of a karyotypically unrelated clone of de novo AML, especially chromosome 7, can occur.687 Studies using multiparameter flow cytometry to identify leukemic cells by aberrant antigen expression have a high positive predictive value with regard to the incidence of relapse.760 Detection of residual disease in AML patients by use of double immunologic marker analysis for terminal deoxnucleotidyl transferase and myeloid markers can be useful, since expressions of these two markers are expressed on leukemic cells in the majority of patients with AML. These findings are rare in normal marrow cells.761,762 In other cases, aberrant combinations of surface antigens761,763 or increased expression of various surface antigens such as CD34 are seen.764 Other methods to detect minimal residual disease include: magnetic resonance imaging; fluorescence DNA in situ hybridization (FISH)765; reverse transcriptase PCR to detect amplification of abnormal fusion genes such as t(15;17), t(8;21), inv 16, 11q23; and DNA PCR for mutations in the RAS coding regions.757
Detecting Inversion 16 Minimal residual disease in AML M4Eo can be detected by nested polymerase chain reaction with allele-specific amplifications (CBFB of 16q and MYH11 on 16p).766,767 and 768 This fusion transcript occurs not only in the majority of cases of AML with marrow eosinophilia (M4Eo) but also in 10 percent of AML M4 without eosinophilic abnormalities, a much higher incidence than the sporadic reports of chromosome 16 abnormalities in AML M4 would suggest. Additional screening by either RT-PCR or FISH should be performed in patients with AML M4, regardless of morphologic features, to evaluate the prognostic usefulness of this fusion transcipt in minimal disease detection.769
Detecting t(8;21) Transloction 8;21 is one of the most common translocations in AML, occurring in 12 to 15 percent of adult and over one-third of pediatric cases. This fuses the AML1 gene on chromosome 21p to ETO on chromosome 8p to produce the fusion gene.770,771,772 and 773 The fusion has been detected in the majority of patients in remission. One study found its persistence in all patients with t(8;21) after chemotherapy or autologous marrow transplantation.774,775 and 776 By PCR, AML1-ETO was found in patients in complete remission for 12 to 150 months but not in those who received allogeneic marrow transplantation. The PGK allele, used as a tracking marker, was identical to that detected in the leukemic blasts from the time of initial diagnosis, confirming the persistence and reappearance of leukemic cells from the same clone.776 This marker may persist after allogeneic marrow transplantation but is compatible with continued remission.777 Quantitation of the amount of the fusion transcript during remission may be more predictive of cure or relapse than a simple qualitative assessment.593,778,779 Real-time quantitative RT-PCR can be used for this purpose.775 A quantitative RT-PCR can predict relapse up to 4 months before the clinical onset.780 Serial quantification of cases with residual t(8;21) with RT-PCR indicates that at least 0.1 femtograms of AML1/ETO competitor-dose is present before cytogenetic relapse occurs.781 Both ETO and AML1 are expressed in normal CD34+ progenitors.782
Detecting t(15;17) Unlike the fusion transcript t(8;21), t(15;17) usually disappears after intensive therapy.568 At least 1 in 100,000 cells with the PML-RARa transcript can be detected by RT-PCR.783 FISH can also be used.784
The technology to detect minimal residual disease has increased in sensitivity and availability. In most cases, the use of detection of minimal residual disease to determine a patient’s treatment or prognosis remains an evolving area of investigation.
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Books@Ovid
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

One comment on “CHAPTER 93 ACUTE MYELOGENOUS LEUKEMIA

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