Acute myelogenous leukemia (AML) represents a heterogeneous group of hematologic malignancies arising from the transformation and expansion of an early myeloid stem or progenitor cell. The term leukemia originated with Virchow, who, in 1845, recognized a clinical entity characterized by too many white blood cells (WBCs), leading him to name the condition white blood, or leukemia.¹ Of some historical interest is that Dr.

John Hughes Bennett’s report of a case of leukemia preceded Virchow’s description by ˜6 weeks.¹ However, Bennett had concluded that the condition was secondary to an infection and referred to it as pyemia. The term myelogenous, or myeloid, derives from the terms myelos, meaning marrow and genesis, meaning birth.

The original cases of Virchow and Bennett probably represented what we now know to be either chronic lymphocytic or myelogenous leukemia. The first likely case of acute leukemia was reported by Friedreich and was believed to be lymphocytic.² It would take the identification of the myeloblast as a precursor cell for granulocytes by Naegeli in 1900 to set the stage for the description of the first cases of AML or what was originally termed acute nonlymphocytic leukemia.³ Even during the first half of the 20th century, reports describing different types of myeloid leukemia made it clear that this was not one but a variety of distinct disorders, all deriving from a bone marrow precursor myeloblast. Initially, cases of monocytic leukemia were described, followed by myelomonocytic leukemia.^3,4 Cases of erythroleukemia, megakaryoblastic leukemia, and acute promyelocytic leukemia (APL) were subsequently described in 1917, 1931, and 1957, respectively.^{5, 6} and ⁷ During the mid-1970s, the French/American/British (FAB) classification system was developed and defined the major categories of AML as M1 through M7.⁸ More recently, the World Health Organization (WHO) provided a new classification system that utilizes genetic, immunophenotypic, biologic, and clinical features in addition to morphology.⁹

The description and classification of AML moved more rapidly than the development of effective treatments. During the mid-1800s, Virchow used diet therapies, ferric iodide, and application of abdominal and foot baths.¹ In 1865, Lissauer used arsenic (Fowler solution) to treat patients with leukemia, but with little success.¹ Radiation therapy was used in the late 1800s, mostly as a form of palliation for chronic leukemias.¹ In 1938, Forkner stated, “Although leukemia is a fatal disease much can be done to add to the comfort, and promote the general health of sufferers from the chronic forms of the disease. Unfortunately acute leukemia does not respond satisfactorily to any form of treatment.”¹ In 1948, Farber demonstrated that the use of the antimetabolite aminopterin could produce transient remissions in children with acute lymphocytic leukemia (ALL).¹⁰ The pioneering work resulted in the National Cancer Institute developing screening programs for other possible antitumor therapies during the 1950s. During the 1960s, several chemotherapeutic agents, particularly cytarabine and anthracyclines, were developed and used in the treatment of AML. During the 1970s, clinical trials demonstrated that combining these two agents would result in long-term remissions for 10% to 15% of patients with AML. The subsequent introduction of more intensive remission induction regimens and post-remission therapy increased the need for more rigorous supportive care measures, and the development of bone marrow transplantation led to current cure rates of about 50%.^11,12

Approximately 6,500 children <20 years of age develop acute leukemia annually in the United States, and AML represents approximately 15%, resulting in approximately 600 new cases/year.¹³ The remaining cases of acute leukemia in children and adolescents are lymphoblastic leukemia. Essentially the opposite ratios exist for adults, with AML accounting for about 80% of acute leukemia and lymphoblastic the remaining 20%. With the exception of a peak in incidence of AML in infants, the incidence of AML is relatively constant until early adolescence following which it continues to rise slowly through young adulthood and beyond 50 years of age the incidence rises dramatically.¹⁴

Some variation in the incidence of AML in children has been reported among different racial and ethnic groups. For example, black children have an incidence of 5.8 cases/million, compared to 4.8 cases/million in white children.^15,16 Children and young adults of Hispanic background have the highest annual incidence at 9 cases per million with the major subtype being APL.^{17, 18, 19} and ²⁰ The annual incidence of AML in children from Japan, Australia, and Zimbabwe has been reported as 8, 8, and 11 per million.²¹ The increasing incidence of secondary leukemia, resulting from chemotherapy and treatment for other malignancies, is a problem of increasing significance in pediatrics.^{22, 23, 24, 25, 26, 27} and ²⁸

The determination of the AML stem cell is not solely of biologic interest but has profound significance for understanding the causes of leukemia and potentially the development of curative therapies. This section discusses the cellular and molecular determinants of AML.

Normal hematopoiesis occurs through a series of complex changes that facilitate multipotential hematopoietic stem cells to both expand and differentiate into various mature blood cell types. Because AML is derived from an abnormal immature hematopoietic precursor cell, these leukemias also have the capacity to expand and to show characteristics of limited differentiation. Thus, myeloid leukemias retain many of the molecular and cellular phenotypic characteristics of their normal hematopoietic origins, providing the means to distinguish subtypes of the disease and define potential leukemic stem cell compartments. For example, although most myeloid leukemia cells often express growth, survival, and differentiation receptors for specific cytokines such as KIT, FLT3, and granulocyte-macrophage colony-stimulating factor receptor, some subtypes also express more lineage-specific surface receptors, such as those for granulocyte colony-stimulating factor (G-CSF) and erythropoietin. The same is true for the expression of differentiation markers that characterize various myeloid lineages such as megakaryoblastic, erythroid, or monocytic. These diverse phenotypic characteristics of different subtypes suggest significant heterogeneity of both the genetic changes and the cell of origin in AML.

Some of the earliest biologic tools used to define the cellular compartment in which leukemic stem cells arise included the use of X-linked glucose 6-phosphate dehydrogenase isoenzyme analysis in female patients with chronic myelogenous leukemia
(CML) and then AML.^29,30 Subsequently, karyotypic abnormalities were examined in the maturing colony-forming units to evaluate which lineage (colony-forming unit stem, colony-forming unit granulocyte-macrophage, colony-forming unit megakaryocyte, colony-forming unit granulocyte, colony-forming unit eosinophil, etc.) contained the aberrant chromosomal marker.³¹ These studies revealed that although CML arises in a very early pluripotential hematopoietic cell, there are cases of AML that arise in more mature pluri- and unipotential progenitor cells.³¹

By depleting samples of AML with antibodies directed against lineage-specific surface antigens, a very small percentage of lineage-negative (Lin^–) cells were isolated that had the capacity to generate AML at a higher percentage than more mature leukemic cells when transferred to immunodeficient mice. These leukemogenic CD34^+, CD38^–, Lin^– cells (termed self-renewing leukemia-initiating cells) were in most cases rare, having a frequency of as few as 0.2 to 200/106 mononuclear cells.^32,33,³⁴,³⁵ Of further significance was that the frequency of the self-renewing leukemia-initiating cell did not correlate with age, sex, or FAB classification, with the exception of some cases of APL.³³ In the case of APL, a significant percentage of cases appeared to be derived from a more committed progenitor cell.^33,36 Subsequent investigations identified both CD34⁺ and CD34^– lineage-negative self-renewing leukemia-initiating cell populations that were present at extremely low frequency, demonstrating that the AML stem cell is in many cases derived from a very immature hematopoietic precursor cell.³⁷

When these results are placed into the context of the hematopoietic differentiation schema, the conclusion can be made that there must be primary genetic changes that occur in a very primitive self-renewing stem cell and that the nature of those genetic changes in part determines the subtype of AML. For example, a t(8;21) abnormality may lead to M1 AML with minimal differentiation, whereas an inv(16) abnormality may result in an M4Eo subtype. The initiating events may primarily affect the ability of the leukemic stem cell to differentiate but retain the ability to self-replicate.^38,39 Subsequent genetic changes, such as mutation pathways regulating apoptosis, cell survival, and proliferation, may further change the phenotype of the leukemia as well as provide the proliferative potential for the leukemia. These might be considered “driver” and “modifier” mutations, respectively. Mutations that do not affect the phenotype may be considered “passenger” mutations. This latter type of genetic change involves mostly secondary mutations that affect the function of growth and survival factor receptors, such as FLT3 or KIT. By themselves, most single mutations are insufficient to cause leukemia. However, when present together in the same cell, they can cooperate and lead to the development of AML. A slightly different alternative way of understanding the etiology of AML in the context of gene mutations is to consider genetic changes such as AML-ETO translocation as a Type I mutation and FLT3-ITD or KIT point mutations as Type II mutations that in combination result in the proliferation of progenitors with limited and aberrant differentiation.⁴⁰

Genome-wide sequencing has confirmed the above models but also revealed many additional subkaryotypic abnormalities including gene mutations encoding classes of proteins involved in epigenetic patterning⁴¹,^42,43 and RNA splicing.^44,45 Such studies have also helped to define the heterogeneity of AML and its clonal evolution during treatment.^46,47 Of interest, although many of the same mutations observed in older adults with AML have been found in children with AML, there is a growing body of evidence that shows significant differences also exist.^{48, 49} and ⁵⁰

These results have important implications not only for understanding the etiology and pathogenesis of AML but also for the development of more effective treatments (Fig. 77.1). The causes of generating genetic mutations contributing to AML involve both inherited and environmental factors. In pediatrics, the former class of factors is particularly important.

The clinical presentation of AML varies greatly with systemic symptoms and severity of illness usually being a result of leukemia cells’ replacement of normal hematopoietic progenitors in the bone marrow as well as their infiltration into various organs. Approximately 1012 leukemia cells have been estimated to be present at the time of diagnosis. The leukemic blasts can invade extramedullary sites, such as soft tissues, skin (leukemia cutis), gingiva, orbit, and brain. Patients typically present with signs and symptoms of neutropenia, anemia, and thrombocytopenia. On occasion, other systems may be involved at presentation, as in the case of coagulopathy seen most commonly in APL, spinal cord compression from chloromas, or end-organ damage due to hyperleukocytosis.

The total WBC count may be low, normal, or high depending upon the number of circulating leukemic cells. The absolute neutrophil count is often less than 0.5 × 10⁹/L and is associated with an increased risk of infections, often life threatening. Blood cultures and broad-spectrum intravenous antibiotic coverage are indicated in any newly diagnosed patient with leukemia and fever. Anemia results in fatigue, lethargy, decreased exercise tolerance, headache, and pallor. Although uncommon at the time of presentation, congestive heart failure (CHF) may occur, particularly with severe anemia, which is usually normocytic and normochromic although evidence of red cell fragmentation may be seen in cases presenting with disseminated intravascular coagulation (DIC); the transfusion of packed red blood cells should usually be done slowly to prevent precipitating or worsening CHF. Thrombocytopenia often leads to bruising and petechiae, and occasionally overt hemorrhage into the gastrointestinal track, lungs, or central nervous system (CNS). Approximately 50% of patients have hepatosplenomegaly and lymphadenopathy. Gingival hyperplasia and leukemia cutis are less frequent but particularly characteristic of myeloid leukemia with monocytic differentiation.

Patients may also present with anemia, which gives rise to fatigue, pallor, and, in extreme cases, hemodynamic instability. The anemia is typically normocytic and normochromic, although evidence of red cell fragmentation may be seen in severe cases of DIC. The median hemoglobin is ˜70 g/L, with a range of 25 to 140 g/L.

Nearly 75% of patients present with a platelet count <100 × 10⁹/L.¹⁷⁹ Thrombocytopenia may cause petechiae, purpura, mucosal bleeding, and, rarely, CNS and pulmonary hemorrhage. Thrombocytopenia is exacerbated by coagulopathy, especially in the M3 and M5 AML subtypes. Although the mechanism for DIC is not known in M5 AML, there is convincing evidence that expression of annexin II, a receptor for fibrinolytic proteins, facilitates plasminogen activation by associating plasminogen and its activator, tissue plasminogen activator, at the APL (M3) leukemic blast cell surface.¹⁸⁰

Patients with peripheral blast counts >200 × 10⁹/L are at risk for CNS stroke due to hyperviscosity, and benefit from leukopheresis to drop the blast count rapidly.¹⁸¹ Similarly, pulmonary insufficiency may occur in patients with very high leukemia blast
counts. Approximately 5% of patients with AML have CNS disease at diagnosis, and a smaller percentage presents with CNS chloromas.¹⁸² These patients may have headaches, cranial nerve palsies, focal neurologic deficits, and, rarely, seizures.

Both FAB and WHO classification systems are used by clinicians treating pediatric AML patients. Generally, both classification systems apply equally well to pediatric and adult patients. However, some important differences exist. FAB subtypes M0, M1, and M2 correspond to AML that is minimally differentiated, without maturation, and with maturation, respectively, are more common in older rather than younger children, with frequencies in children 10 to 15 years of age very similar to reported adult frequencies.^139,140 On the other hand, FAB subtypes M5 (acute monocytic leukemia) and M7 (AMKL) are significantly more common in younger children.^139,141 Likewise, the increased frequency of M7 AML in young patients is mostly due to the high rate of the M7 subtype in patients with DS.¹⁴² Younger children are less likely to have t(8;21) and t(15;17) but more frequently have chromosome abnormalities involving 11q23. M0 AML is defined as AML without morphologic signs of differentiation and by expression of CD13, CD33, and CD117 (c-KIT) and myeloperoxidase by flow cytometry or electron microscopy (Table 77.1).