Chapter 46: The Acute Myelogenous Leukemias

• Acute myelogenous leukemia (AML) is a malignancy originating in a multipotential hematopoietic cell characterized by clonal proliferation of abnormal blast cells in the marrow and impaired production of normal blood cells, resulting in anemia; thrombocytopenia; and low, normal, or high white cell counts depending on the number of leukemic cells in the blood. It occurs in nine morphologic variants, each with characteristic cytologic, genetic, and sometimes clinical features.

• The chronic clonal myeloid diseases may progress to florid AML (e.g., polycythemia vera, Chap. 43; essential thrombocythemia, Chap. 44), clonal cytopenias, Chap. 42; chronic myelogenous leukemia, Chap. 47).

• AML may develop with increased frequency in patients with certain congenital (Down syndrome) or inherited abnormalities (e.g., Fanconi anemia, familial platelet syndrome) as shown in Table 46–1.

• Non-syndromic, familial occurrence, suggesting an inherited predisposition gene, has been documented but is uncommon.

• Most cases arise de novo and are associated with acquired cytogenetic changes, including translocation, inversions, deletions, and others. These changes lead to the mutation of protooncogenes and the formation of oncogenes. Frequently, the latter encode mutant transcription factors that result in disruption of cell signaling pathways that cause malignant transformation.

• AML results from a series of somatic mutations in a multipotential hematopoietic cell or, in a small proportion of cases, a more differentiated, lineage restricted progenitor cell. In acute promyelocytic leukemia (APL), some cases of monocytic leukemia, and some young persons with other forms of AML, the disease originates in a mutated granulocytic-monocytic progenitor cell.

• AML requires at least two types of mutation: a primary oncogenic mutation, such as involving core-binding factor subunit genes (CBF-β or RUNX1), and an activating mutation, in a hematopoietic tyrosine kinase, such as FMS-like tyrosine kinase 3 (FLT3). The mutations in AML result in deregulated signaling pathways that disrupt differentiation and maturation, regulation of proliferation and of cell survival in varying combinations.

• AML accounts for 80 percent of acute leukemias in adults and 15 to 20 percent in children.

• AML is the most frequent leukemia in neonates. This results in a bimodal incidence curve with a peak at less than 1 year of age of approximately 2 per 100,000 infants, dropping to approximately 0.4 cases per 100,000 at age 7 years, and then increasing to 1.0 per 100,000 by age 25 years. Thereafter, incidence increases exponentially to 20 cases per 100,000 persons in octogenarians.

• An exception to the striking change in incidence with age in adults is found in APL in which the incidence by age does not vary significantly.

• Four exposures: high-dose radiation, chronic benzene exposure usually in an industrial setting, treatment of other cancers with alkylating agents, topoisomerase II inhibitors or other cytotoxic drugs, and prolonged tobacco smoking—have been established as causative factors. Numerous other possible environmental factors have been studied but are unproven as causal factors.

• The risk of AML in a nonidentical sibling is approximately 2.5-fold that of unrelated individuals under age 15 years in persons of European descent.

• The risk of AML appears to be increased in Jews of Eastern European descent and the APL subtype among Latinos.

• AML develops clinically in nine morphologic variants that can be identified by a combination of blood cell and marrow morphology on stained slides, immunophenotype (CD profile) measured by flow cytometry (Table 46–2), and histochemical analysis, if necessary. Cytogenetic analysis provides a second level of classification. The diversity of specific cytogenetic abnormalities (hundreds) makes this useful only for the few most prevalent chromosome alterations (see Laboratory Features section below).

• Frequent presenting symptoms and signs are those reflecting anemia: pallor, fatigue, weakness, palpitations, and dyspnea on exertion; or thrombocytopenia: ecchymoses, petechiae, epistaxis, gingival bleeding, conjunctival hemorrhages, and prolonged bleeding after minor cuts.

• Minor pyogenic infections of the skin are common. Major infections are uncommon at diagnosis, prior to cytotoxic therapy.

• Anorexia and weight loss may occur.

• Fever may be present at onset.

• Mild splenomegaly or hepatomegaly is present in about one-third of patients. Lymph node enlargement is uncommon, except with the monocytic variant.

• Leukemic cells may infiltrate any organ in the body, but consequent organ dysfunction is unusual. Occasionally, large accumulations of myeloblasts (myeloid sarcoma) may develop in virtually any tissue. Monoblasts frequently infiltrate tissues, and these sites can be symptomatic (e.g., leukemia cutis, gingival hyperplasia, and others).

• Anemia and thrombocytopenia are nearly always present at diagnosis. Half the patients with AML have a platelet count < 50 × 10⁹/L.

• Red cell morphology is mildly abnormal (anisocytosis and occasional misshapen cells), although in occasional cases, more marked dysmorphia occurs.

• Total leukocyte count is below 5.0 × 10⁹/L in about one-half of patients, and the absolute neutrophil count is less than 1.0 × 10⁹/L in more than one-half of patients at diagnosis. Mature neutrophils may be hypersegmented, hyposegmented, or hypogranular.

• Myeloblasts comprise from 3 to 95 percent of the leukocytes in the blood, and a small percent of the blast cells may contain Auer rods.

• Marrow contains leukemic blast cells, identified as myelogenous by reactivity with cytochemical stains (e.g., peroxidase), presence of Auer rods, or reactivity with antibodies to epitopes specific for myeloblasts or derivative cells (Table 46–2).

• The World Health Organization defines AML as having ≥ 20 percent blasts in the marrow. This breakpoint is not based on rational biologic considerations. APL, acute monocytic leukemia, acute myelomonocytic leukemia, and AML with evidence of maturation may not and often do not have ≥ 20 percent blast in the marrow (see also Chap. 42). Moreover, patients with 10 to 20 percent blasts in the marrow may behave as AML or progress rapidly to such behavior and require treatment for AML. The physician should eschew medicine by algorithm. Some of these approaches may be required for multi-institutional clinical trials but should not be transposed to the care of individual patients.

• Overt cytogenetic abnormalities (aneuploidy or pseudodiploidy) are present in about three-quarters of patients. t(8;21), t(15;17), inv 16, and translocations involving 11q are the most common, but several hundred unique cytogenetic abnormalities have been described in the cells of AML patients. The most prevalent abnormalities are shown in Table 46–3.

• Serum uric acid and lactic acid dehydrogenase levels are frequently elevated.

• Electrolyte abnormalities are infrequent, but severe hypokalemia may occur, and spurious hyperkalemia may be found in patients with very high leukocyte counts.

• Patients with very high leukocyte counts may also have spurious hypoglycemia and hypoxia as a result of consumption by the blast cells after the specimen is obtained.

• Hypercalcemia and hypophosphatemia may be present.

• One-quarter of cases occur as a complication of AML.

• Bone pain (80% of cases) and fever (70% of cases) the two most frequent signs.

• Marrow aspirate is watery and serosanguineous. Marrow cells are indistinct and lose staining characteristics with pyknotic cells exhibiting karyorrhexis.

• Prognosis most closely related to underlying disease.

• Signs and symptoms due to extreme elevations of the leukocyte count, usually to greater than 100 × 10⁹/L, appear in about 5 percent of patients.

• Leukostasis is most likely to occur (a) in the circulation of the central nervous system, leading to intracerebral hemorrhage; (b) in the lungs, resulting in pulmonary insufficiency; or (c) in the penis, causing priapism (see Chap. 41).

• Hypoplastic leukemia. AML may present with pancytopenia and a hypoplastic marrow. Careful microscopic and cell flow analysis examinations usually identify leukemic blast cells in marrow.

• Oligoblastic myelogenous leukemia. The disease may present with anemia and thrombocytopenia and a lower proportion of blast cells in the blood and marrow. This presentation is often referred to as myelodysplasia (specifically, refractory anemia with excess blasts) and is discussed in Chap. 42. Although median survival without remission-induction therapy is measured at about 20 months, it may be morbidly symptomatic, be progressive soon after diagnosis, and in the appropriate patient require AML-type therapy, especially in cases in which the marrow blast percentage is 10 to 20 percent at the time of diagnosis.

• Mediastinal germ-cell tumors and AML may coexist, and there is evidence for a clonal identity of the neoplastic cells of the two tumors.

• Transient abnormal myeloproliferation, i.e., markedly elevated leukocyte count with blast cells in the blood and marrow, present at birth or appearing shortly thereafter and resolving slowly over weeks or months without treatment.

• Similar cases with a cytogenetic abnormality may resolve and then later reappear as acute leukemia. Such disorders have been referred to as transient leukemia. These events occur in approximately 10 percent of newborns with Down syndrome.

• Apparently phenotypically normal newborns may have congenital leukemia or develop neonatal leukemia. However, these syndromes are 10 times more common in infants with Down syndrome. The leukemia in Down syndrome is usually acute megakaryocytic leukemia and is very responsive to chemotherapy.

• Higher frequency of unfavorable prognostic cytogenetic changes.

• Higher frequency of drug-resistant phenotypes.

• Higher frequency of comorbid conditions.

• Lower tolerance to intensive chemotherapy.

• Lower rate of remission and shorter survival with current therapeutic approaches.

• Leukemias in which individual cells may have both myeloid and lymphoid markers (chimeric), or in which individual cells may have either myeloid or lymphoid markers but appear to arise from the same clone (mosaic). In some cases, individual cells may have markers for two or more myeloid lineages, such as granulocytic and megakaryocytic.

• Myeloid-Natural Killer Cell and t(8;13) myeloid–lymphoid hybrids are two explicit syndromes representing this phenomenon.

• Mixed leukemias are rare entities in which myeloid and lymphoid cells are present simultaneously, each derived from a separate clone (e.g., chronic myelogenous leukemia and chronic lymphocytic leukemia occurring simultaneously).

• Table 46–4 presents the features of the morphologic variants of AML.

• The most common variants have phenotypic features of granulocytic, monocytic, erythroid, or megakaryocytic cells.

• Acute eosinophilic, basophilic, mastocytic, or histiocytic leukemias arising de novo are rare forms of AML.

• Images of morphologic variants and features of leukemic cells are shown in Fig. 46–1.

• Extensive proliferation of promyelocytes in the marrow may occur upon recovery from agranulocytosis induced by drugs or bacterial infection and transiently may mimic APL. This blood and marrow appearance resolves spontaneously in several days and has been called pseudoleukemia.

• In patients with hypoplastic marrows, it may be difficult to differentiate acute leukemia from aplastic anemia. Careful, and sometimes repeated, evaluation of blood and marrow cytology should permit the correct diagnosis.

• Leukemoid reactions and nonleukemic pancytopenias do not have an increase in leukemic myeloblasts in the marrow or blood.

• Patient and the family should be informed about the nature of the disease, the treatment, and the potential side effects of the treatment.

• Treatment should be initiated as soon as possible after diagnosis, unless the patient is so frail or burdened by unrelated illness to make treatment inadvisable based on mutual understanding.

• Associated problems such as hemorrhage, infection, or anemia should be treated concurrently.

• Pretreatment laboratory studies should establish the specific diagnosis using immunologic, genetic, and molecular techniques, and assess the general condition of the patient, including blood chemistry tests, radiographic examinations, and cardiac studies, as indicated. Hemostasis should also be evaluated, in detail if screening tests show any abnormalities, if severe thrombocytopenia is present, or if the patient has APL or monocytic leukemia.

• An indwelling central venous catheter should be inserted prior to beginning treatment.

• Treatment with allopurinol, usually 300 mg daily orally, should be given if the serum uric acid level is greater than 7 mg/dL, if the marrow is hypercellular with increased blast cells, or if the blood blast cell count is moderately or markedly elevated. Intravenous uricase, a rapidly acting preparation, is also available for more urgent situations. Therapy may be discontinued after control of the uric acid level and cytoreduction.

• Exposure to pathogenic infectious agents should be minimized by hand washing by attendants, meticulous care of the intravenous catheter, assignment to an unshared room. Raw seafood and exposure to plants should be avoided.

Remission Induction Therapy

AML Variants Other than APL

• Cytotoxic chemotherapy is based on the concept that the marrow contains two competing populations of stem cells (leukemic monoclonal and normal polyclonal) and that profound suppression of the leukemic cells, such that they can no longer be detected morphologically in marrow aspirates or biopsies, is necessary in order to permit recovery of normal hematopoiesis (Fig. 46–2).

• Therapy is usually initiated with two drugs, including an anthracycline antibiotic or anthraquinone and cytosine arabinoside (Table 46–5).

• Remission is inversely correlated with a patient's age and blood blast count. Those who have AML induced by prior chemotherapy or radiotherapy, and those who evolved to AML from an antecedent predisposing clonal myeloid disease, have lower remission rates than patients with de novo AML.

• Patients with leukocyte counts of 100 × 10⁹/L or more should be treated to achieve more rapid cytoreduction using hydroxyurea 1.5 to 2.0 g, orally, every 6 hours for about 36 hours with downward titration of dose as blast count diminishes. Leukapheresis (coupled with hydroxyurea) can further accelerate reduction of the white cell count (see Chap. 94). Hydration sufficient to maintain urine flow of at least 100 mL/h is necessary during the first several days of cytotoxic therapy.

• Severe neutropenia and other factors resulting from cytotoxic therapy frequently result in infection and require cultures and rapid institution of broad-spectrum antibiotic therapy until cultures results are known. If an organism is identified, antibiotic therapy can be tailored to its sensitivity spectrum.

• Red cell and platelet transfusions are often required. Patients should receive leukoreduced blood products to avoid allergic reactions and allosensitization and those who are candidates for allogeneic hematopoietic stem cell transplantation should receive irradiated blood products.

• Patients with evidence of intravascular coagulation or excessive fibrinolysis should be treated for those conditions (see Chaps. 86 and 87). If findings are equivocal, monitor patients with fibrinogen, D-dimer, and coagulation assays. These complications are of highest prevalence in patients with APL and acute monocytic leukemia but may occur uncommonly with other subtypes.

Treatment for APL

• About 80 percent of patients with APL develop complete remissions when treated with all-trans-retinoic acid (ATRA) (45 mg/m² per day orally, divided into two doses) and an anthracycline antibiotic (sometimes coupled with cytosine arabinoside) administered concurrently.

• The use of ATRA has markedly decreased the frequency of the hemorrhagic complications of APL. However, the lethal complication of intracerebral hemorrhage still occurs in about 5 to 10 percent of patients, despite effective therapy. ATRA should be started urgently on the suspicion that the acute leukemia is APL.

• Arsenic trioxide is being studied to determine its role in the initial therapy of APL. Arsenic trioxide coupled with ATRA is an effective regimen.

Remission Maintenance Therapy

• Intensive postremission therapy results in longer duration of remission.

• There is no agreement on best current postremission therapy, in part because the age, cytogenic alteration, morphologic subtype, and other factors may dictate different options.

• Three principal modalities are available:

  — Intensive cytotoxic drug therapy (e.g., high-dose cytarabine).

  — Very intensive chemotherapy and autologous stem cell infusion.

  — Pretransplant conditioning regimen (e.g., chemoradiation) followed by allogeneic hematopoietic stem cell transplantation in patients deemed suitable for this approach based on availability of a suitable donor, age, comorbidities, probability of a salutary outcome, the patient's agreement, and other factors evaluated by the responsible transplant physician.

Relapsed or Refractory Patients

• Chemoradiation followed by allogeneic stem cell transplantation in patients with AML in second remission can induce long-term survival in about 25 percent so treated. Treatment with chemotherapy alone in this group is unlikely to result in long-term remission.

• Patients who relapse more than 12 months after initial chemotherapy can be given the same treatment again.

• Another therapy for relapsed patients is high-dose cytosine arabinoside with or without additional drug(s), such as mitoxantrone, amsacrine, or etoposide. Several options are shown in Table 46–6.

• Patients with APL who relapse may respond to arsenic trioxide treatment and chemotherapy.

• Chemoradiation followed by allogeneic hematopoietic stem cell transplantation may be used in refractory patients. Approximately 10 percent of such AML patients may be cured, and approximately 25 percent may achieve remissions of at least 3 years with marrow transplantation.

Special Therapeutic Consideration

• It may be necessary to reduce the dose of cytotoxic drugs administered to patients older than 60 years of age if concurrent illnesses (e.g., heart disease, diabetes) or other factors so dictate.

• Treatment of pregnant patients in the first trimester with antimetabolites increases the risk of congenital anomalies in the infant. However, babies born after intensive chemotherapy administered in the late second and third trimesters may develop normally.

• Intensive multidrug chemotherapy has been used successfully in patients younger than 17 years of age in whom long-term remission rates are in the 40 to 50 percent range. Infants younger than 1 year of age with neonatal AML do not respond well to chemotherapy and should be considered for allogeneic hematopoietic stem cell transplantation.

Special Nonhematopoietic Adverse Effects of Treatment

• Skin rashes develop in over 50 percent of the patients with AML during chemotherapy, often caused by one of the following drugs: allopurinol, β-lactam antibiotics, cytosine arabinoside, trimethoprim-sulfamethoxazole, miconazole, and ketoconazole.

• Cardiomyopathy may develop in patients receiving anthracycline antibiotics and other agents. The adverse effect on the heart may be quite delayed developing decades after therapy.

• Systemic candidiasis syndrome presents with fever, abdominal pain, and hepatomegaly and is associated with multiple hepatic candidiasis lesions detected radiographically or by ultrasound. May respond to prolonged therapy with antifungal agents, such as azoles or echinocandins.

• Patients receiving intensive cytotoxic therapy may develop necrotizing inflammation of the cecum (typhlitis), which can simulate appendicitis, and may require surgical intervention.

• Fertility may be sustained or be recovered in men and women undergoing intensive cytotoxic therapy, but infertility can occur especially after intensive regimens used for hematopoietic stem cell transplantation.

Results of Treatment

• By using current therapeutic approaches, remission rates approach 90 percent in children, 70 percent in young adults, 60 percent in the middle aged, and 25 percent in older patients.

• Median survival of all patients in the full age-range is about 18 months because of the high proportion of patients over 65 years of age. The influence of age on survival of patients with AML is shown in Table 46–7.

• Relapse or development of a new leukemia has occurred rarely after 8 years in adults and 16 years in children.

Features Influencing the Outcome of Therapy

• Both the probability of remission and the duration of response decrease with increasing age at the time of diagnosis.

• Cytogenetic abnormalities such as inv(16), t(16;16), del(16q), t(8;21), or t(15;17) indicate a better prognosis, while –5, del(5q), –7, del(7q), t(9;22), and others indicate a poorer prognosis. A normal karyotype, +6, +8, and others are intermediate in outlook.

• Table 46–8 indicates frequency of better prognosis chromosome abnormalities with age at diagnosis. These are relative prognostic projections, and a better prognosis may not be an excellent prognosis. They may also influence the decision as whether to use allogeneic hematopoietic stem cell transplantation in first remission.

• AML that develops after prior cytotoxic therapy for another disease or after a clonal cytopenia or oligoblastic leukemia (myelodysplastic syndromes) has a significantly lower remission rate and shorter remission duration on average than de novo AML.

• A leukocyte count greater than 30 × 10⁹/L or a blast cell count greater than 15 × 10⁹/L decreases the probability and the duration of remission.

• Many other laboratory findings are correlated with decreased remission rate or duration (see Williams Hematology, 8th ed, Table 89–9, p. 1310).