Acute Myeloid Leukemia
ETIOLOGY AND EPIDEMIOLOGY
Acute myeloid leukemia (AML) is an aggressive and frequently lethal hematologic malignancy, with a median age of presentation beyond the sixth decade. Approximately 12,000 new cases of AML are diagnosed in the United States each year, and most cases are idiopathic. However, AML is increasingly seen in survivors of other cancers who were previously exposed to chemotherapy and radiotherapy. Alkylating agents, such as melphalan and chlorambucil, can give rise to therapy-related AML, with a median time of onset of 5–10 years, and associated abnormalities in chromosomes 5 and 7. Inhibitors of topoisomerase, such as etoposide and anthracyclines, can also cause a therapy-related AML, with a median time of onset of 2–3 years. These cases of AML are often associated with balanced chromosomal translocations at 11q23 and involve alterations of the mixed lineage leukemia (MLL) protein. Myelodysplastic syndrome and myeloproliferative disorders, such as polycythemia vera and myelofibrosis, can also progress to AML. The “secondary” leukemias that derive from previous therapy or other myeloid diseases have significantly worse outcomes than the “de novo” cases of AML. Of note, the risk of leukemia is 20-fold higher in patients with Down’s syndrome (1). Common mutations with prognostic value in AML include the FLT3-internal tandem duplication (ITD) mutation and the NPM1 (nucleophosmin) mutation. The FLT3-ITD mutation, identified in approximately a quarter of patients, leads to the production of an abnormal, constitutively active FLT3 receptor tyrosine kinase on the surface of leukemic cells. This in turn leads to uncontrolled proliferation of undifferentiated blasts and a higher propensity for relapse and poor outcomes (2, 3). The NPM1 mutation, on the other hand, is associated with a better prognosis if present as an isolated lesion, and affects a larger proportion of patients with AML. This mutation leads to the aberrant sequestration of altered nucleophosmin proteins in the cytoplasm, and disruption of regulated cell cycling in malignant cells (4, 5).
• Most cases of AML are idiopathic.
• AML may arise secondary to prior chemotherapy or radiotherapy, or from underlying myelodysplastic/myeloproliferative processes.
PATHOPHYSIOLOGY
Acute leukemia is a clonal disease derived from leukemic stem cells. DNA mutations render myeloid precursor cells incapable of normal differentiation and maturation and promote unchecked proliferation, leading to the acute leukemic phenotype. The myeloblasts proliferate in the bone marrow compartments, resulting in hematopoietic insufficiency and progressive cytopenias. When myeloblasts expand outside of the bone marrow, severe peripheral leukocytosis may result, leading to additional sequelae, such as leukostasis and significant tumor lysis. Rarely extravascular solid tumors, known as chloromas or granulocytic sarcomas, may arise in tissue.
DIAGNOSIS
AML can be subtle in its presentation with some patients presenting with days to weeks of nonspecific symptoms, such as fatigue, shortness of breath, and bleeding. A complete blood count, examination of the peripheral blood smear, and bone marrow aspirate and biopsy are essential in establishing the diagnosis of acute leukemia. The myeloblasts classically have distinct nucleoli, fine chromatin, scant cytoplasm, and azurophilic granules. The characteristic Auer rods are formed by azurophilic granules within lysosomes, although they are not essential for diagnosis. Histochemical stains can be helpful; for example, acute monocytic leukemia can be differentiated using a nonspecific esterase stain. Immunophenotyping by flow cytometry helps to establish a definitive diagnosis and distinguish AML from acute lymphoblastic leukemia (ALL). As examples, CD33 is positive in approximately 75% of patients with AML, CD13 is positive in approximately 70% of patients with AML, and CD14 is positive in more than 50% of the monocytic and myelomonocytic subtypes. The most widely used classification system for AML is that developed by the World Health Organization (WHO), and organizes this malignancy according to morphologic, karyotypic, and molecular features (6) (Table 24-1).
TABLE 24-1 2008 WHO CLASSIFICATION OF ACUTE MYELOID LEUKEMIA (AML) AND RELATED NEOPLASMS
(Adapted from Reference 6.)
• History and exam may reveal fatigue, shortness of breath, pallor, pete-chiae, fever, night sweats, and occasionally splenomegaly. Skin, gum, and CNS lesions can be seen, but are more frequent in monocytic variants.
• On laboratory examination, the white blood cell count may be normal, high, or low. Anemia and thrombocytopenia are frequent. Examination of the peripheral blood smear is essential and often reveals myeloblasts and other early progenitor cells, and occasionally a myelophthisic picture.
• Diagnostic evaluation includes a bone marrow aspirate and biopsy with flow cytometry, histochemical stains, cytogenetics, and molecular evaluation (e.g., fms-like tyrosine kinase [FLT3] and nucleophosmin [NPM1]). Definition of AML: >20% myeloblasts in peripheral blood or bone marrow.
TREATMENT
Treatment of AML traditionally involves remission induction chemotherapy, followed by post-remission therapy (consolidation). The most commonly used form of induction chemotherapy is the so-called “7+3” regimen, consisting of 3 days of an anthracycline, such as idarubicin 12 mg/m2/day, and 7 days of infusional cytarabine at a dose ranging from 100 to 200 mg/m2 (7). Experimental trials are underway to assess the addition of novel agents such as the proteosome inhibitor bortezomib or oral antagonists to the FLT3 tyrosine kinase, which is altered in a sizeable percentage of patients (8). The addition of the anti-CD33 humanized antibody-drug conjugate gemtuzumab ozogamicin to induction chemotherapy led to an improvement in overall survival in AML patients aged 50–70 years old in one study (9). This agent is not available for use in the United States, but may become an important adjunct to therapy in the future, based on these results.
For patients with so-called “favorable-risk” disease, such as those with the karyotypic abnormalities inversion 16 or translocation 8;21 or those harboring isolated NPM1 alterations, consolidation chemotherapy is given for 2–4 months following achievement of remission, usually with high doses of cytarabine, in doses of 3 g/m2/bid on days 1, 3, and 5 of therapy for 3–4 cycles. Consolidation chemotherapy with high-dose cytarabine can also be considered for those patients without favorable- or poor-risk features, who thus fall into an “intermediate-risk” category. The landmark study performed by the Cancer and Leukemia Group B (CALGB) showed superior survival to the high dose ara-c regimen compared to lower doses (7, 10). As yet, there is no established role for maintenance therapy for patients with AML (11).
Patients with a high risk of relapse, considered “high-risk,” including those with complex cytogenetic abnormalities or secondary AML, should be considered for allogeneic stem cell transplantation in first remission. Long-term disease-free survival rates for patients with AML in first remission receiving an allogeneic transplant from a fully matched sibling donor are 60%–70% with a transplant-related mortality of 10%–15%. Results are significantly worse for patients in second or subsequent remission.
Elderly patients or patients with significant comorbidity may not tolerate induction chemotherapy well. Elderly patients are more likely to have poor risk cytogenetics and a history of myelodysplasia. Patients under the age of 70 years with a good performance status should be considered for induction chemotherapy (12, 13). Some older and frailer patients may be considered for treatment with DNA methyltransferase inhibitors (DMNTIs) such as 5-azacitidine or decitabine. A phase III randomized study of 5-azacitidine in myeloid malignancies included a large number of AML patients and demonstrated a survival benefit for this agent (14). Because DNMTI therapy can be given on an outpatient basis and is not as intensive and morbid as induction chemotherapy, it is now increasingly used in older patients with advanced myelodysplastic syndromes and AML. Older patients may also be treated with supportive or palliative approaches including the use of the cytoreductive agent hydroxyurea (13) or lower doses of cytarabine (13, 15). The palliative benefit of such therapy is undefined.
The majority of patients with AML relapse, but the optimal treatment of relapsed disease has not been defined. Relapsed AML is not curable with standard chemotherapy alone. Patients who relapse more than 1 year after their initial therapy can be treated with idarubicin and cytosine arabinoside again. Patients who relapse within 1 year after their first induction are treated with combinations that include other agents such as mitoxantrone and etoposide. If a second remission is achieved, these patients should be considered for allogeneic stem cell transplantation as a curative attempt.
• Induction chemotherapy with an anthracycline and infusional cytarabine is the traditional approach to initial management of AML.
• Consolidation chemotherapy with high-dose cytarabine following achievement of first remission can lead to cure in a subset of patients with favorable- or intermediate-risk AML.
• Allogeneic stem cell transplantation is advised for patients at high risk of relapse or for patients in second complete remission.
COMPLICATIONS
Both AML and its treatment can pose several life-threatening complications. The death rate from complications of induction therapy is approximately 5%–10%. Leukostasis is more common with a blast count >100,000 and can be characterized by pulmonary infiltrates, visual changes, and CNS bleeding. The treatment consists of intravenous fluids, hydroxyurea to lower the white blood count, or leukapheresis.
Infection is the most common cause of death in patients with AML. Patients are functionally neutropenic even if their neutrophil count is not suppressed. Gram-positive infections, such as those caused by Staphylococcus and Streptococcus, have become the most common bacterial infections; gram-negative infections, however, may be more immediately life threatening. The use of quinolones for prophylaxis has created the emergence of resistant gram-negative organisms. Candida and Aspergillus are the most common fungal infections. Aspergillus should be considered in patients with nodular or cavitary pneumonias. All febrile patients with AML should be presumed to have an infection and treated with broad spectrum gram-negative antibiotics, such as cefepime or cefotaxime. Broad gram-positive coverage with vancomycin should be initiated if there is suspicion of skin infection, intravenous line involvement, or documented gram-positive infection.
Tumor lysis syndrome occurs because of the rapid destruction of tumor cells with release of intracellular electrolytes and uric acid (see Chapter 20). The syndrome can progress to severe electrolyte imbalance, acute renal failure, and life-threatening cardiac arrhythmias. Intravenous fluids and allopurinol should be started before the start of chemotherapy. The recombinant urate oxidase rasburicase abruptly lowers the uric acid level and should be employed in patients at high risk of or experiencing tumor lysis (16). Laboratory parameters for electrolytes, uric acid, and LDH should be followed closely, every few hours, in newly diagnosed patients and those recently started on therapy.
Bleeding is usually related to thrombocytopenia, and patients should receive prophylactic platelet transfusions for platelet counts below 10 × 109/l. Disseminated intravascular coagulation (DIC) is most commonly seen with acute promyelocytic leukemia (APL, see below) but can also be seen with other variants of AML, particularly the monocytic variants. Treatment involves replacement of clotting factors with fresh frozen plasma and repletion of fibrinogen with cryoprecipitate.
Leukemic meningitis occurs in less than 10% of adult AML patients at the time of diagnosis, more frequently in patients with the monocytic variants of AML. Leukemic meningitis is treated with intrathecal therapy with methotrexate or cytarabine given via lumbar puncture twice weekly until the CNS is cleared of involvement.
• Management of leukostasis includes aggressive cytoreduction with an agent such as hydroxyurea, prompt start of induction therapy, and leukapheresis. Red blood cell transfusions can increase leukostasis acutely and should be avoided unless absolutely necessary.
• Platelet, fresh frozen plasma, and cryoprecipitate transfusions can be employed to decrease risk of bleeding or complications from DIC.
• Fevers on presentation are broadly covered with antibiotics.
• For suspicion of tumor lysis syndrome, preventive measures with allopurinol and IV hydration are employed. Rasburicase can be used to effectively decrease uric acid in patients at risk for or experiencing severe tumor lysis.
PROGNOSIS
The overall 5-year survival for patients with AML is 25%, 40% for patients under age 60 years, and 10% for patients over age 60 years. Remission is achieved in the majority of patients, but relapse is common, particularly in older patients. Older age, complex cytogenetic abnormalities, and secondary AML are poor prognostic factors (Table 24-2). Cytogenetics can help define prognostic categories and determine who should receive more aggressive post-remission therapy, such as bone marrow transplantation (Table 24-3). Patients with the karyotypic abnormalities, translocation (8;21) or inversion 16, have a more favorable prognosis. Patients with abnormalities of chromosomes 5 or 7 or complex (>3) cytogenetic abnormalities have a worse prognosis. Approximately 40% of adult AML patients have normal cytogenetics at diagnosis and, thus, have an “intermediate-risk” prognosis. Molecular markers are also important in delineating prognosis in this group of patients. FLT3-ITD (internal tandem mutation) alterations connote a poor prognosis, and isolated NPM1 (nucleophosmin) gene mutations carry a more favorable prognosis, with the recommended approach being stem cell transplantation after obtaining remission for the population of patients carrying isolated FLT3-ITD mutations and chemotherapy-based consolidation for those carrying isolated NPM1 mutations (5, 17).
TABLE 24-2 ACUTE MYELOID LEUKEMIA (AML)—PROGNOSTIC FEATURES
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