Amir T. Fathi
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
Acute myeloid leukemia with recurrent genetic abnormalities
-AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
-AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11
-APL with t(15;17)(q22;q12); PML-RARA
-AML with t(9;11)(p22;q23); MLLT3-MLL
-AML with t(6;9)(p23;q34); DEK-NUP214
-AML with inv(3)(q21;q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
-AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
-AML with mutated NPM1
-AML with mutated CEBPA
Acute myeloid leukemia with myelodysplasia-related changes
Therapy-related myeloid neoplasms
Acute myeloid leukemia, not otherwise specified
-AML with minimal differentiation
-AML without maturation
-AML with maturation
-Acute myelomonocytic leukemia
-Acute monoblastic/monocytic leukemia
-Acute erythroid leukemia: pure erythroid leukemia or erythroleukemia, erythroid/myeloid
-Acute megakaryoblastic leukemia
-Acute basophilic leukemia
-Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Myeloid proliferations related to down syndrome
-Transient abnormal myelopoiesis
-Myeloid leukemia associated with Down syndrome
Blastic plasmacytoid dendritic cell neoplasm
(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 NPM1mutations (5, 17).
TABLE 24-2 ACUTE MYELOID LEUKEMIA (AML)—PROGNOSTIC FEATURES
Poor-Risk Prognostic Features
-Age over 65 y
-Presence of a FLT3-ITD mutation
-Poor-risk cytogenetics (e.g., -7, -7q, -5, or complex [> 3 chromosomal abnormalities])
-AML arising from preceding myelodysplasia or chronic myeloproliferative states
-Therapy-related disease (AML secondary to prior chemotherapy or radiation exposure)
-Presence of granulocytic sarcoma (extramedullary disease)
-Acute bilineal or biphenotypic leukemia
Better-Risk Prognostic Features
-Presence of an NPM1 mutation (without concurrent FLT3-ITD mutation)
-Presence of a CEBPα mutation
-“Good” risk cytogenetics (e.g., t(15;17), inv(16), t(16;16), t(8;21))
TABLE 24-3 CYTOGENETIC ABNORMALITIES IN THE ACUTE MYELOID LEUKEMIAS
ACUTE PROMYELOCYTIC LEUKEMIA
ETIOLOGY AND EPIDEMIOLOGY
Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia, accounting for only 10%–15% of all AMLs diagnosed in the United States.
PATHOPHYSIOLOGY
The breakpoint on chromosome 15 in APL occurs at the PML transcription unit and on chromosome 17, at the retinoic acid receptor alpha gene. A chimeric PML-RAR-alpha gene product is created. This PML-RAR-alpha transcript renders the aberrant promyelocytes sensitive to the differentiating effects of therapy with all trans-retinoic acid (ATRA) and arsenic trioxide.
DIAGNOSIS
It is critical to make the diagnosis of APL quickly since treatment is different than for other subtypes of AML and since patients are at acute risk of mortality due to complications related to DIC. Characteristic morphology (Figure 24-1) is the presence of promyelocytes with intense azurophilic (red) granules. However, in the microgranular variant of APL, the granules can be very small and difficult to visualize on Wright stain. The diagnosis of APL can be made by cytogenetics revealing the classic t(15;17) translocation. Molecular diagnostics by PCR analysis can confirm the presence of PML-RAR-alpha. The white blood cell count is frequently lower in patients with APL than in the other subtypes of AML, and a higher white blood cell count at presentation portends a worse prognosis.
FIGURE 24-1 Aberrant promyelocytes of acute promyelocytic leukemia (APL), with prominent azurophilic granules seen within the cytoplasm. Also seen are Auer rods, needle-shaped inclusion bodies containing clumps of azurophilic granules, which are found in the cytoplasm of malignant cells in various forms of AML, including APL.
• Initial assessment of APL involves a detailed history and physical exam, with careful attention to bleeding and thrombosis, possible signs of ongoing DIC.
• Laboratory evaluation should include CBC, chemistry panel, uric acid, LDH, PT, PTT, and a full DIC screen. Bone marrow biopsy with collection of specimens for cytogenetics and molecular diagnostic studies for PML-RAR-alpha are essential diagnostic steps.
TREATMENT
It is important to start therapy for APL promptly; up to 17% of patients with APL die before or at the time of diagnosis (18). If the diagnosis of APL is suspected, treatment should be started with all-trans retinoic acid (ATRA) (19). Initial induction therapy for APL begins with ATRA given orally; cytotoxic chemotherapy, such as daunorubicin 50 mg/m2/day for 4 days and cytarabine 100 mg/m2/day for 7 days, begins 3–4 days after ATRA. The French APL trial reported a complete remission rate of 92% and a relapse rate of 6% with the ATRA plus chemotherapy approach. ATRA rapidly corrects the coagulation defects in APL-associated DIC. Consolidation following induction chemotherapy consists of a combination of ATRA with anthracyclines and arsenic trioxide, although consolidation approaches can vary. The role of maintenance therapy is controversial (20). The incorporation of arsenic trioxide into therapy for APL has led to recent improvements in outcomes. Arsenic trioxide is the most active agent in APL and is thought to act by direct degradation of the PML-RAR-alpha transcript, allowing transcription of target genes and normal differentiation (21). The combination of ATRA and arsenic trioxide is highly active and becoming the initial treatment of choice.
Elderly patients can be treated with ATRA alone or ATRA in combination with arsenic. Arsenic trioxide is often included in the treatment of relapsed APML. Electrolyte replacement and frequent EKG monitoring for prolonged QTc are part of routine monitoring during arsenic therapy. For relapsed patients, a regimen of arsenic trioxide to achieve a second remission followed by autologous stem cell transplant for PCR-negative patients will cure an additional 60% of relapsed patients (21–24).
• With suspicion for APL, start ATRA promptly
• Upon confirmation of the diagnosis, continue ATRA followed by anthracycline-based chemotherapy.
• Consolidation chemotherapy for APL includes cycles of ATRA plus an anthracycline, and of arsenic trioxide.
• Maintenance therapy with ATRA can be considered for some patients.
• For relapsed patients, arsenic trioxide followed by autologous SCT is an effective approach for long-term disease-free survival.
COMPLICATIONS
Tumor lysis, infection, bleeding, and leukostasis can occur with APL, as with the other AML variants. DIC and bleeding are often more prominent and lethal features of APL, and although the process of DIC in APL is complex, release of tissue factor and increased production of prothrombin complexes have been demonstrated in the malignant cells of patients (25–27). DIC can present with acute intravascular sequelae such as thrombosis or bleeding, including those involving the central nervous system. Prompt treatment for DIC can include reversal of coagulopathy with infusion of cryoprecipitate, fresh frozen plasma, and platelets as necessary.
APL also has the unique potential complication of ATRA syndrome. This syndrome is related to the infiltration of the lung and other organs with tumor cells that have differentiated into granulocytes under the influence of ATRA, and can occur within the first few days of ATRA administration. It can be associated with a rapid rise in the white blood cell count, and onset of fever, weight gain, and shortness of breath with pulmonary infiltrates. ATRA syndrome can be treated by promptly starting dexamethasone 10 mg twice daily. Severe cases may require temporary discontinuation of ATRA or initiation of cytoreduction with hydroxyurea.
A rare complication of ATRA therapy is pseudotumor cerebri, characterized by increased intracranial pressure, headaches, nausea, and visual changes. This complication is more common in children, and is treated by discontinuation of ATRA and diuretics such as mannitol. It can at times be difficult to distinguish this significant syndrome from severe headaches, which are a common toxicity associated with ATRA (21, 22).
• ATRA syndrome can manifest as weight gain, leukocytosis, and pulmonary infiltrates, and can be initially managed with IV dexamethasone.
• To prevent bleeding due to DIC, transfuse cryoprecipitate to fibrinogen >150, fresh frozen plasma to normalize PT, and platelets to platelet count >50,000 or higher depending on clinical presentation and risks.
• Prompt (<24 h) initiation of ATRA therapy is necessary to avoid potentially fatal complications of DIC and bleeding.
PROGNOSIS
APL has the most favorable prognosis of all the acute leukemias in adults. More than 90% of patients will achieve complete molecular remission after induction and consolidation therapy. Marrows performed at 10–14 days after chemotherapy will often be cellular and hard to interpret; therefore, unlike other AML subtypes, the bone marrow should be assessed 4–5 weeks post-chemotherapy, at the time of count recovery. The majority of patients will have molecular evidence of disease after induction therapy, but after consolidation therapy, molecular testing for PML-RAR-alpha by PCR should be negative. Conversion from negative to positive PML-RAR-alpha is a harbinger of hematologic relapse. Over 80% of patients will be long-term survivors (18, 19).
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