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Leukemia, Acute Myeloid
Jan Cerny, MD, PhD
image BASICS
DESCRIPTION
  • Acute myeloid leukemia (AML) is characterized by proliferation and accumulation of abnormal immature myeloid progenitors (blasts) with reduced capacity to differentiate into more mature cellular elements. This leads to bone marrow failure and results in a variety of systemic symptoms.
  • Previously, the French-American-British (FAB) classification system divided AML based on the cell morphology with the addition of cytogenetics (subtypes M0-M7).
  • The World Health Organization (WHO) classification attempts to provide more meaningful prognostic information.
    • AML with characteristic genetic abnormalities: translocation t(8;21), t(15;17), and inversion in chromosome 16 inv(16)
    • AML with multilineage dysplasia: presence of a prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) that transformed into AML
    • AML and MDS, therapy related
    • AML not otherwise categorized
    • Acute leukemias of ambiguous lineage (biphenotypic acute leukemia)
EPIDEMIOLOGY
  • ˜13,500 cases diagnosed in 2007; second most common type of leukemia in adults
  • Predominant sex: male ≥female
Incidence
The incidence of AML increases with age, and median age is >70 years.
ETIOLOGY AND PATHOPHYSIOLOGY
Precise causes unknown, but some risk factors have been identified (see “Risk Factors”).
Genetics
  • Unknown; some are familial.
  • Cytogenetics and genetics play an important role in diagnosis and prognosis of AML and have implications for therapy.
  • Three risk groups
    • Good risk: inv(16), t(8;21), t(15;17)
    • Standard risk: normal karyotype
    • Poor risk: monosomy 5 and 7 (typically secondary AML), deletion 5q, abnormalities of 11q23 or complex karyotype
  • FLT3 gene mutations, especially internal transmembrane duplications (FLT3-ITD), have been associated with poor survival in AML. These and growing list of (onco)gene (e.g., NPM1, DNMT3A, and P53) mutations have been studied to further risk-stratify patients (1,2)[A].
RISK FACTORS
  • Genetic predisposition (e.g., Down syndrome); other familial disorders are Bloom syndrome (˜25% develop AML), Fanconi anemia (52%), neurofibromatosis, Li-Fraumeni syndrome, Wiskott-Aldrich syndrome, Kostmann syndrome, and Diamond-Blackfan anemia
  • Radiation exposure
  • Immunodeficiency states
  • Chemical and drug exposure (nitrogen mustard and alkylating agents; benzene)
  • MDS
  • Cigarette smoking
GENERAL PREVENTION
None currently identified, but treatment of highrisk MDS with demethylating agents (Vidaza, 5-azacitidine) has been shown to prolong time to transformation from MDS into AML (3)[A].
COMMONLY ASSOCIATED CONDITIONS
The following are oncologic emergencies:
  • Disseminated intravascular coagulopathy (DIC) especially in acute promyelocytic leukemia (APL) but may be seen in any AML
  • Leukostasis (high blast number and increased adhesive ability of blasts)
  • Tumor lysis syndrome (TLS): spontaneous or in response to chemotherapy
image DIAGNOSIS
PHYSICAL EXAM
  • Mostly nonspecific and related to marrow or tissue infiltration
    • Fever
    • Bleeding
    • Pallor
    • Splenomegaly
    • Hepatosplenomegaly
    • Lymphadenopathy (usually reactive)
  • If CNS is involved, symptoms of increased intracranial pressure can be present.
  • Occasionally, patients will present with prominent extramedullary sites of leukemia (e.g., skin infiltration or ultimately as a myeloid sarcoma).
DIFFERENTIAL DIAGNOSIS
  • Virus-induced cytopenia, lymphadenopathy, and organomegaly
  • Immune cytopenias (including systemic lupus erythematosus [SLE])
  • Drug-induced cytopenias
  • Other marrow failure and infiltrative diseases (e.g., aplastic anemia, paroxysmal nocturnal hemoglobinuria, MDSs, Gaucher disease)
DIAGNOSTIC TESTS & INTERPRETATION
  • CBC shows subnormal RBCs, neutrophils, and platelets.
  • Bone marrow for histology, flow cytometry, and cytogenetics to establish diagnosis and prognosis
  • ESR
  • Lactate dehydrogenase (LDH) and uric acid can be elevated (e.g., TLS).
  • Coagulation profile can be normal or prolonged (e.g., DIC).
  • Drugs that may alter lab results: chemotherapy agents, corticosteroids
  • Other special tests: Spinal tap may reveal fluid with leukemic cells.
  • Ultrasonography or CT scan of the abdomen may discover organomegaly.
Diagnostic Procedures/Other
Bone-marrow studies are usually necessary to make the diagnosis.
  • Aspirates: for cell morphology, cytochemistries, immunophenotyping (can confirm differentiation stage of AML); cytogenetics: chromosomal aberration (prognostic value; see “Genetics”)
  • Biopsies provide valuable information for cellularity, architecture, and so forth.
Test Interpretation
  • Marrow is usually hypercellular and the normal architecture effaced; leukemic blast count is 20% or more.
  • Liver and spleen may be infiltrated with leukemic cells.
image TREATMENT
  • Chemotherapy is the backbone of AML therapy; it consists of induction and consolidation phase ± maintenance (APL).
  • Bone marrow transplantation (BMT) for high-risk AML
  • Only modest improvements have been made in AML induction chemotherapy. Supportive care has improved significantly.
GENERAL MEASURES
  • Ongoing assessment of bone marrow, liver, heart, and kidney functions during therapy
  • Close monitoring of coagulation parameters (risk for DIC)
  • Supportive therapy with
    • Good hydration
    • Transfusions of packed RBCs and platelets based on patient's needs (threshold as for platelets as low as 5,000); use leuko-reduced, irradiated blood products, as all patients can be considered for BMT.
    • Avoid antiplatelet agents (e.g., aspirin products).
    • Follow febrile neutropenic guidelines in neutropenic patient who becomes febrile (even low-grade fever).
Geriatric Considerations
  • Older patients (>60 to 65 years of age) remain a therapeutic challenge. These patients are offered socalled reduced-intensity or nonmyeloablative BMT.
  • Adding growth factors (granulocyte-colony stimulating factor [G-CSF]) may reduce toxicity in older patients (but is not broadly accepted).
  • Hypomethylating agent, such as 5-azacitidine, significantly prolongs survival in older adults with low marrow blast count (<30%).
Pediatric Considerations
Tolerate intense treatments better
P.601

Pregnancy Considerations
Chemotherapy is a viable option in the 2nd and 3rd trimesters.
MEDICATION
First Line
  • APL (APL, AML with t[15;17])
    • All-trans retinoic acid (ATRA) and arsenic trioxide both promote maturation to granulocytes.
    • Idarubicin is often added to induction therapy.
  • Treatment of AML in younger adults: AML (other than APL)
    • Induction (daunorubicin or idarubicin [anthracycline and cytarabine]): The generally accepted combination is 3 + 7 (anthracycline is given for 3 days and cytarabine for 7 days) or more intensive regimens with high dose of cytarabine (HiDAC) or high dose of anthracycline.
  • Remission is typically consolidated in younger patients by the following:
    • In good-risk AML, 3 to 4 cycles of HiDAC and BMT is reserved for time of recurrence.
    • In poor-risk patients, 1 to 2 cycles of HiDAC (until donor is identified) are followed by allogeneic BMT.
    • Intermediate-risk AML should be treated based on individual patient's features, donor availability, and access to clinical trials. A meta-analysis showed that even intermediate-risk patients benefit from allogeneic BMT (4)[A].
  • Treatment of AML in older adults (>65 years of age) remains a challenge. These patients have poor performance status, more likely secondary AML, higher incidence of unfavorable cytogenetics, comorbidities, shorter remissions, and shorter overall survival.
    • Intensive chemotherapy may be feasible for patients with good performance status; alternative regimens with mitoxantrone, fludarabine, and clofarabine. New drugs (hypomethylating agents as above, FLT3 inhibitors, monoclonal antibodies, etc.) are being studied in clinical trials (5)[A].
  • Contraindications: comorbidities; therapy has to be individualized.
  • Precautions
    • If organ failure, some drugs may be avoided or dose reduced (e.g., no anthracyclines in patients with preexisting cardiac problems).
    • Patients will be immunosuppressed during treatment. Avoid live vaccines. Administer varicellazoster or measles immunoglobulin as soon as exposure of patient occurs.
  • Significant possible interactions: Allopurinol accentuates the toxicity of 6-mercaptopurine.
Second Line
Healthy, younger patients usually are offered reinduction chemotherapy and allogeneic BMT.
ISSUES FOR REFERRAL
  • AML should be managed by specialized team led by a hematologist/oncologist.
  • Refer patient to a transplant center early because a search for a donor may be necessary.
SURGERY/OTHER PROCEDURES
  • BMT: Decision between myeloablative and nonmyeloablative approach should be based on patient's performance status, comorbidities, and AML risk factors.
    • Allogeneic BMT is acceptable in first remission in intermediate- or high-risk AML or in second remission in all other AML patients. Matched related donor used to be preferred over matched unrelated donor (lower risk of graft-versus-host disease); recent data suggest equal outcomes, as allogeneic transplant regimens and posttransplant care have improved significantly.
  • Haploidentical transplants and cord blood may be used as alternative sources of hematopoietic stem cells for adults.
  • Autologous BMT may be acceptable in specific situations (e.g., no donor is available).
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Induction treatment for AML requires inpatient care, usually on a specialized ward. Episodes of febrile neutropenia typically require admission and IV antibiotics.
IV Fluids
Appropriate hydration to prevent TLS
Nursing
IV may lead to chemical burns in the event of extravasation.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Ambulatory, as tolerated; no intense or contact sports; no aspirin due to risk of bleeding.
Patient Monitoring
  • Repeat bone marrow studies to document remission and also if a relapse is suspected.
  • Follow CBC with differential, coagulation studies, uric acid level, and other chemistries related to TLS (creatinine, potassium, phosphate, calcium); monitor urinary function at least daily during induction phase and less frequently later.
  • Physical evaluation, including weight and BP, should be done frequently during treatment.
DIET
Ensure adequately balanced calorie/vitamin intake. Total parenteral nutrition (TPN) in case of severe mucositis
PATIENT EDUCATION
  • Leukemia Society of America, 600 Third Avenue, New York, NY 10016, 212-573-8484
  • National Cancer Institute, Bethesda, MD, has pamphlets and telephone education.
  • Baker LS. You and Leukemia: A Day At a Time. Philadelphia, PA: Saunders; 1978.
PROGNOSIS
AML remission rate is 60-80%, with only 20-40% long-term survival. The wide variable prognosis is due to prognostic group (age, cytogenetics, and genetics).
REFERENCES
1. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453-474.
2. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089.
3. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
4. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301(22):2349-2361.
5. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28(4):562-569.
Additional Reading
&NA;
O'Donnell MR, Appelbaum FR, Coutre SE, et al. Acute myeloid leukemia. J Natl Compr Canc Netw. 2008;6(10):962-993.
See Also
&NA;
Disseminated Intravascular Coagulation; Leukemia, Acute Lymphoblastic in Adults (ALL); Leukemia, Chronic Myelogenous; Myelodysplastic Syndromes; Myeloproliferative Neoplasms
Codes
&NA;
ICD10
  • C92.00 Acute myeloblastic leukemia, not having achieved remission
  • C92.01 Acute myeloblastic leukemia, in remission
  • C92.02 Acute myeloblastic leukemia, in relapse
Clinical Pearls
&NA;
  • Prognosis of leukemia depends on the cytogenetic and molecular profile of the disease.
  • Allogeneic transplant remains the only therapy with curative potential for patients with intermediateand high-risk AML.