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Category: Hematology | Oncology

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Acute myeloid leukemia overview

Updated: July 29, 2009

Acute myeloid leukemia, or AML is the most commonly diagnosed type of adult leukemia, and accounts for about half the cases of childhood leukemia. It is specifically a malignancy of the myeloid line of white blood cells.


The incidence of acute myelogenous leukemia (AML) is 2.7 per 100,000 population.

Estimated new cases and deaths from acute myeloid leukemia (AML) in the United States in 2005.

  • New cases: 11,960.
  • Deaths: 9,000.


Slightly higher in males than in females. There are two theories to explain slightly higher incidence in males: Occupational exposure to chemical carcinogens and the higher incidence of myelodysplastic syndrome in males.


AML affects all age groups. Age-specific incidences of AML are similar to those of other solid tumors in adults, with an exponential rise after age 40 years. The median age of onset is 65.

Race and ethnicity

The incidence of acute leukemia is slightly higher in populations of European descent (whites). Also, a report from the University of Southern California indicates that acute promyelocytic leukemia (APL) is more common in Hispanic populations than in other ethnic groups.


AML is more commonly diagnosed in developed countries.

Causes and risk factors

It is unlikely that there is one common etiology for leukemogenesis and most patients who present with de novo AML have no identifiable risk factor. There are, however, some accepted risk factors for acute myeloid leukemia.

Chemical exposure

Increased incidence has been reported in persons with prolonged exposure to benzene and petroleum products. Exposure to benzene is also associated with aplastic anemia and pancytopenia. These patients often develop AML. Chromosomal damage in these subjects is common, many of which demonstrate M6 morphology. The interval between exposure and onset of leukemia is long (up to 10-30 years).

Pesticide exposure also has been linked to some forms of AML. The incidence of AML is beginning to rise in developing countries, as industrialization and pollution increase.

Exposure to hair dyes, smoking, and nonionic radiation may also increase the risk of leukemia.

Antecedent hematological disorders

The most common risk factor is the presence of an antecedent hematological disorders, the most common of which is MDS. Other antecedent hematological disorders include:

  • Chronic myeloid leukemia: Most patients with chronic myelogenous leukemia, a myeloproliferative disorder, eventually develop a blast phase indistinguishable from acute myeloid leukemia.
  • Myelofibrosis
  • Aplastic anemia
  • Paroxysmal nocturnal hemoglobinuria
  • Polycythemia vera

Prior chemotherapy & radiotherapy

This has become more common as more patients with cancer survive their primary malignancy and more patients receive intensive chemotherapy (including bone marrow transplantation [BMT].

Alkylating agents

Use of alkylating agents, such as cyclophosphamide (Cytoxan, Neosar) and melphalan (Alkeran), in the treatment of lymphomas, myelomas, and breast and ovarian cancers has been associated with the development of AML, usually within 3-5 years of exposure and often preceded by a myelodysplastic phase. Cytogenetic abnormalities, particularly monosomy 5, 7, 11, and 17, are common.


Concurrent radiation exposure slightly increases the risk of leukemogenesis posed by alkylating agents.

Topoisomerase II

  • Topoisomerase II inhibitors (etoposide [VePesid], teniposide [Vumon]
  • Doxorubicin and its derivatives, and mitoxantrone [Novantrone])

These agents, in contrast to alkylators, are associated with a short latency period (9-12 months) without antecedent myelodysplasia and with cytogenetic abnormalities involving chromosome 11q23 or 21q22 in the malignant clone.

Genetic disorders

An increased incidence of AML is seen in patients with:

  • Fanconi's anemia
  • Ataxia-telangiectasia
  • Down syndrome
  • Bloom syndrome
  • Wiskott-Aldrich syndrome

Familial syndromes

Familial syndromes are rare such as those of familial erythroleukemia (a subtype of AML). Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia.

Symptoms and signs

AML is usually diagnosed in adults after a few days of nonspecific symptoms which are due to abnormal blood cell number, such as fatigue, weakness, bruises, small rash-like spots, gum and nose bleeds or infection. In some patients, particularly younger ones, present with acute symptoms over a few days to 1-2 weeks. Others have a longer course, with fatigue or other symptoms lasting from weeks to months. A longer course may suggest an antecedent hematologic disorder such as MDS.

Generally speaking, manifestations result from either bone marrow failure, organ infiltration with leukemic cells or both.

Effects on hematopoeisis

Most of the symptoms associated with AML (such as fatigue, weakness, bruises, small rash-like spots, gum and nose bleeds or infection) are all reflections of the anemia, thrombocytopenia, and decrease in functional neutrophils associated with marrow replacement by malignant cells.

So, whereas, classically elevated WBCs are expected in leukemia this only happens in about 10% of the patients and constitutes a bad prognostic sign as they are at increased risk of CNS disease, tumor lysis syndrome, and leukostasis due to impedance of blood flow from intravascular clumping of blasts, which are "stickier" than mature myeloid cells. More commonly patients present with pancytopenia and a decrease in WBCs as a result of a decrease in functional neutrophils associated with marrow replacement by malignant cells.

Physical findings

Physical findings in AML are usually minimal.

  • Pallor (anemia).
  • Increased ecchymoses or petechiae, retinal hemorrhage (thrombocytopenia, coagulopathy).
  • Fever may occur due to infection (leukopenia).
  • Signs relating to leukostasis include respiratory distress and altered mental status (leukocytosis).
  • Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.
  • Manifestations of organ infiltration include: Gingival hypertrophy, and cutaneous involvement (leukemia cutis). Visceral involvement (hepatosplenomegaly and, to a lesser degree, lymphadenopathy) is also rare, occurring as an initial manifestation of AML in < 5% of cases, but it may be more frequent during subsequent relapses. These focal collections of blasts, called chloromas or granulocytic sarcomas, can present as soft-tissue masses, infiltrative lesions of the small bowel and mesentery, or obstructing lesions of the hepatobiliary or genitourinary system. Organ inflitration is generally more common with monocytic (M4 or M5) variants of AML than with other variants of AML.


Hyperuricemia with possible interstitial or ureteral obstruction is seen predominantly in AML with moderate leukocytosis; this condition may be exacerbated by a rapid response to chemotherapy and the "tumor lysis syndrome" (hyperuricemia with renal insufficiency, acidosis, hyperphosphatemia, and hypocalcemia), which may occur within the first 24-48 hours after initiating chemotherapy. To prevent this complication, all patients should receive allopurinol (Zyloprim) and urine alkalinization before marrow-ablative chemotherapy is initiated.


Coagulopathies can also complicate the hemostatic defects associated with thrombocytopenia. Disseminated intravascular coagulation (DIC) is most often seen in APL (French-American-British Cooperative group [FAB] subtype M3) due to release of procoagulants from the abnormal primary granules, which activate the coagulation cascade, leading to decreased factors II, V, VIII, and X, and fibrinogen, as well as rapid platelet consumption. Lysozyme released from monoblasts in M4 and M5 subtypes of AML can also trigger the clotting cascade.


Clinical suspicion

The clinical picture and abnormalities on the CBC raise the possibility of leukemia.



AML is usually accompanied by an abnormal white blood cell count and differential, hematocrit/ hemoglobin, and platelet count.

Bone marrow examination

The diagnosis is substantiated pathologically by a bone marrow examination which exhibits an abnormal bone marrow with at least 20% blasts.

Immunophenotyping & cytogenetics

All patients should have cytochemistry, immunophenotyping by fluorescentactivated cell sorter (FACS) using monoclonal antibodies directed at leukemiaspecific antigens and cytogenetic analysis of the marrow or peripheral blood blasts at diagnosis.


A chest x-ray, abdominal ultrasound may help in the assessment of infection and organ infiltration.

Lumbar puncture

A lumbar puncture should be performed at diagnosis in all patients with neurologic symptoms regardless of age and pathology.

Other tests

Other tests used to evaluate metabolic abnormalities (electrolytes, creatinine, and liver function tests) and coagulopathies are also needed at diagnosis.


Myeloid leukemias are characterized as "acute" or "chronic" based on how quickly they progress if not treated. They can be further characterized morphologically, cytochemically, or by characterization of the underlying chromosomal abnormality. The old French-American-British (FAB) classification system groups these into seven different diseases (M0, M1, M2, M3, M4, M5, M6, & M7).

The FAB classification

  • M0 - Undifferentiated leukemia
  • M1 - Myeloblastic without differentiation
  • M2 - Myeloblastic with differentiation
  • M3 - Promyelocytic
  • M4 - Myelomonocytic
  • M4eo - Myelomonocytic with eosinophilia
  • M5 - Monoblastic leukemia
  • M5a - Monoblastic without differentiation
  • M5b - Monocytic with differentiation
  • M6 - Erythroleukemia
  • M7 - Megakaryoblastic leukemia

The WHO classification

AML with recurrent cytogenetic translocations
AML with t(8;21)(q22;q22) AML1/CBFalpha/ETO
Acute promyelocytic leukemia:
AML with t(15;17)(q22;q12) and variants PML/RARalpha
AML with abnormal bone marrow eosinophils inv(16)(p13;q22) vagy t(16;16)(p13;q22) CBFbeta/MYH1
AML with 11q23 MLL abnormalities
AML with multilineage dysplasia
With prior MDS
Without prior MDS
AML with myelodysplastic syndrome, therapy related
Alkylating agent related
Epipodophyllotoxin related
Other types
AML not otherwise categorized
AML minimally differentiated
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monocytic leukemia
Acute erythroid leukemia
Acute megakaryocytic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Acute leukemias of ambiguous lineage

The changes in the WHO classification can be easily summarized: the leukemias with consistent cytogenetic abnormalitites and those that are MDS related were taken into separate groups, the rest of the old FAB classification was put under the "AML not otherwise categorized" entry.

Common cytogenetic abnormalities in AML


Genes involved Morphology Response
t(8;21)(q22;q22) AML/ETO M2 Good
inv(16)(p13;q22) CBFb/MYH11 M4eo Good
Normal Multiple Varies Intermediate
-7 Multiple Varies Poor
-5 Multiple Varies Poor
+8 Multiple Varies Intermediate-poor
11q23 MLL Varies Intermediate-poor
Miscellaneous Multiple Varies Intermediate-poor

Immunophenotyping of AML cells



CD13 Myeloid
CD33 Myeloid
CD34 Early precursor
HLA-DR Positive in most AML, negative in APL
CD11b Mature monocytes
CD14 Monocytes
CD41 Platelet glycoprotein IIb/IIIa complex
CD42a Platelet glycoprotein IX
CD42b Platelet glycoprotein Ib
CD61 Platelet glycoprotein IIIa
Glycophorin A Erythroid
TdT Usually indicates acute lymphocytic leukemia, however, may be positive in M0 or M1

Staging and prognostic factors


Cytogenetic analysis provides the strongest prognostic information available, predicting outcome of both remission induction and postremission therapy.

Cytogenetic abnormalities that indicate a good prognosis include:

  • t(8;21)
  • inv(16)
  • t(15;17)

Cytogenetic abnormalities that indicate a average prognosis include:

  • Normal cytogenetics.

Cytogenetic abnormalities that indicate a poor prognosis include:

  • Deletions of the long arms or monosomies of chromosomes 5 or 7
  • Translocations or inversions of chromosome 3, t(6;9), t(9;22)
  • Abnormalities of chromosome 11q23

Associated antecedent hematological disorders

History of myelodysplastic syndrome confers poor prognosis.

Therapy-related AML

Therapy-related AML has a particularly poor prognosis.


Remission rates in adult AML are inversely related to age, with an expected remission rate of >65% for those younger than 60 years. Data suggest that once attained, duration of remission may be shorter in older patients. Increased morbidity and mortality during induction appear to be directly related to age.

Other factors

  • Central nervous system involvement with leukemia
  • Systemic infection at diagnosis
  • Elevated white blood cell count (>100,000/mm3)
  • Leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product) have an inferior outcome.
  • Presence of the unique fusion transcript PML-RARa (measured in bone marrow by polymerase chain reaction) in M3 AML patients who achieve complete remission may indicate those who are likely to relapse early.


Chemotherapeutic treatment is divided into two main phases: induction and postremission therapy.

Induction therapy

In all FAB subtypes except M3, the usual treatment includes cytarabine and an anthracycline (such as daunorubicin or idarubicin). Complete remission is obtained in about 70 percent of newly diagnosed adults. The bone marrow is examined for malignant cells after each course of treatment: remission can be achieved after one to three courses.

One of the following equivalent combination chemotherapy regimens

  • Dose-intensive cytarabine-based induction therapy.
  • Cytarabine + daunorubicin.
  • Cytarabine + idarubicin.
  • Cytarabine + daunorubicin + thioguanine.
  • Mitoxantrone + etoposide.

Treatment of central nervous system leukemia, if present:

  • Intrathecal cytarabine or methotrexate.


  • The overall rate of CR in large cooperative group studies is approximately 65%.

Clinical trials

The role of high-dose cytarabine in induction therapy is controversial; randomized trials have shown prolongation of disease-free survival or no effect compared with conventionally-dosed cytarabine-based induction chemotherapy.

Treatment of secondary AML

AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML.

Bone marrow transplantation

Data suggests that patients with these subsets of leukemia may be treated primarily with allogeneic bone marrow transplantation if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy which appears to have no effect on disease free survival.


  • Disease-free survival is approximately 20%.

Supportive care

Supportive care during remission induction treatment should routinely include:

  • Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality.
  • Red blood cell and platelet transfusions when appropriate.
  • Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.
  • Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients.
  • White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that do not respond to antibiotics.
  • Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100/mm3 for 2 weeks). Norfloxacin and ciprofloxacin have both been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection. Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.
  • Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.

Promyelocytic Leukemia

Induction therapy

ATRA (Tretinoin)

  • Oral administration of tretinoin (all-trans-retinoic acid (ATRA); 45 mg/mm2/day) can induce remission in 70% to 90% of patients with M3 AML.
  • 2 large cooperative group trials have demonstrated a statistically significant relapse-free and overall survival advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.

ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RARa gene rearrangement.

ATRA induces terminal differentiation of the leukemic cells, followed by restoration of nonclonal hematopoiesis.

ATRA - chemotherapy combinations

A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared with ATRA induction followed by chemotherapy given in remission (relative risk (RR) of relapse at 2 years, 0.41, P=.04).

ATRA plus anthracycline induction followed by 3 cycles of consolidation and maintenance therapy has showed an improvement in disease free survival.

A retrospective review of randomized trials from the Southwest Oncology Group has suggested that the dose-intensity of daunorubicin administered in induction and consolidation chemotherapy may significantly impact on remission rate, disease-free survival, and overall survival in patients with M3 AML.

Complete remission in AML

Adult acute myeloid leukemia (AML) in remission is defined as a normal peripheral blood cell count and normocellular marrow with less than 5% blasts in the marrow, and no signs or symptoms of the disease. In addition, there are no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.

Postremission therapy

Although individual patients have been reported to have long disease-free survival or cure with a single cycle of chemotherapy, postremission therapy is always indicated in therapy that is planned with curative intent.

In a small randomized study conducted by the Eastern Cooperative Oncology Group (ECOG), all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration.

Postremission therapy can include more intensive chemotherapy, or bone marrow transplant.

1. Nontransplant consolidation therapy

A large randomized trial that compared 3 different cytarabine-containing consolidation regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine.A large randomized trial that compared 3 different cytarabine-containing consolidation regimens showed a clear benefit in survival to patients younger than 60 years who received high-dose cytarabine.

  • Nontransplant consolidation therapy using cytarabine-containing regimens has reported disease-free survival rates from 20% to 50%.
  • Treatment-related death rates are usually less than 10% to 20%.

2. Allogeneic bone marrow transplantation

  • Disease-free survival rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.
  • The mortality from allogeneic bone marrow transplantation that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series.

Allogeneic bone marrow transplantation results in the lowest incidence of leukemic relapse, even when compared with bone marrow transplantation from an identical twin (syngeneic bone marrow transplantation). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic bone marrow transplantation as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis.

The use of matched, unrelated donors for allogeneic bone marrow transplantation is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with disease-free survival rates less than 35%.

3. Autologous bone marrow transplantation

  • Autologous bone marrow transplantation yielded disease-free survival rates between 35% and 50% in patients with AML in first remission.
  • Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%.

Autologous bone marrow transplantation has also cured a smaller proportion of patients in second remission.

Maintenance therapy

Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States as there is no convincing evidence in AML that maintenance therapy provides prolonged disease-free survival beyond shorter-term, more dose-intensive approaches.

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