Acute Myelocytic Leukemia

Acute myelocytic leukemia is a myeloproliferative disorder characterized by the accumulation of abnormal myeloid precursors in the bone marrow. The disease may be associated with end organ dysfunction resulting from an infiltration with leukemic cells, but mortality is most commonly due to the consequences of bone marrow failure.

Acute Myelocytic Leukemia originates from neoplastic processes.

Presentation

AML is associated with progressive bone marrow failure. Accordingly, patients usually present with symptoms related to anemia, granulocytopenia/neutropenia, and thrombocytopenia.

Of note, leukocytosis is not uncommon in AML patients. In the case of hyperleukocytosis (>100 x 109/l), symptoms of leukostasis may manifest. Such symptoms comprise ocular and cerebrovascular hemorrhages and dysfunction [10].

On the other hand, leukemic cells may infiltrate distinct end organs, interfere with their function and cause discomfort or pain. Findings like hepatosplenomegaly (early satiety and abdominal fullness), leukemia cutis (multiple, indolent cutaneous nodules), granulocytic sarcoma (isolated mass of leukemic blasts), and bone pain may thus also indicate AML.

Workup

Laboratory analyses of blood samples including a complete cell count with differential count are generally the first step towards the diagnosis of AML. Indeed, the incidental detection of hematological anomalies that precede the onset of clinical symptoms is not uncommon in older patients undergoing routine screenings and may allow for an early diagnosis of leukemia and a timely initiation of treatment. Pancytopenia or any combination of anemia, granulocytopenia, and thrombocytopenia are often observed and may indicate imminent or existing bone marrow failure. As has been mentioned above, leukocytosis and even hyperleukocytosis may also be observed.

Subsequently, an aspiration of bone marrow needs to be performed. Immunohistochemical staining for myeloperoxidase expression or immunophenotyping of bone marrow blasts should be performed to confirm the involvement of the myeloid lineage. In general, the presence of more than 20% leukemic blasts in bone marrow specimens is required for the diagnosis of AML [11]. Furthermore, samples should be analyzed regarding their cytogenetic and molecular features. A detailed characterization of blasts is necessary for prognostic and therapeutic reasons.

In order to prevent and identify possible complications of AML, a comprehensive metabolic profile, as well as coagulation studies, should be ordered. Diagnostic imaging may be indicated to assess the condition of the patient's heart, lungs and possible central nervous system involvement.

Treatment

Cytotoxic chemotherapy and hematopoietic stem cell transplantation are the mainstays of therapy. Distinct chemotherapeutic regimens have been used in AML patients, but the standard induction therapy consists of anthracyclines (e.g., daunorubicin at a minimum dose of 60 mg/m², idarubicin at a dose of approximately 10 mg/m², for three days) and cytarabine (at a dose of up to 200 mg/m², for seven days) [11]. Such treatment should be initiated as soon as possible and leads to complete remission in the majority of adults aged less than 60 years. Older patients known to have adverse cytogenetics may be considered for alternative approaches, e.g., investigational regimens or mild cytoreductive therapy.

Post-remission strategies include intense chemotherapy with high-dose cytarabine, prolonged maintenance treatment, as well as autologous and allogeneic stem cell transplantation. Precise recommendations depend on prior risk assessment and genetic features displayed by clonal tumor cells. For instance, allogeneic stem cell transplantation is associated with the lowest rates of recurrence, but also with high treatment-related mortality. Thus, it is typically considered for high-risk AML patients if a matched donor is available.

Patients presenting with bone marrow failure should be stabilized before further therapeutic measures are undertaken. Here, medical care may include the transfusion of blood products, antimicrobial therapy, and leukapheresis, as needed. AML treatment may be restricted to palliative measures in patients suffering from severe comorbidities.

It is beyond the scope of this article to discuss target-oriented therapy for individual types of AML, but excellent reviews on this topic are available elsewhere [12].

Prognosis

AML is generally associated with an unfavorable prognosis; if left untreated, it is uniformly fatal. Despite the provision of optimum medical care, most patients die from bone marrow failure. Five years after diagnosis, only 21% of AML patients remain alive, but this value is highly age-dependent: More than half of AML patients aged less than 45 years survive for more than five years, in contrast to less than 10% of those aged 65 years and older [7].

It is important to note that median survival times observed in patients diagnosed with distinct subtypes of AML vary largely [8]:

  • Translocations t(8;21)(q22;q22), t(15;17)(q24;q21), and inv(16)(p13;q22) are associated with a favorable prognosis and a 5-year-survival rate of 55%.
  • Patients with AML and normal cytogenetics constitute the largest subgroup and are usually assigned an intermediate prognosis; their 5-year-survival rates range between 24 and 42%. Here, the identification of genetic abnormalities of malignant cells may allow for a more reliable prognosis. The interested reader is referred to an extensive review on this topic [9].
  • Monosomy 5 or 7, 11q23 rearrangements and complex chromosomal aberrations are related to a poor prognosis; the respective 5-year-survival rate is only 11%.

Etiology

AML is the result of anomalies in hematopoietic cell differentiation and proliferation. These are essentially due to chromosomal aberrations that are discussed in detail below. Both endogenous and exogenous factors may contribute to the malignant transformation of myeloid precursors. In this context, the following risk factors have been identified [2]:

Epidemiology

AML is the most common acute leukemia in adults, and about 20,000 cases are diagnosed each year in the United States alone [3]. The latter corresponds to an annual incidence of about 1 in 15,000 inhabitants, and similarly, high incidence rates have only been reported in Europe and Australia [4]. Age-specific incidence rates follow a bimodal distribution: Infants and young children are more likely to develop AML than older children and young adults, while highest incidence rates are observed in the elderly population. Accordingly, the patients' median age at symptom onset is 65 years. People age 65 years and older have a tenfold increased risk of developing AML when compared with young adults [2]. Moreover, incidence rates depend on race and gender. For instance, Caucasians are more prone to develop AML at very young ages compared to patients of African descent, while the disease is more frequently diagnosed in older black children and adolescents. Males are affected slightly more often than females.

Sex distribution
Age distribution

Pathophysiology

Only a minor proportion of cases can unequivocally be related to either of the above -mentioned risk factors. Indeed, AML is most likely not the result of a single event or gene defect, but the consequence of a susceptible myeloid precursor being subjected to additional influences that induce leukemogenesis. According to the so-called "2-hit-hypothesis", a first mutation confers a proliferative and survival advantage to the respective cell. Only subsequent rearrangements provoke the onset of leukemia: They result in a maturation arrest and reduced apoptosis [5]. The molecular mechanisms underlying this development vary depending on the precise chromosomal aberration(s) and environmental factor(s). The heterogeneity of leukemogenesis is best illustrated by the diversity of acquired cytogenetic anomalies that may be detected in bone marrow specimens obtained from AML patients:

  • Partial or complete loss of chromosomes 5 or 7
  • Trisomy 8 or 21
  • Translocations t(8;21)(q22;q22), t(15;17)(q24;q21), t(16;16)(p13;q22), inv(16)(p13;q22)
  • 11q23 rearrangements

As the presence of genetic features is of prognostic and therapeutic relevance, the identification of recurrent genetic abnormalities constitutes the basis of modern AML classification [6]. Furthermore, AML may be related to Down syndrome, myelodysplasia or prior chemotherapy. It is important to note that the current World Health Organization classification of myeloid neoplasms and acute leukemia additionally lists AML, not otherwise specified, as a subtype of AML.

Prevention

According to the information given above, avoidance of risk factors may be of help to prevent AML. Corresponding measures may include refraining from tobacco consumption and reducing the exposure to radiation and chemical carcinogens, inter alia by implementing occupational safety standards.

Summary

The term acute myelocytic leukemia (AML), possibly also referred to as acute myeloid leukemia or acute myelogenous leukemia, describes a group of myeloproliferative disorders. In all types of AML, malignant transformation of myeloid precursor cells is associated with a maturation arrest and impaired apoptosis. This may affect precursors of granulocytes, monocytes, mast cells, erythrocytes or platelets. With regards to the prevailing stage of degenerated blasts, the following subtypes of AML may be distinguished (French-American-British classification, [1]):

  • Acute myeloblastic leukemia
  • Acute promyelocytic leukemia
  • Acute myelomonocytic leukemia
  • Acute monoblastic leukemia
  • Acute monocytic leukemia
  • Acute erythroid leukemia
  • Acute megakaryoblastic leukemia
  • Mixed lineage leukemia (both myeloproliferative and lymphoproliferative features)

In any case, the clonal population of tumor cells interferes with bone marrow function and hematopoiesis. Affected individuals thus tend to develop pancytopenia and present with symptoms consistent with anemia, immunodeficiency and a propensity to bleed. To date, treatment of AML mainly consists of non-specific measures like cytotoxic chemotherapy and hematopoietic stem cell transplantation. Unfortunately, this approach continues to be related to poor survival rates.

Recent studies shed more light on the molecular mechanisms underlying leukemogenesis in single types of AML and emphasize the need for a personalized, target-oriented therapy. Treatment recommendations are thus to be expected to change in the near future.

Patient Information

Acute myelocytic leukemia (AML), sometimes also referred to as acute myeloid leukemia, is a myeloproliferative disorder and hematological malignancy. It is characterized by an excess proliferation of myeloid precursors in the bone marrow. These cells originate from hematopoietic stem cells and are supposed to differentiate into red blood cells, white blood cells and platelets. Because the development of these cell populations involves distinct intermediate stages, patients may suffer from different subtypes of AML. Acute promyelocytic leukemia, for instance, is defined as an accumulation of abnormal promyelocytes, which are granulocyte precursors. In any case, the presence of abundant tumor cells in the bone marrow interferes with this organ's function and hematopoiesis. Eventually, this condition may lead to bone marrow failure. Symptoms of imminent bone marrow failure may be anemia, recurrent infections with opportunistic pathogens and a propensity to bleed.

Although several endogenous and exogenous factors have been related to the onset of AML, the etiology of this type of blood cancer remains poorly understood. Few cases are related to Down syndrome, Klinefelter syndrome, myelodysplasia, prior cytotoxic chemotherapy, as well as exposure to chemical carcinogens and radiation, but in the majority of patients, causes cannot be identified. In order to diagnose AML, bone marrow specimens have to be analyzed. A detailed characterization of tumor cells is necessary for prognostic and therapeutic reasons. To date, treatment primarily consists of cytotoxic chemotherapy and hematopoietic stem cell transplantation, but more specific approaches may be feasible in certain types of AML. To summarize, an individual patient's prognosis depends on the type of AML, on the genetic features displayed by degenerated myeloid precursors, on the patient's age and overall condition, and the involvement of extramedullary sites.

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References

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