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From Acute myeloid leukemia (AML)

Acute myeloid leukemia (AML)

   By Kottapurath Kunjumoideen MD

Acute myeloid leukemia (AML) is a type of leukemia (increased production of abnormal white blood cells due to bone marrow dysfunction). AML is diagnosed in approximately 3.6 per 100,000 individuals in the United States annually. The median age at diagnosis is 65 years, with the incidence of AML rising from 1.8 per 100,000 individuals below age 65 years to 16.3 per 100,000 individuals at age 65 years and over.

What causes acute myeloid leukemia?
Most cases of acute myeloid leukemia (AML) are the result of genetic mutations (alteration in normal gene) that occur in stem cells in the bone marrow. It also seems that the majority of these mutations are acquired during an individual's lifetime, as opposed to being inherited. Environmental factors like chemicals (benzene etc.), drugs (alkylator chemotherapy), radiation etc. have been implicated as a causative factors for AML in many cases. Genetic mutations result in two type of gene anomalies i.e translocations or deletions. Translocations result when two chromosome exchange genetic materials and deletions occur when a chromosome lose genetic material. Translocations are found in less than 10% of patients over the age of 60 years with de novo acute myeloid leukemia (AML). In contrast, genetic deletions seem to be more characteristic of older AML patients.

Symptoms and Signs of acute myeloid leukemia

Common symptoms of acute myeloid leukemia (AML) include unexplained fever, weakness and fatigue, bleeding (gums, skin bruising etc.), lymph node swelling over neck, armpits or groin and gum swelling. This is due to bone marrow dysfunction leading to decreased normal white blood cells (causes infection & fever), decreased platelets (causing bleeding) and anemia (causing fatigue).

How do you diagnose acute myeloid leukemia?
Acute myeloid leukemia is initially suspected on a complete blood count done in patients who have the above symptoms. Diagnosis is further confirmed by bone marrow biopsy and specialized tests on the bone marrow biopsy specimen namely immunohistochemistry with cytogenetic analysis are mandatory (analysis of chromosomal abnormalities). Additional tests to evaluate the extent of the disease may include renal and liver function tests. Imaging tests include a chest roentgenogram and ultrasound of abdomen and pelvis.

Classification and Prognostic factors of AML
Treatment of acute myeloid leukemia (AML) depends upon the exact sub-type of leukemia. Acute myeloid leukemia (AML) is classified into seven subtypes M1 to M7 by the French American British (FAB) classification system. Out of these M3 has got the best prognosis as a targeted therapy called ATRA (all-trans retinoic acid) is available for its treatment. The prognosis in all other AML is based on the cytogenetic analysis with most favorable outcome in translocations (8;21) and (16;16). Patients with deletion in chromosome 5, 7 or 3 have worst prognosis. In general, patients with AML whose cells have translocations seem to fare better than those whose cells have deletions. The poor prognosis associated with increased age may be related to the higher incidence of genetic deletions. Also drug and chemical induced AML have worse prognosis.

Traditional Treatment for Newly Diagnosed AML
The standard treatment of AML is systemic chemotherapy and consists of two phases: The intensive induction phase during which the majority of leukemic stem cells are killed and the consolidation phase during which the minimal residual disease left behind is attempted to be eradicated.

1. Induction chemotherapy : This comprises a seven day course of two drugs, cytosar arabinoside for seven days and anthracycline for three days (the 7+3 regimen). This is followed by a period of prolonged bone marrow suppression for around three weeks during which the patient is monitored for life threatening infections and bleeding.

2. Consolidation Phase: This comprises of intensified chemotherapy high dose cytosar arabinoside (HDAC) for 3-4 cycles over next 4 months in cases of favorable cytogenetics or an allogenic stem cell transplant (transplantation with stem cells obtained from a donor) if a suitable sibling donor is available with an HLA matched bone marrow, in cases of unfavorable cytogenetics. If no suitable donor is available for SCT, then unfavorable cytogenetic patients are also treated with 3-4 cycles of HDAC.

Monoclonal Antibody Therapy in Acute myeloid leukemia (AML)
One of the more innovative approaches to treatment of malignancy within the last decade has been the development of monoclonal antibody (MAb) therapy. By targeting features unique to malignant cells, these treatments conceptually allow for eradication of malignant clones while sparing normal tissue. Anti CD-33 antiobody Gemtuzumab is currently investigational in US. Gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories; Madison, New Jersey) has been approved by the FDA for relapsed/refractory CD33-positive AML in patients aged 60 years or older who are not considered candidates for other types of cytotoxic chemotherapy.

Role of Supportive Care in AML
Besides the cytotoxic chemotherapy AML patients require intensive supportive care preferably in intensive care units (ICU) with blood components, empirical antibiotics, growth factors (controversial) and good nutritional support.

The treatment of AML is advancing rapidly, and, like therapy in other malignant states, is favoring treatment strategies "tailored" to specific leukemia subtypes. As more becomes known about the genetic and molecular characteristics of leukemia cells, and the pathways of leukemogenesis are further elucidated, it is hoped that future therapies will be directed specifically toward the least toxic clonal malignant cells. The use of more supportive measures to allow for more intensive therapies may begin to change the disappointing outcomes now seen in older patients.

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