Acute Myeloid Leukemia (AML)

What is Acute Myeloid Leukemia?

Acute Myeloid Leukemia (AML) is a disorder of the process that normally produces neutrophils, a type of white blood cell. These abnormal cells rapidly fill up the bone marrow space, suppressing the normal cells. AML may sometimes be called Acute Myelogenous Leukemia, Acute Myelocytic Leukemia, and or Acute Nonlymphocytic Leukemia. Unlike chronic leukemia, acute leukemia develops quickly and generally needs immediate treatment. Acute Myeloid Leukemia is the most common type of acute leukemia which affects adults and chances of getting Acute Myeloid Leukemia increases with age.

What Causes Acute Myeloid Leukemia?

Acute Myeloid Leukemia is caused by damage to the DNA of developing cells in bone marrow. Though exact cause of Acute Myeloid Leukemia is not known, several risk factors for developing Acute Myeloid Leukemia have been identified. General risk factors for AML include the following:

• Exposure to the chemical benzene
• Being male.
• Smoking, especially after age of 60
• Treatment with chemotherapy or radiation therapy in the past
• Treatment for childhood acute lymphoblastic leukemia (ALL) in the past
• Being exposed to radiation from an atomic bomb
• History of a blood disorder such as myelodysplastic syndrome
• Weakened immune system due to an organ transplant
• Certain genetic disorders, including Down’s syndrome and Fanconi’s anaemia

What are the Symptoms of Acute Myeloid Leukemia?

The symptoms are usually similar to ALL which are as under. In certain types of AML, like Acute Monocytic Leukemia, the gum around the teeth swells up abnormally. In a distinct variety of AML called Acute Promyelocytic Leukemia (APML), the presenting symptom is often severe and persistent bleeding.

• Fever
• Fatigue
• Weight loss or loss of appetite
• Shortness of breath
• Anaemia
• Easy bruising
• Severe Bleeding
• Petechiae (flat, pin-head sized spots under the skin caused by bleeding)
• Bone and joint pain
• Persistent or frequent infections
• Abnormal swelling of gums around teeth

How do we Diagnose Acute Myeloid Leukemia?

• Complete Blood Count: The characteristic finding of AML is high white blood cell count with low haemoglobin and platelets. Routine examination of the blood gives the diagnosis.
• Peripheral Blood Smear: Presumptive diagnosis of AML can be made via examination of the peripheral blood smear when there are circulating leukemic blasts.
• Bone Marrow Examination: This is necessary for confirmation of the diagnosis. There must be more than 20% of abnormal cells (Blasts) in the bone marrow to call it leukemia. However, in certain types of Acute Myeloid Leukemia, presence of the characteristic abnormality in chromosome is enough to call it Acute Myeloid Leukemia even with fewer than 20% blasts in the marrow.
• Flow Cytometry: AML has seven subtypes (AML-M1 ---- AML-M7). There are further subtypes in the individual categories. This has got implications on the choice of treatment and outcome. Although the initial classification was based on what was seen under the microscope with special stains, Flow Cytometry is necessary for more precise classification.
• Cytogenetics: This is testing for abnormalities in the chromosomes.
  • Certain genes are brought next to each other by a process called ‘translocation’ leading to uninterrupted growth of these cells. The classical example is the translocation of a part of chromosome 15 to 17 resulting in the PML gene juxtaposed to the RARA gene (called PML-RARA). Both are normal genes, but when they interact they result in stoppage of cell maturation. Several such translocations have been detected in AML, such as 8:21, 16:16, 6:9 etc.
  • Missing pair of a chromosome in positions 5, 7, 8 is also a feature of AML. This is called Monosomy.
  • Certain changes in sequence of the genes called mutations are also seen which have an impact on outcome.

How do we classify Acute Myeloid Leukemia to decide on the outcome?

Unlike cancers of solid organs, ALL and other blood cancers are not staged by the extent of involvement. Certain features related to the patient, the disease and the impact of treatment are taken into account to classify them as Standard-Risk or Good-Risk, Intermediate-Risk and High-Risk. This is predominantly based on the abnormality of chromosomes or genes.

What is Minimal Residual Disease (MRD)?

Minimal Residual Disease (MRD) means patient still has a minimum disease and has not fully recovered. Response to treatment is conventionally defined by the number of blasts we see under the microscope. If we see less than 5% such cells it is called COMPLETE REMISSION (CR). However, CR means that the number of leukemia cells in the body are less than 109 or 1000 million cells. Further treatment which spans over months of intensive treatment and years of oral treatment are geared to reduce the number of leukemia cells to a level where our immune system can eliminate the remaining cells.

MRD is the detection of cells below 1%, which can range of 1 in 1000 to 1 in a million cells. This enables us to monitor the effect of treatment and change it if needed.

How do we treat Acute Myeloid Leukemia?

Chemotherapy: Chemotherapy for AML is divided in two phases, INDUCTION and CONSOLIDATION. About 60-70% of patients achieve primary control of the leukemia called COMPLETE REMISSION (CR). The outcome of treatment with chemotherapy depends on the RISK CATEGORY.

The chances of a sustained remission or cure are as follows:

• Good Risk : 50-70%
• Intermediate Risk : 30%
• High Risk : Less than 10%

What is different about treatment of APML or AML-M3?

This is a unique condition which responds to high doses of a form of Vitamin A called ALL-TRANS RETINOIC ACID (ATRA) and ARSENIC TRIOXIDE. Very little if any chemotherapy is required in this condition. The cure rate in this condition reaches 90%.

Bone Marrow Transplantation (BMT) for Acute Myeloid Leukemia

When is BMT needed for AML?

• Chemotherapy is curative in only one-third of patients with AML. All patients with AML apart from those with GOOD chromosomes benefit from an Allogeneic BMT.
• BMT is best done when the disease is in first CR.
• Very few patients who RELAPSE or do not respond to treatment are cured.

How is Conditioning for BMT done in AML?

High to Moderate dose of chemotherapy is generally used in conditioning for BMT.

Who can be a donor for BMT?

Although we prefer a matched family donor, a Half matched (Haploidentical) family donor or an unrelated cord blood are suitable alternatives.

However, a HAPLOIDENTICAL DONOR who has Natural Killer Cell mismatch with the patient provides the best chance of cure

What are the results of BMT in AML?

• BMT reduces the risk of relapse ie recurrence of disease by 80% compared to chemotherapy
• If the patient is MRD negative before BMT, the risk of relapse is low
• BMT is the only cure for patients, who relapse after chemotherapy