Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic leukemia (ALL), is a cancer that starts from white blood cells called lymphocytes in the bone marrow (the soft inner part of the bones, where new blood cells are generated).

The term "acute" means that the leukemia can progress quickly, and if not treated, would probably be fatal within a few months. 'Lymphoblastic' means it develops from early (immature) forms of lymphocytes, a type of white blood cell.

Acute Lymphoblastic Leukemia is the commonest childhood cancer. This arises from abnormalities in the precursors of normal lymphocytes which are otherwise a normal part of our immune system necessary to fight infections. These abnormal cells rapidly fill up the bone marrow space suppressing the normal cells.

In most cases, the disease is characterised by certain abnormalities in the chromosomes which promote abnormal growth of certain lymphoid cells rather than maturation to normal lymphocytes.

This is not known in most cases. However, exposure to radiation, exposure to high voltage electric wires and chemical exposures are few known risk factors.

Symptoms

• General weakness
• Fatigue
• High temperature (fever)
• Weight loss
• Frequent infections
• Bruising easily or with no obvious cause
• Bleeding from the gums or nose
• A fine rash of dark red spots (called purpura)
• Blood in urine or stools
• Pain in the bones or joints
• Breathlessness
• Swollen lymph glands
• Enlarged liver or spleen

Complete Blood Count

The characteristic finding of Acute Lymphoblastic Leukemia is high white blood cell count with low haemoglobin and platelets. Routine examination of the blood under the microscope may confirm the presence of abnormal cells (blasts).

Bone Marrow Examination

This is necessary for confirmation of the diagnosis. There must be more than 30% of abnormal cells (blasts) in the marrow for it to be called Acute Lymphoblastic Leukemia.

Flow Cytometry

ALL has two broad subtypes- B cell Acute Lymphoblastic Leukemia and T cell Acute Lymphoblastic Leukemia. There are further subtypes in the individual categories. This has got implications on the choice of treatment and the likely outcome.

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 and proliferation of white blood cell precursors in the bone marrow (e.g., Philadelphia Chromosome). Both are normal genes, but when they interact they produce an abnormal protein which drives the cancer. The absolute increase (Hyperdiploid) or decrease (Hypodiploid) in the number of chromosomes in the cancer cells are also features of ALL. Certain changes in sequence of the genes called mutations are also seen which have an impact on outcome of treatment.

Classification

Unlike cancers of solid organs, Acute Lymphoblastic Leukemia and other blood cancers are not staged by the extent of involvement. Certain features related to the patient and the disease help in classifying the patients as: Standard-Risk or Good-Risk, Intermediate-Risk and High-Risk.

• Age: if the patient is 2–10 years old, it is considered favourable
• Cytogenetics: Certain chromosomal abnormalities such as increase in number of chromosomes (Hyperploidy) and translocation are features of a favourable outcome.
• Response to Treatment: Response to steroids after 7 days is probably a very good indicator of how the disease is going to respond to further treatment.

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 checked with a bone marrow morphology which establishes COMPLETE REMISSION (CR). However, CR means that the number of leukemia cells in the body are less than 10⁹ or 1000 million cells. At this level, they cannot be seen under the microscope.

MRD is the detection of cells below 1%, which can range from 1 in 1000 to 1 in a million cells. This enables us to check for response to treatment with a much higher sensitivity than possible under the microscope.

Treatment Phases

• Induction Therapy: The first phase of treatment to kill most of the leukemia cells in the blood and bone marrow and restore normal blood cell production.
• Consolidation Therapy: Also known as post-remission therapy. Aimed at destroying any remaining leukemia cells in the body.
• Maintenance Therapy: Helps in preventing leukemia cells from regrowing. Treatments used in this stage are often given at lower doses over a long period of time.
• Preventive treatment to the spinal cord: Patients suffering from acute lymphocytic leukemia may also receive treatment to kill leukemia cells located in the central nervous system. In this treatment, chemotherapy drugs are injected directly into the fluid that surrounds the spinal cord.
• Radiation Therapy: Radiation therapy uses high-powered beams, such as X-rays, to kill cancer cells. If the cancer cells have spread to the central nervous system, your doctor may recommend radiation therapy.

Depending on patient's evaluation, the phases of treatment for acute lymphocytic leukemia can span up to 2-3 years.

Role of Chemotherapy

• 90% of the children with Standard Risk Acute Lymphoblastic Leukemia are cured with Chemotherapy alone.
• 60-70% of children with Intermediate Risk Acute Lymphoblastic Leukemia are cured with Chemotherapy alone.
• 40% of children with High Risk Acute Lymphoblastic Leukemia are cured with Chemotherapy alone.

ALL has a tendency to spread to the brain. Hence, the treatment involves giving intrathecal chemotherapy periodically through a Lumbar Puncture. Intravenous chemotherapy is also given over 6 months, followed by oral drugs for 18-30 months. Boys are treated for a longer duration than girls.

Adolescents and Young Adults (AYA)

Patients between ages 16 and 25 are called Adolescents and Young Adults (AYA). The results in this age group are slightly inferior than in younger children.

When is BMT needed?

• Most children with Standard or Intermediate Risk Acute Lymphoblastic Leukemia are cured with chemotherapy and do not need a BMT.
• Most children with High Risk Acute Lymphoblastic Leukemia might need a BMT.
• Most Children with a positive MRD after intensive chemotherapy would benefit from a BMT.

Conditioning

Total Body Radiation is an important component of conditioning for BMT.

Who can be a donor?

Although we prefer a matched family donor, a Half matched (Haploidentical) family donor or an unrelated donor can also be used.

Results of BMT

• BMT reduces the risk of relapse i.e. recurrence of disease by 50% compared to chemotherapy.
• If the child is MRD negative before BMT, the risk of relapse is negligible.
• BMT is the only cure for patients who relapse early after chemotherapy.