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Acute Childhood Leukemia

Introduction

Leukemia refers to cancer of blood cells. There are three major types of mature blood cells. These are red blood cells which help carry oxygen to different parts of the body, white blood cells which help to fight infections and platelets which help to stop bleeds. These blood cells are made from immature parent cells called precursor cells or progenitors. These parent cells reside inside the bone marrow. The bone marrow is in the center of the long bones of the body, the bones of the spine and the scalp. Leukemia can arise from any of these cells but in children it tends to arise mainly from the white blood cells. There are two major groups of white blood cells. One group is called lymphocytes. This group of white blood cells helps us fight infection by producing antibodies. They also fight infection caused by fungus and viruses. The leukemia arising from parent cell of lymphocytes (called lymphoblast) is called lymphoblastic leukemia. There are two types of lymphocytes: B-lymphocytes which make antibodies and the T-lymphocytes which help in fighting fungal and viral infections. So lymphoblastic leukemia can be either a B-cell lymphoblastic leukemia or a T-cell lymphoblastic leukemia.

The second class of white blood cells are called myeloid cells they consist of different cells named eosinophils, basophils, monocytes and neutrophils. The neutrophils are very important in fighting bacterial infections because they actually ingest these organisms and also make substances to kill them. The monocytes also perform similar functions. This group of cells all arise from the same precursor (parent) cell inside the bone marrow. This parent cell is called the myeloblast. Thus leukemia arising from these precursor cells is called myelogenous leukemia.

Leukemia can arise acutely in which case it is called Acute Leukemia. In other cases it may arise over a long period of time in which case it is called Chronic Leukemia. Chronic leukemia is more commonly seen in the elderly. Acute leukemia is the commonest type of leukemia seen in children.


Acute Leukemia

Acute leukemia is the commonest type of cancer seen in children worldwide. It accounts for about 25% to 30% of all cancers in children. There are two major types seen in children. These are 1. Acute Lymphoblastic Leukemia also referred to as ALL and 2. Acute Myeloid leukemia also referred to as AML. These leukemias arise because a group of precursor cells developing in the bone marrow have acquired an abnormality that prevents them from maturing into the mature cells seen in the blood. These immature precursors cells also acquire the ability to continue to divide and grow so eventually they replace all the normal precursor cells within the bone marrow and then they get released into the blood stream.

Acute lymphoblastic leukemia accounts for approximately 75% of childhood leukemias and acute myeloid leukemia accounts for about 20%. Chronic leukemia is rare in children. It accounts for 3% of childhood leukemia. There are two major types of chronic leukemia. These are Juvenile Chronic myelogenous leukemia and adult type chronic myeloid leukemia.


Incidence

Incidence of acute leukemia is about 1 in 25,000 of population up to the age of 15 years.

The peak age of occurrence is between the ages of 2 years and 5 years. It is thought to occur at a relatively higher frequency amongst Caucasians compared to African Americans. Incidence is also slightly higher in boys compared to girls.


Factors Associated With Leukemia

The cause of leukemia is unknown. The factors listed below have been identified to increase the risk of developing leukemia.

  1. Ionizing radiation e.g. from atomic bomb, nuclear plants.
  2. Chemicals e.g. benzene, heavy metals, pesticides
  3. Drugs e.g. drugs used to treat other cancers
  4. Radiotherapy
  5. Genetic factors: (a) Identical twins: a twin has 20% risks of developing leukemia if second twin develops leukemia within the first 5 years of life. (b). The incidence of leukemia in siblings of children with leukemia is about 4 times greater than the risk of the general population. (c) Children with congenital syndromes such as Down's syndrome, Bloom syndrome, Poland syndrome, congenital agammaglobulinemia, neurofibromatosis, Li-Fraumeni and Fanconi's anemia have higher risk of developing leukemia.


Symptoms

Symptoms that result from loss of normal blood cells

The common symptoms of leukemia result from the absence of mature red cells , white cells and platelets in the blood. These cells live in the peripheral blood for a given period of time before a die and are removed by a organ called Spleen. The life span of a normal red cell is about 90 days. For a neutrophil and lymphocyte it is about 3 days, and for platelets it is about 4 days. Since the bone marrow gets replaced by abnormal immature cells, very soon the number of normal mature blood cells becomes reduced. If the number of red blood cells is reduced, one gets anemia so the child looks pale and gets tired easily. If the number of normal white cells is reduced there is increased risks of infection. A reduction in the number of platelets in blood results in increased tendency to bleed so the child begins to bruise easily or have nose bleeds or gum bleed after brushing. Sometimes children bleed into the brain especially after any form of head trauma. The child with leukemia also develops that does not respond to antibiotics.

Cancer (leukemia) cells leave the bone marrow and lodge into other organs in the body

Symptoms that result from spread to other organs

  1. They could also travel via blood stream and get into the fluid that surrounds the brain and spinal cord. This results in leukemia of the central nervous system. The child may then complain of morning headaches, vomiting, weakness or paralysis of arms and/ or legs, back pain, problems with bladder control, constipation.
  2. In boys the leukemia cells can lodge in the testis and result in swelling of either one or both testis.
  3. In girls it may spread and involve the ovaries.
  4. Some times leukemia cells spread into the skin and result in small nodules being formed. These are called chloromas. These are usually seen in newborns that have acute myeloid leukemia. It is rarely seen in acute lymphoblastic leukemia
  5. They sometimes have enlargement of the abdomen. This results from enlargement of the liver and spleen. The leukemia cells can also lodge in lymph nodes and cause them to enlarge. Sometimes they develop enlarged kidneys and occasionally present with blood in the urine, hypertension (high blood pressure) and kidney failure.
  6. Occasionally the number of leukemia in the blood is very high and results in blockage of the veins within the brain and in the lung. This is called leukostasis. This could result in brain bleed and stroke. If it occurs in the lungs it could result in difficult in breathing or evening bleeding into the lungs.


Diagnosis

The diagnosis is considered when a child is found to have decreased numbers of mature blood cells. Since there are other reasons for having decreased numbers of red cells, white cells or platelet, the diagnosis of leukemia is usually considered when two different cell types are affected at the same time. Usually the red blood cell and the platelets are decreased. The white cell count may be normal, increased or decreased. An increase in number of white cells usually signifies a higher number of immature white cells in the blood. These immature cells are the leukemia cells and they are called blasts. In normal people, about 1% of all the cells in the bone marrow are blast. And there are no blast in the blood stream. In a child with leukemia, blast can be found in the blood stream.

To confirm the diagnosis of leukemia, the doctors have to do a procedure called bone marrow aspirate and biopsy. This is a procedure whereby a special needle is placed at a specific point in the hip bone and it is inserted into the center of the bone to obtain a sample of bone marrow and also a sample of the bone. Sometimes it is hard to obtain a sample of the bone marrow because the leukemia has totally replaced the normal marrow. The sample obtained is then sent for special studies which help determine if the leukemia is lymphoblastic or myeloid or a combination of both. If it is lymphoblastic they also have test to determine if it is B-cell type or T-cell type. For the myeloid leukemia, there are several types and there are special tests done to determine the type of myeloid leukemia. It is important to determine the exact type of leukemia because this will help in choosing the appropriate treatment. Bone marrow cells are also studied for abnormalities of chromosomes. Certain chromosomal abnormalities have been found to predict outcome of treatment.

Other tests that are required

  1. Chest x-ray
  2. Blood chemistry
  3. Examination of the spinal fluid for presence of leukemia cells.
  4. Cardiac studies: EKG and echocardiogram
  5. Screen for prior exposure to specific viral infections especially chicken pox, cytomegalovirus, hepatitis, and HIV.
  6. Study other family members for possibility of bone marrow donation if bone marrow transplant is being considered in treatment plan.


Treatment

There are three major categories of treatment.

  1. Drugs: Use of drugs to kill cancer cells is called chemotherapy. These drugs are given in cycles. The guidelines for the administration of these drugs have been developed over the years from studies done on leukemia patients. These guidelines are called Protocols. In general there are four major steps in the treatment of leukemia. The first is called INDUCTION OF REMISSION. As the name suggests the chemotherapy is given at high doses so as to kill all the leukemia cells in the bone marrow and those lodge in other organs of the body. This step usually takes about 4 weeks and the end of which the child would have another bone marrow aspirate done. It is hoped that by this time the bone marrow aspirate will show complete absence of abnormal cells. If this is so the child is said to have achieved remission. The second step of chemotherapy is called CONSOLIDATION. In these cycle different sets of chemotherapy drugs are given. The aim of this cycle is to kill off any leukemia cells that might have been left behind after the first cycle of therapy. Some protocols then have a second induction and consolidation cycle. These is done if the leukemia is considered high risk. The final phase of treatment is called MAINTENANCE. This lasts for about 2 years for girls and 3 years for boys. Chemotherapy drugs are toxic to other normal cells of the body. Side effects include loss of appetite, vomiting, loss of hair, diarrhoea, constipation, dryness of eyes, bone pain, jaw pain, lowering of normal white cell count and increased risks of infection, lowering of platelet count and increased risks of bleeding, and many others which are specific to the drug been used and which will be explained by the doctors and nurses taking care of your child. A drug also used in the treatment of leukemia is Prednisone. This is a steroid. In high doses it has been shown to kill leukemia cells. High doses of steroids has its own side effects which include weight gain, increased appetite, development of high blood pressure and diabetes, increased risk for fungal infection and poor wound healing to mention a few. These drugs can been given into the vein (intravenously), into the muscle (intramuscularly), by mouth (orally) and into the spinal fluid (intrathecally). Even if there is no evidence of leukemia within the nervous system, treatment is still given as prophylaxis because it is known that if the leukemia should relapse it may relapse in the nervous system.
  2. Radiation: This is given to older children that have leukemia of the central nervous system. A given doses of special radiation is given to the brain and spine in divided doses over a course of time.
  3. Bone marrow transplant: Bone marrow transplant is offered to children that have AML after they have responded to induction and consolidation therapy. It is also offered to children with ALL who are considered high risks or who have relapsed after being treated for ALL. Bone marrow transplant entails the use of very high doses of chemotherapy to kill all the cells in the bone marrow so as to make room for new bone marrow cells which have been obtained from a donor, this new cells are infused into the body via a vein (just like a blood transfusion). Bone marrow transplant is done in specialized centers.
  4. Supportive care: Includes transfusion of platelets and red blood cells. Fevers and infections are treated aggressively with intravenous antibiotics. Physical therapy may be required. The child would require home tutoring for some time.


Prognosis

Certain factors predict outcome of treatment. These factors help the doctors determine if the child has a high risk leukemia or standard risk leukemia.

Standard risks leukemia

  1. Age between 2 to 10 years.
  2. White cell count <50,000/mm3
  3. Absence of central nervous system leukemia
  4. Favorable chromosomal abnormalities.

High Risks

  1. Age <2 years or> 10 years
  2. White cell count > 50,000/mm3
  3. Presence of central nervous system leukemia
  4. Presence of unfavorable chromosomal abnormalities.

Standard risks ALL is associated with better outcome compared to high risk ALL. About 80% of children with leukemia remain cured.