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Childhood acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many immature lymphocytes (a type of white blood cell). There are subgroups of childhood ALL. Family history and exposure to radiation may affect the risk of developing childhood ALL. Possible signs of childhood ALL include fever and bruising. Tests that examine the blood and bone marrow are used to detect (find) and diagnose childhood ALL. Certain factors affect prognosis (chance of recovery) and treatment options.

Childhood acute lymphoblastic leukemia (ALL) is a type of cancer in which the bone marrow makes too many immature lymphocytes (a type of white blood cell). Childhood acute lymphoblastic leukemia (also called acute lymphocytic leukemia or ALL) is a cancer of the blood and bone marrow. This type of cancer usually gets worse quickly if it is not treated. It is the most common type of cancer in children. Normally, the bone marrow makes blood stem cells (immature cells) that develop into mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. The myeloid stem cell develops into one of three types of mature blood cells:

Red blood cells that carry oxygen and other materials to all tissues of the body. Platelets that help prevent bleeding by causing blood clots to form. Granulocytes (white blood cells) that fight infection and disease.

The lymphoid stem cell develops into a lymphoblast cell and then into one of three types of lymphocytes (white blood cells):

B lymphocytes that make antibodies to help fight infection. T lymphocytes that help B lymphocytes make the antibodies that help fight infection. Natural killer cells that attack cancer cells and viruses.

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Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In ALL, too many stem cells develop into lymphoblasts and do not mature to become lymphocytes. These lymphoblasts are called leukemia cells. The leukemia cells do not work like normal lymphocytes and are not able to fight infection very well. Also, as the number of leukemia cells increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may lead to infection, anemia, and easy bleeding. This summary is about acute lymphoblastic leukemia. See the following PDQ summaries for information on other types of leukemia:

Adult Acute Lymphoblastic Leukemia Treatment. Chronic Lymphocytic Leukemia Treatment. Adult Acute Myeloid Leukemia Treatment. Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment. Chronic Myelogenous Leukemia Treatment. Hairy Cell Leukemia Treatment.

There are subgroups of childhood ALL. There are different subgroups of ALL based on the following:

Whether the type of blood cell that is affected looks more like a B lymphocyte or a T lymphocyte. The age of the child at diagnosis. For example, whether the child is younger than one year, one year to 10 years old, or older than 10 years (teenager). Whether there are certain changes in the chromosomes. Philadelphia chromosome -positive ALL is one type of chromosome change that may occur.

See the Childhood Acute Lymphoblastic Leukemia Subgroups section for more information. Family history and exposure to radiation may affect the risk of developing childhood ALL. Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesnt mean that you will not get cancer. People who think they may be at risk should discuss this with their doctor. Possible risk factors for ALL include the following:

Having a brother or sister with leukemia. Being white or Hispanic. Living in the United States. Being exposed to x-rays before birth. Being exposed to radiation. Past treatment with chemotherapy or other drugs that weaken the immune system. Having certain changes in genes or genetic disorders, such as Down syndrome.

Possible signs of childhood ALL include fever and bruising. These and other symptoms may be caused by childhood ALL. Other conditions may cause the same symptoms. A doctor should be consulted if any of the following problems occur:

Fever. Easy bruising or bleeding. Petechiae (flat, pinpoint, dark-red spots under the skin caused by bleeding). Bone or joint pain. Painless lumps in the neck, underarm, stomach, or groin. Pain or feeling of fullness below the ribs. Weakness, feeling tired, or looking pale. Loss of appetite.

Tests that examine the blood and bone marrow are used to detect (find) and diagnose childhood ALL. The following tests and procedures may be used:

Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient's health habits and past illnesses and treatments will also be taken.

Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following: o The number of red blood cells and platelets. o The number and type of white blood cells. o The amount of hemoglobin (the protein that carries oxygen) in the red blood cells. o The portion of the sample made up of red blood cells. Enlarge

Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.

Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for signs of cancer.

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Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patients hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.

Cytogenetic analysis: A laboratory test in which the cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes in the lymphocytes. For example, in Philadelphia chromosome-positive ALL, part of one chromosome is moved to another chromosome. This is called the Philadelphia chromosome. Other tests, such as fluorescence in situ hybridization (FISH), may also be done to look for certain changes in the chromosomes.

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Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The bcr-abl gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.

Immunophenotyping: A test in which the cells in a sample of blood or bone marrow are looked at under a microscope to find out if malignant lymphocytes (cancer) began from the B lymphocytes or the T lymphocytes. Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it. Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.

Certain factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery) and treatment options may depend on:

Age at diagnosis and race.

How quickly and how low the leukemia cell count drops after initial treatment. Whether the leukemia cells began from B lymphocytes or T lymphocytes. Whether there are certain changes in the chromosomes of lymphocytes. Whether the leukemia has spread to the brain and spinal cord. Whether the child has Down syndrome.

If leukemia recurs (comes back) after initial treatment, the prognosis and treatment options may depend on:

How long it is between the end of initial treatment and when the leukemia recurs. Whether the leukemia recurs in the bone marrow or outside the bone marrow.

Once childhood ALL has been diagnosed, tests are done to find out if the cancer has spread to the central nervous system (brain and spinal cord), testicles, or to other parts of the body. The extent or spread of cancer is usually described as stages. For childhood acute lymphoblastic leukemia (ALL), risk groups are used instead of stages. The following tests and procedures may be used to determine the risk group:

Lumbar puncture: A procedure used to collect cerebrospinal fluid from the spinal column. This is done by placing a needle into the spinal column. This procedure is also called an LP or spinal tap. Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body. The chest x-ray is done to see if leukemia cells are forming a mass in the middle of the chest. Testicular biopsy: The removal of cells or tissues from the testicles so they can be viewed under a microscope by a pathologist to check for signs of cancer. This procedure is done only if there seems to be anything unusual about the testicles during the physical exam.

There are three ways that cancer spreads in the body. When cancer cells spread outside the blood, a solid tumor may form. This process is called metastasis. The three ways that cancer cells spread in the body are:

Through the blood. Cancer cells travel through the blood, invade solid tissues in the body, such as the brain or heart, and form a solid tumor. Through the lymph system. Cancer cells invade the lymph system, travel through the lymph vessels, and form a solid tumor in other parts of the body. Through solid tissue. Cancer cells that have formed a solid tumor spread to tissues in the surrounding area.

The new (metastatic) tumor is the same type of cancer as the primary cancer. For example, if leukemia cells spread to the brain, the cancer cells in the brain are actually leukemia cells. The disease is metastatic leukemia, not brain cancer. In childhood ALL, risk groups are used instead of stages.

Because ALL is a disease of the blood cells, it has already spread throughout the body at diagnosis. There is no staging system for ALL. Risk groups are used to plan treatment. Risk groups are described as:

Standard (low) risk: Includes children aged 1 to 9 years who have a white blood cell count of less than 50,000/L at diagnosis. High risk: Includes children younger than 1 year or older than 9 years and children who have a white blood cell count of 50,000/L or more at diagnosis.

Other factors that affect the risk group include the following:

Whether the leukemia cells formed from B lymphocytes or T lymphocytes. Whether there are certain changes in the chromosomes of the lymphocytes. How quickly the leukemia responds to initial therapy.

It is important to know the risk group in order to plan treatment. Children with high-risk ALL usually receive more aggressive treatment than children with standard risk ALL.

CHAPTER 97 ACUTE LYMPHOBLASTIC LEUKEMIA

CHAPTER 97 ACUTE LYMPHOBLASTIC LEUKEMIA Williams Hematology CHAPTER 97 ACUTE LYMPHOBLASTIC LEUKEMIA CHING-HON PUI Definition and History Etiology and Pathogenesis Incidence Risk Factors Acquired Genetic Changes Clinical Features Signs and Symptoms Physical Findings Laboratory Features

Diagnosis and Cell Classification Differential Diagnosis Therapy Supportive Care Antileukemic Therapy Course and Prognosis Relapse Treatment Sequelae Prognostic Factors Chapter References Acute lymphoblastic leukemia (ALL) is a malignant disorder that originates in a single B- or T-lymphocyte progenitor. The proliferation and accumulation of blast cells in the marrow results in suppression of hematopoiesis and, thereafter, anemia, thrombocytopenia, and neutropenia. Extramedullary accumulations of lymphoblasts may occur in various sites, especially the meninges, gonads, thymus, liver, spleen, or lymph nodes. The disease is most common in children but can occur at any age. ALL has many subtypes and can be classified using morphologic, immunologic, cytogenetic, and molecular genetic methods. These approaches can identify biologic subtypes that require different treatment approaches. These differences include the specific drug combination, drug dosages, and duration of treatment required to achieve optimal results. For example, childhood ALL with a hyperdiploid karyotype responds well to extended treatment with methotrexate and 6-mercaptopurine, while cases with adverse genetic changes, such as MLL-AF4 fusion, require intensive treatment with genotoxic agents. The relative lack of therapeutic success in adult ALL corresponds to a high frequency of cases with unfavorable genetic lesions, such as the BCRABL oncogene resulting from the rearrangement of chromosomes 9 and 22. This poor outlook in adults is improving, however, as a result of better drug combinations and the use of allogeneic stem cell transplantation. Currently, 80 percent of children and 35 percent of adults can expect long-term leukemia-free survival, and probable cure, following intensive therapy on contemporary protocols. As cure rates increase, new approaches are required to prevent second malignancies, cardiotoxicity, growth stunting, and other severe side effects that may accompany long-term survivors.