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Acute Lymphoblastic Leukemia

Understanding acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia (ALL) is a cancer of the blood and bone marrow in which the bone marrow makes excess lymphocytes (a type of white blood cell). This type of cancer usually gets worse quickly if it is not treated.Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell gets converted into one of three types of mature blood cells:

  • Red blood cells (RBCs): Carry oxygen and other substances to body tissues
  • Platelets: Help in forming blood clots to stop bleeding
  • Granulocytes (white blood cells or WBCs): Fight infection and disease

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  • B lymphocytes: Make antibodies to help fight infection
  • T lymphocytes: Help B lymphocytes make antibodies that help fight infection
  • Natural killer cells: Attack cancer cells and viruses

In ALL, too many stem cells become lymphoblasts, B lymphocytes, or T lymphocytes. These cells are also called leukemia cells. These leukemia cells are not able to fight infection very well. As the number of leukemia cells increases in the blood and bone marrow, there is less space for healthy white blood cells, red blood cells, and platelets. This may lead to infection, anemia, and easy bleeding.

How common is ALL?

The age-adjusted incidence rate of ALL in the United States is 1.7 per 100,000 individuals per year with approximately 6,020 new cases and 1,440 deaths estimated in 2014.1,2 The average age at diagnosis for ALL is 14 years. Sixty percent of patients are diagnosed at younger than 20 years, whereas 24% are diagnosed at 45 years or older.1, 2 Approximately 11% are diagnosed at 65 years or older.1,3 ALL represents approximately 20% of all leukemias among adults.1, 4, 5

What is Philadelphia Chromosome?

Sometimes in ALL, 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.

About one-quarter of cases of adult ALL are Philadelphia chromosome-positive (Ph+). Presence of the Philadelphia chromosome suggests a poorer prognosis (chance of recovery).

The presence of Philadelphia chromosome can be detected by cytogenetic analysis. This is a test in which the cells in a sample of blood or bone marrow are seen under a microscope to find out if there are certain changes in the chromosomes in the lymphocytes. Specialized tests, such as fluorescence in situ hybridization (FISH), may also be done to look for certain changes in the chromosomes.

Signs and symptoms

Possible signs of adult ALL include fever, feeling tired and easy bruising or bleeding. Patients are recommended to visit their doctor if they encounter any of the following problems:

  • Weakness or feeling tired
  • Fever or night sweats
  • Easy bruising or bleeding
  • Petechiae (flat, pinpoint spots under the skin, caused by bleeding)
  • Shortness of breath
  • Loss of appetite
  • Weight loss
  • Pain in the bones or stomach
  • Pain or feeling of fullness below the ribs
  • Painless lumps in the neck, underarm, stomach, or groin
  • Repeated infections

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Risk Factors

A risk factor is something that affects the chance of getting a disease such as cancer. Some risk factors, like smoking, can be controlled. Others, like a person’s age can’t be changed.

But risk factors don’t tell us everything. Having a risk factor, or even several risk factors, does not mean that the patient will definitely get the disease. And many people who get the disease may have few or no known risk factors. Even if a person has one or more risk factors and develops cancer, it is often very hard to know how much they might have contributed to the cancer.

Risk Factors You Cannot Change

Risk factors for ALL which you cannot change include:

Race/Ethnicity: ALL is more common in Whites than in African Americans, but the reasons for this are not clear.6

Gender: ALL is slightly more common in males than in females.6 The reason for this is unknown.

Inherited syndromes: Some inherited syndromes with genetic changes (e.g., Down syndrome, Fanconi anaemia, Ataxia-telangiectasia, Neurofibromatosis, Klinefelter syndrome and Bloom syndrome) seem to raise the risk of ALL. 6

Age: Older age greater than 70 years.1, 7, 8

Risk Factors Linked to Things You Do or Are Exposed To

Radiation exposure: Being exposed to high levels of radiation is a risk factor for ALL. Japanese atomic bomb survivors had a greatly increased risk of developing acute leukemia, usually within 6 to 8 years after exposure.6

The possible risks of leukemia from being exposed to lower levels of radiation, such as from medical imaging tests (such as X-rays) are not well-known. Exposure of a fetus to radiation within the first months of development may carry an increased risk of leukemia, but the extent of the risk is not clear.6

Exposure to benzene: Exposure to chemical called benzene at work increases the risk of developing ALL. Workers in the rubber manufacturing industries also have an increased risk of developing ALL.9

Past chemotherapy: People who have been treated with some chemotherapy drugs (e.g., etoposide, mitoxantrone and idarubicin) have a slightly increased risk of developing ALL many years later.6

Certain viral infections: Infection with the human T-cell lymphoma/leukemia virus-1 (HTLV-1) can cause a rare type of T-cell acute lymphocytic leukemia. Most cases occur in Japan and the Caribbean area. This disease is not common in the United States.6

About Treatment

Treatment options for adult ALL include:

  • Chemotherapy: Chemotherapy is the use of drugs to fight cancer. The drugs may be put into a vein or given by mouth.
  • Radiation
  • Stem Cell Transplantation
  • Targeted Therapy

Chemotherapy

In general, treatment for ALL falls into separate phases:

Induction Therapy: The purpose of the first phase of treatment is to kill most of the leukemia cells in the blood and bone marrow and to restore normal blood cell production. Patients receive induction therapy with combinations of chemotherapeutic agents, including non-liposomal vincristine, prednisone, cyclophosphamide, doxorubicin, and L-asparaginase, which are given over 4-6 weeks. The attempt of induction therapy is to achieve remission. Remission is achieved when the blood counts return to normal and there are no signs or symptoms of leukemia. A bone marrow study at this time should show < 5% abnormal cells.

Consolidation Therapy: If remission is achieved after induction, then the patient receives consolidation therapy. Also called post-remission therapy, this phase of treatment is aimed at destroying any remaining leukemia cells in the body, such as in the brain or spinal cord using multiagent therapy, additionally including cytarabine and methotrexate.

Maintenance Therapy: The third phase of treatment prevents leukemia cells from regrowing. The treatments used in this stage are often given at much lower doses over a long period of time. This therapy includes drugs such as 6-mercaptopurine, methotrexate, steroids, and non-liposomal vincristine.

Central Nervous System (CNS) Sanctuary Therapy/ CNS Prophylaxis: Because standard doses of chemotherapy may not reach leukemia cells in the CNS (brain and spinal cord), the cells are able to "find sanctuary" (hide) in the CNS. High doses of certain anticancer drugs, intrathecal chemotherapy with drugs such as methotrexate and cytarabine, and radiation therapy to the brain are able to reach leukemia cells in the CNS. They are given to kill the leukemia cells and keep the cancer from recurring (coming back).

Radiation Therapy

Radiation therapy is a cancer treatment that 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. External radiation therapy (using a machine outside the body to send radiation toward the cancer) can be used to treat adult ALL that has spread, or may spread, to the brain and spinal cord. This is commonly used as part of CNS prophylaxis along with intrathecal chemotherapy.

Stem Cell Transplantation

A stem cell transplant may be used as consolidation therapy in people at high risk of relapse or for treating relapse when it occurs. This procedure allows someone with leukemia to re-establish healthy stem cells by replacing leukemic bone marrow with leukemia-free marrow from a healthy person. Initially, high doses of chemotherapy or radiation are administered to destroy any leukemia-producing bone marrow. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the bone marrow is replaced by bone marrow from a compatible donor (allogeneic transplant).

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Targeted Therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Targeted therapy drugs called tyrosine kinase inhibitors (TKIs) are used to treat some types of adult ALL. These drugs block the enzyme, tyrosine kinase, which causes stem cells to develop into more white blood cells (blasts) than the body needs.

Prognosis

The prognosis (chance of recovery) and treatment options depend on the following: 1, 10, 11

  • Age: Younger patients tend to have a better outlook
  • Spread to the brain or spinal cord
  • Changes in the genes, including the Philadelphia chromosome: Presence of the Philadelphia chromosome suggests a poorer prognosis.
  • Whether the cancer has been treated before or has recurred (come back)
  • Initial WBC count: Higher initial WBC count is associated with decreased duration of remission

Treatment of Relapse1, 12

The prognosis for patients who experience relapse after front-line therapy is poor, with very few patients surviving long term; the best outcome is obtained if patients achieve a second remission and then proceed to allogeneic stem cell transplantation. Patients who are in complete remisson within 4 weeks of starting therapy have better prognosis. Most of the chemotherapy regimens used for front-line therapy of ALL can be used in the relapse setting; however, response rates are low and remission durations are short.


  • References:
  • 1. NCCN Clinical Practice Guidelines in Oncology Version 1. 2014, Acute Lymphoblastic Leukemia
  • 2. Seigel R, Ma J, Zou Z, Jamal A. Cancer Statistics, 2014. CA Cancer J Chin, 2014; 64:9-29. Available at http://www.ncbi.nlm.nih.gov/pubmed/24399786.
  • 3. National Cancer Institute. SEER Cancer statistics Review, 1975-2011: Overview, Age Distribution of Incidence Cases by Site. 2014. Available at http://seer.concer.gov/csr/1975 2011/.
  • 4. Jabbour EJ, Faderl S, Kantarjin HM. Adult acute lymphoblastic leukemia. Mayo Clin Proc 2005; 80:1517-1527. Available at http://www.ncbi.nlm.nih.gov/pubmed/16295033
  • 5. Esparza SD, Sakamoto KM. Topics in pediatric leukemia-acute lymphoblastic leukemia. MedGenMed 2005; 7:23. Available at http://www.ncbi.nlm.nih.gov/pubmed/16369328
  • 6. American Cancer Society. Cancer Facts & Figures 2014. Atlanta, Ga: American Cancer Society; 2014. Available at http://www.cancer.org/acs/groups/cid/documents/webcontent/003109-pdf.pdf
  • 7. Hasle H. Pattern of malignant disorders in individuals with Down’s syndrome. Lancet Oncol 2001; 2:429-436. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11905737
  • 8. Whitlock JA. Down syndrome and acute lymphoblastic leukaemia. Br J Haematol 2006; 135:595-602. Available at:http://www.ncbi.nlm.nih.gov/pubmed/17054672
  • 9. Cancer Facts and Figures 2014. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003109-pdf.pdf
  • 10. Adult Acute Lymphoblastic Leukemia Treatment (PDQ®): Treatment - Patient Information [NCI] - General Information About Adult Acute Lymphoblastic Leukemia. Available at: http://www.webmd.com/cancer/tc/leukemia-acute-lymphoblastic-adult-treatment-patient-information-nci-pdq-general-information-about?page=3 Last accessed on: 11-Nov-2014
  • 11. http://emedicine.medscape.com/article/207631. Last accessed on: 11-Nov-2014
  • 12. http://emedicine.medscape.com/article/2004705. Last assessed on: 11-Nov-2014

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