1. What is Chronic Myelogenous Leukemia( CML )?

2. The root cause of CML.

3. Known risk factor for Leukemia

4. Treatment options for Chronic phase CML

5. Why Gleevec can be the first option for CML?

6. Gleevec history

7. Gleevec mechanism of action

8. Why Gleevec can't cure most of CML patients?

1. What is Chronic Myelogenous Leukemia( CML )?

CML is a clonal myeloproliferative blood system disorder in which too many white blood cells are in the bone marrow. This is resulted from an acquired (Not inherited) injure to the DNA of a hematology stem cell in the marrow. This DNA mutation confers a growth and survival advantage on the malignant stem cell, mainly causes uncontrolled growth of white blood cell, but actually affects myeloid, monocytic, erythroid, megakaryocytic, and B-cells lineage. At early chronic phase, malignant cells function almost normally. As time goes on, they may crowd out normal white blood cells, red blood cells, and platelets in marrow. This makes it hard for blood to do its work.

Chronic myelogenous leukemia has three phases:

Chronic phase: There are mostly mature leukemia white blood cells(5% or fewer ) in the blood and bone marrow and there may be no symptoms of leukemia. Initially, patients in this phase usually have minor symptoms and their cancer is usually detected by routine blood test. This phase lasts from several months to several years, with an average duration of five years.

Accelerated phase: There are some immature leukemia white blood cells in the blood and bone marrow (between 5% to 30%). Patients may have fever, poor appetite and weight loss. The leukemia cells may have new chromosome changes, in addition to the Philadelphia chromosome. This phase lasts from 6 to 18 months.

Acute phase: Also called blast phase or blast crisis. In this phase, there are mostly immature white blood cells in the blood and bone marrow (more than 30%). Symptoms such as anemia, tiredness, fever, an enlarged spleen and recurring infections are typical. This phase is the final phase of the disease and lasts about three to six months.

Most of the 4,500 Americans diagnosed with CML each year are middle-aged or older, although this CML can occur in children.

2. The Root Cause Of CML

In most (>=90%) CML patients, the chromosome in the leukemia cells have an translocation mutation, called the Philadelphia chromosome.

The translocation occurs between chromosomes 9 and 22 (human DNA is packaged in 23 pairs of chromosomes) and produces an abnormal gene called BCR-ABL on shorten end of chromosome #22. This abnormal gene produces Bcr-Abl tyrosine kinase which plays an important role in regulating cell growth and division. The normal ABL gene will turn on or off, producing tyrosine kinase to promote cell growth as needed. But the abnormal BCR-ABL gene is always turn on as it lacks a critical piese that enables the gene to turn it off.

As a consequence, bcr-abl floods the white blood cell with the instruction to divide constantly and also prevents the leukemia cells from undergoing normal programmed cell death, apoptosis, a process that helps to regulate white blood cell numbers.

3. Known Risk Factor for Leukemia

No one knows the exact causes of leukemia. Research has shown that people with certain risk factors are more likely than others to develop leukemia. Studies have found the following risk factors for leukemia:

1. People exposed to high levels of radiation are much more likely

than others to develop leukemia.

2. Exposure to high levels of certain chemical such as benzene,

formaldehyde etc can cause hign risk of leukemia.

3. Cancer patients treated with certain cancer-fighting drugs such as

alkylating agents sometimes develop leukemia many years later.

4. Certain genetic diseases caused by abnormal chromosome may

increase the risk.

5. HTLV-I(Human T-cell leukemia virus-I causes a rare type of chronic

lymphocytic leukemia known as human T-cell leukemia. However,

leukemia does not appear to be contagious.

6. People with myelodysplastic syndrome blood disease are at

increased risk of developing acute myeloid leukemia.

4. Treatment Options for Chronic phase CML

Chemothreapy.

Chemotherapy is the major form of treatment for leukemia. This treatment uses chemical agents to kill leukemia cells which are rapidly multiplying cells and often more sensitive to the effects of chemotherapy.

Hydroxyurea is oral chemotherapy agents, typically used with CML patients who do not respond to or cannot tolerate IFN-Alfa. Both of these therapies treat the symptoms of CML,but they do not prolong life. However, they are generally better tolerated than IFN-Alfa therapy.

Interferon-alfa.

Interferon is an antiviral agent that works to stop the spread of leukemic cells and helps bolster patient's immune system.Interferons are naturally produced by the body. Giving patients an injection of IFN-Alfa may slow down the growth of leukemia cells(and prolong life), but it does not provide a cure for CML. IFN-Alfa is sometimes given alone, and sometimes given with the drug cytarabine (ara-C).

The most significant problem with this therapy is tolerability. Many patients cannot tolerate the side effects this therapy.

Imatinib mesylate (Gleevec).

The Food and Drug Adminstration has approved this drug as a first line treatment for people newly diagnosed with chronic myeloid leukemia.

Bone marrow/Stem Cell transplant.

This process replaces patient's leukemic bone marrow with cancer-free marrow/stem cells. Chemotherapand/or radiation therapy destroy body's bone marrow first. Then doctor re-injected some of patient's own bone marrow that has been saved and purged or uses marrow from a compatible donor to replace patient's bone marrow.

Cell-specific antibodies.

The vaccine made from individual patient's leukemic cells. Patients undergo a blood-filtering process to collect white blood cell first. Then white blood cells will be made to the personalized vaccines. This vaccine is designed to contain leukemia’s ‘fingerprint.’ Injection of the this vaccine may cause the body to attack any cells bearing this cancer fingerprint.

Currently trail for AG-858 vaccine is ongoing.

Radiation

Radiation therapy uses X-rays or other high-energy rays to damage leukemic cells and stop their growth.

5. Why Gleevec can be the first option for CML?

On May 10 2001, Gleevec, also known as STI571, is a new drug that the Food and Drug Administration approved for the second line treatment of PH+ chronic myeloid leukemia (CML).

On Dec 20 2002,the Food and Drug Administration (FDA) announced the approval of Gleevec (imatinib mesylate) for the first-line treatment of patients with PH+ chronic myeloid leukemia (CML).

Gleevec is the first FDA approved drug that directly turns off the signal of a protein known to cause a cancer. Unlike other drugs used in cancer treatment, Gleevec does not kill normal cells in addition to cancer cells.

6. Gleevec History

7. Gleevec Mechanism of action

Gleevec is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase created by philadelphia chromosome. It inhibits proliferation and induces apoptosis in BCR-ABL positive cell line .

8. Why Gleevec can't cure most of CML patients?

Gleevec can attack the philadelphia chomosome positive stem cell which is the root of CML.But It is still too early to say whether Gleevec can cure CML. Basically we don't know final answer yet. One thing we saw is Gleevec can't cure most of CML patients. Here are some unofficial/reasonable guess/explainations.

1. Leukemia cell is deviding much more actively due to BCR-ABL gene. It is possible that in CML patient, there are some leukemia cells has BCR-ABL with minor change, as it is different from BCR-ABL,with time goes on, these cells will be the resistance to Gleevec because Gleevec can't kill them.

2. Most of the CML primitive stem cell are quiescent at any given time and are relatively invulnerable to BCR-ABL kinase inhibitor. This may cause Gleevec can’t cure CML.