Chronic Myeloid Leukemia

Diagnosis, useful terms and treatment of chronic myeloid leukemia - chronic phase.

Chronic Myeloid Leukemia

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor 8/2018

Chronic myeloid leukemia (CML) is the abnormal growth of relatively mature myeloid (white blood) cells. Half of all patients with CML are diagnosed after the age of 67.

CML is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.

The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.

Initially in CML, there is a gradual increase in mature, abnormal myeloid cells in the bone marrow. These cells eventually spill into the blood and other organs, causing symptoms such as fatigue from anemia or an enlarged spleen. The increase in leukemic cell numbers occurs slowly at first and is referred to as the chronic phase, but these cells invariably begin to increase more rapidly and/or include less mature cells, resulting in the accelerated or blastic phase. In order to understand the best treatment options available for chronic myeloid leukemia, it is important to know the phase of leukemia, since all new treatment information concerning chronic myeloid leukemia is categorized and discussed by the phase of disease.

Staging of Chronic Myeloid Leukemia

Chronic Phase: Patients in the chronic phase of CML have stable disease with only minor symptoms, no cancer outside the bone marrow or spleen and white blood cell and platelet blood counts that are usually greater than normal.

Accelerated Phase: When chronic myeloid leukemia is difficult to control with Gleevec® (imatinib) or other therapies, the white blood count begins to increase. New symptoms may appear and old symptoms may worsen. The spleen may enlarge and/or new abnormal chromosomes can be detected in the bone marrow cells. Eventually, the leukemia becomes completely resistant to treatment and the bone marrow becomes overburdened with large numbers of immature white blood cells known as “blasts”. A diagnosis of accelerated phase requires at least one of the following:

  • The persistent presence of 10-30% myeloblasts in the bone marrow or peripheral blood.
  • A major increase of the white blood cell count to over 50,000, platelet counts that are increased or decreased and red blood cell levels that are low despite treatment.
  • Progressive enlargement of the spleen.
  • Growth of leukemia outside the bone marrow or spleen.
  • The presence of any cytogenetic abnormality in addition to a Philadelphia chromosome.
  • Persistent unexplained fever or bone pain.

Blastic Phase: Greater than 30% myeloblasts in marrow or blood

Treatment of Chronic Phase Chronic Myeloid Leukemia

The diagnosis of CML is first suggested in approximately 20% of affected individuals by detecting a high white blood cell count on routine blood testing. Patients are usually without symptoms and often have difficulty understanding the serious nature of their disease since they do not feel ill.

The hallmark of CML is the Philadelphia chromosome or the BCR-ABL gene, which is not found in normal blood cells and is not passed down from parents to children. The BCR-ABL gene is a fusion gene—a new gene that is formed when two genes are joined together. The BCR-ABL gene makes the BCR-ABL protein, a type of protein called a tyrosine kinase. Tyrosine kinases are proteins that are located on or near the surface of cells and send signals telling cells when to grow and divide. The BCR-ABL protein is abnormal. It is locked in the “on” position so that it always sends signals for cells to keep growing and dividing. This causes blood stem cells to make too many white blood cells.

Historically the only curative treatment for individuals diagnosed with CML was an allogeneic stem cell transplant. This changed when Gleevec® (imatinib) was approved by the FDA for treatment of CML in 2001. Gleevec® is a targeted medicine that belongs to a class of drugs called tyrosine kinase inhibitors (TKI) and these drugs now form the basis for the overall management of CML. TKI’s are well tolerated and prolong survival.1 Allogeneic stem cell transplantation can eradicate the abnormal clone in CML cells and cure many patients who fail or are intolerant to initial treatment but is associated with significant treatment related morbidity and mortality. All current therapies, other than stem cell transplantation, are aimed at controlling the growth of abnormal cells and attempting to delay the transformation or progression from the chronic phase of CML to the blastic phase resembling acute leukemia.

The following is a general overview of the management of chronic phase CML. Each person with CML is different, and the specific characteristics of your condition will determine how it is managed. The information on this Web site is intended to help educate you about treatment options and to facilitate a shared decision-making process with your treating physician. New treatments for CML are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer.

Treatment of CML with Tyrosine Kinase Inhibitors

The majority of CML cases are caused by a specific genetic abnormality, referred to as the Philadelphia chromosome. The Philadelphia chromosome occurs through a switching of specific genetic information. The gene that results from this genetic switching produces a protein called the Bcr-Abl tyrosine kinase. The Bcr-Abl tyrosine kinase influences cellular function and growth in an uncontrolled manner, leading to excessive replication and growth of cells – the hallmark trait of CML and cancer.

TKI’s bind to a specific site on the Bcr-Abl tyrosine kinase and block the growth effects of the protein. This, in turn, halts the excessive replication and growth of leukemia cells. There are currently several TKI’s approved for the treatment of CML.

Gleevec® (imatinib)

Tasigna® (nilotinib)

Sprycel® (dasatinib)

Iclusig® (ponatinib)

Bosulif® (bosutinib)

Recent studies have demonstrated that Tasigna® is superior to Gleevec® for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia (PH+CML), according to the results of the six-year update from the ENESTnd trial.(2.3)

The ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients) directly compared three treatments: Tasigna® 300 mg twice daily to Tasigna® 400 mg twice daily or Gleevec®, 400 mg once daily in adult patients with newly diagnosed Ph+ CML in chronic phase. The estimated rates of patients whose disease did not progress on study at 72 months in the Gleevec®, Tasigna 300 mg and Tasigna® 400 mg twice-daily arms were 92.2%, 95.8% and 97.8%, respectively.

The estimated rates of freedom from death due to a CML-related cause at 72 months in the Gleevec®, Tasigna® 300 mg and Tasigna® 400 mg treatment groups were 93.9%, 97.7% and 98.5%, respectively demonstrating all three treatments to be highly effective and suggesting Tasigna® 400 mg may be the optimal treatment for newly diagnosed patients with chronic phase CML.

Measuring Response to Treatment

Initial response to therapy is indicated by normalization of the peripheral blood counts (white blood cells, platelets and red blood cells) and return of increased bone marrow cellularity to normal. Most patients are followed with peripheral blood tests rather than repeated bone marrow examination. Cells collected from the bone marrow or peripheral blood will contain the Philadelphia chromosome, and cytogenetic tests (tests that detect chromosomal abnormalities) are used to monitor response to therapy. Currently the majority of newly diagnosed patients with CML will achieve a complete cytogenetic remission (no evidence of Philadelphia chromosome-positive cells). More importantly, in patients with a complete cytogenetic remission a test called polymerase chain reaction (PCR) can determine the completeness of a “molecular” remission by measuring the presence of the BCR-ABL gene. As a general rule, the greater the degree of molecular response the longer the survival of an individual patient.

Monitoring TKI Treatment

Monitoring of treatment with cytogenetics and PCR is essential for optimal treatment of patients with CML. Unfortunately adequate monitoring is reported to be underutilized by many physicians and their patieients.4 It is recommended that monitoring with laboratory testing occur at three-month intervals. Patients need to understand that the treatment goal is to achieve a complete hematologic response first, followed by a complete cytogenetic response, ideally within the first 12-month period. Following that, the goal is to achieve a major molecular response, which can be assessed by PCR testing. Monitoring is made easier by performing tests on peripheral blood rather than bone marrow when available.

Useful Definitions for Chronic Myelogenous Leukemia (CML)

Blood stem cell: An immature cell from which other types of blood cells develop.

Bone marrow: The soft, sponge-like tissue in the center of most bones where blood cells are made.

Chromosomes: Long strands of bundles of coded instructions in cells for making and controlling cells.

Philadelphia Chromosome: CML is associated with a chromosomal abnormality in which genetic material from chromosome 9 is transferred to chromosome 22. The chromosome containing the genetic switch is called the Philadelphia chromosome; this chromosome plays a role in the development of CML.

BCR-ABL: The exchange of genetic information that produces the Philadelphia chromosome brings together two genes: the BCR (breakpoint cluster region) gene on chromosome 22 and the ABL (Ableson leukemia virus) gene on chromosome 9. The combination of these two genes into the single BCR-ABLgene results in the production of a protein that contributes to uncontrolled cell growth.

Gene: Set of coded instructions in cells for making and controlling cells.

Human leukocyte antigens (HLA): Special proteins on the surface of white blood cells that help the body to identify its own cells from foreign cells.

HLA type: A unique set of HLA proteins on a person’s white blood cells. HLA types differ among people just like blood types differ among people. HLA testing is used to determine a person’s HLA type. HLA testing is done before a type of treatment that transfers blood stem cells from another person to the patient. It’s very important that their HLA types are a near-perfect match for this treatment to work. This is because the HLA type affects how the body responds to foreign substances.

Cytogenetics: The study of chromosomes the long strands of bundles of coded instructions for making and controlling cells. Cytogenetics involves examining a sample of cells with a microscope to look for changes in the cells’ chromosomes. This type of test is used to detect abnormal chromosomes and measure the number of cells that have them. The pathologist will use a microscope to examine a “map” of the chromosomes, called a karyotype. The pathologist will assess the size, shape, number, arrangement, and structure of the chromosomes on the karyotype to look for any abnormal changes. Cytogenetics is used to diagnose leukemia and other cancers. It is also used to monitor how well treatment is working. Cytogenetic testing can be performed on cells from the peripheral blood, but bone marrow is preferred because the yield from peripheral blood is very poor.

Fluorescence in situ hybridization (FISH): A test used to detect the Philadelphia chromosome and the BCR-ABL fusion gene. This test may be used on a peripheral blood sample if a bone marrow sample can’t be collected. FISH uses color “probes” to find the BCR gene and the ABL gene in chromosomes. The BCR-ABL fusion gene, located on the Philadelphia chromosome, is shown by the overlapping colors of the two probes. FISH analysis of peripheral blood may be used to diagnose CML when bone marrow cytogenetics isn’t possible. But, FISH is not recommended for monitoring the response to treatment.

QPCR (Quantitative reverse transcriptase polymerase chain reaction): A very sensitive test that detects and measures the BCR-ABL gene. QPCR makes thousands of copies of the DNA in cells from a blood or marrow sample to see how many cells have the BCR-ABL gene. Copies of BCR-ABL found by QPCR are also called BCR ABL transcripts. The number of BCR-ABL copies detected by QPCR is called the transcript level. The transcript level reflects the number of BCR-ABL genes in your body. Changes in BCR-ABL levels are measured in logs—a log reduction means the BCR-ABL level has decreased by a certain amount. QPCR can detect one CML cell among more than 100,000 normal cells. This test is used to confirm (diagnose) CML as well as to monitor the treatment response. The QPCR test should always be done in the same lab, preferably a lab that uses the International Scale. The International Scale is a standardized scale for measuring and reporting QPCR test results. QPCR test results from different labs are converted to the International Scale so that all test results are consistent and can be compared between labs.

Flow cytometry: A test looks at certain substances on the outside surface of cells to identify the specific type of cells present. This test is used for advanced phases of CML to determine if the leukemia cells are mostly myeloid or lymphoid cells. This test is important because the cell type may affect which treatment option is best. Flow cytometry can be performed on a sample of bone marrow or peripheral blood.

BCR-ABL gene mutation analysis: Sometimes new changes (mutations) develop in the part of the BCR-ABL gene that makes the BCR-ABL protein. These mutations change the shape of the BCR-ABL protein, affecting how and which targeted cancer drugs can bind to it to block the growth signals. A mutation analysis is a test that looks for new mutations in the BCR-ABL gene that may occur during treatment for CML. This test may be performed on a peripheral blood or bone marrow sample after months of treatment based on how well treatment is working. Mutational analysis is important because new or different gene mutations can affect which treatment option is best for you.

References:

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