Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

      PKGhatak,MD

Chronic Myeloid Leukemia (CML), also called chronic myelogenous leukemia, develops due to an acquired abnormality of a chromosome and has become an important milestone in medicine in more than one way.

In 1959 Dr. Peter Nowell, a pathologist at the University of Pennsylvania, PA, while microscopically examining the blood of a Leukemic patient, detected an abnormal chromosome. Dr. David Hungerford, a Zoologist working on his Ph.D. at the Fox Chase hospital in Philadelphia, corroborated with Dr. Nowell. They established that the abnormality was on chromosome 22. They named this abnormal chromosome as Philadelphia Chromosome (Ph Chromosome). The Ph chromosome is present in all CML cases. It is also present in 20% of acute lymphatic leukemia and 2% of mixed types of leukemia.

The long arm of chromosome 9 breaks away at ABL (Abelson Leukemia virus) and the broken piece gets attached to the breakpoint BRC (Breakpoint Cluster Region) of chromosome 22. This results in a fusion gene called the BCC-ABL gene. The broken piece from chromosome 22 attaches to chromosome 9. The process of swapping genetic materials between two chromosomes is called Reciprocal Translocation.
This discovery was the first of a Chromosomal abnormality as the cause of human leukemia, and the abnormal chromosome was visible on blood smears. This discovery generated a lot of interest in research in finding genetic mutations in the development of malignancy.
In 1973 Dr. Janet Rowling at the University of Chicago identified the mechanism behind reciprocal translocation.
The scientific notation for this translocation is t (9;22) (q34.1; q11.2)

t stands for translocation; 9 and 22 within the parentheses are chromosomes no. 9 and no. 22. In the next parentheses, q stands for the long arm of chromosomes and the two digits are for the band location on Chromosomes.

The normal ABL gene carries instructions for the synthesis of a protein called Tyrosine Kinase (TK). TK speeds up the rate of cell division and also repairs corrupt DNA. The rate of synthesis of TK is auto-regulated. When ABL is fused with the BCR gene, this fusion gene loses its auto-regularity property and begins producing an excess quantity of TK. Some myelocytes contain this fusion gene.  An excessive number of white cells appear in the blood, and only a small fraction of granulocytes carries this Ph gene in their nucleus. The protein produced by BCR-ABL is named according to the molecular weight and location (p120 to p180). The protein p230 is associated with CML.

The normal BCR gene regulates cell movement and cell functions. It may work as an on and off molecular switch within the cell.

Clinical Features of CML:

CML patients present in three distinct phases of the illness-

Chronic phase CML, Accelerated phase CML and Acute Blast phase or Acute leukemic phase.

Chronic CML:

The patients are generally symptom free. The disease is detected in a routine blood test done for other reasons. The white cell counts (WBC) over 50,000/mcL are usual. Further, tests detect the Ph chromosome. A bone marrow biopsy is required to establish a CML diagnosis.

When patients develop symptoms, they are likely to complain of night sweats, lack of energy, low grade fever, left sided abdominal pain, joint pain and increased WBC counts of 100,000/mcL or more. Enlargement of the spleen is usually detected. And a ratio of BCR-ABL / ABL (abnormal over normal gene ratio), detected by PCR test (polymerase chain ratio), of the white cells and bone marrow shows a ratio over 0.01(the range of 0.02 to 0.25). This ratio helps to determine when to start treatment. It is also an important indicator of the effect of therapy and adjustment of medications.

When mature white cell numbers fall, viral or bacterial infections result. When the WBC count reaches 150,000/mcL or higher, the blood becomes thick and blocks capillaries of the retina and blurred vision results. A segmental visual field loss is the rule. Similarly, obstruction of brain vessels may occur and produce strokes.

About 18 years ago Imatinib, an oral medication, was introduced to treat CML. It blocks the uncontrolled production of Tyrosine Kinase by the fusion BCR-ABL gene. Since then, the outlook of patients with CML has changed dramatically. About 98% of CML patients respond to this drug and patients remain in stable condition for 10-15 years or more. Some patients may even be taken off the medication and are observed with blood tests only.

However, a minority of patients either do not respond to Imatinib or develop resistance to medication. The BCR- ABL/ABL ratio increases, so also the WBC count. In these cases, other TK inhibitors - Nilotinib, Dasatinib and Bosutinib are effective.

The accelerated phase of CML:

Those patients who do not respond to Tyrosine Kinase Inhibitors (TKI) or develop further mutation of BCR-ABL gene, develop worsening of fatigue, weight loss, weakness, fever, gum bleeding, and pain in the abdomen and joints. Anemia and an enlarged liver may be present on examination. An increase in WBC count over 200,000/mcL, 10 to 19% basophils in blood, an increase in BCR-ABL/ABL ratio and an increase in blast cells in blood and bone marrow are present. A new mutation in the BCR-ABL gene may be detected. T315I mutation is resistant to several TKI drugs.

Patients generally respond to increasing dose of TKI or switching to different TKI and at the time a combination of two TKI drugs are used. Those patients who still do not respond are treated with a new TKI drug, Ponatinib, with a good response. Some young patients may be considered for allogenic Stem Cell Transplantation but transplant results are mixed.

Acute Blast Phase or Blast Crisis:

Patients are sick with increased intensity of all existing symptoms. Increasing weight loss, high fever diarrhea, sepsis, high blood sugar, and pain over bones and joints, nose bleeding, cerebral bleeding, and abdominal pain usually develop.

Anemia and a very high WBC count and decreased platelet count, blast cells over 20% in the peripheral blood, and 20% or more blast cells in bone marrow are usual. Internal organs show blast cell infiltration. Testing for mutation of BCR-ABL gene is mandatory before treatment is initiated because the selection of medications depends on the detection of the correct mutation. Acute Lymphoblastic Leukemia develops in 20% of cases. Acute myeloblastic leukemia in 2% and mixed Acute Leukemia are also seen.

Treatment of Myeloid blast crisis consists of administrating one or two TKI drugs and multiple chemotherapeutic agents to induce remission. Afterward, suitable TKI drug or drugs are continued. Omacetaxine, a non-TKI drug is approved for use in the blast and accelerated stages of CML. It may produce severe bone marrow depression, cerebral hemorrhage, elevated liver enzymes, and diarrhea.

Early allogenic stem cell (stem cells obtained from a donor) transplantation is recommended in blast crisis. But the results are not that impressive.

The introduction of tyrosine kinase inhibitors has changed the outlook of over 90% of CML patients. The majority of them can expect to live their lives normally. Peripheral blood PCR test helps an accurate evaluation of the disease progression and early detection of the emergence of resistance and modification of treatment are possible before more serious complications could develop.

****************************************************************