Chronic Myeloid Leukemia
Its history, treatment, molecular biology and genetics and potential as a subject for revolutionary new drug design – The development of Gleevec.
Chronic Myeloid Leukemia, or CML, is the most extensively studied of human malignancies. Despite its relative rarity, it was the first recognized leukemia, identified as a specific illness in the 1840s. CML was later the subject of a landmark discovery in the 1960s when the exact chromosomal anomaly that triggers this remarkable cancer was isolated, the first such discovery for any malignancy. It was also the first cancer to have the exact molecular anomaly involved identified, and the simplicity of this molecular cause has made CML an ideal candidate for the development of a new generation of highly specific drugs.
CML is an adult onset leukemia, with no known predisposition factors except for an increase incidence after exposure to ionizing radiation, noticed initially in Japan among the survivors of the nuclear blasts of 1945. It is a haemapoetic stem cell malignancy, characterized by the replacement of healthy bone marrow by malignant cells and the overproduction of myeloid cells. These cells spread through the blood, resulting in sometimes painful enlargement of the liver and spleen. Other early symptoms are common with other leukemias and include weight loss, night sweats, some anaemia, dizziness and fainting.
The Chronic stage of the disease is the first in its development and is characterized by relatively minor symptoms. Patients are often unaware that they are ill at all. CML is often diagnosed in incidental blood tests when an abnormally high white blood cell count is noticed.
Later, if untreated, the disease progresses to more severe Accelerated and Blast phases, where more dangerous and more obvious symptoms occur, including jaundice, high fever, and uncontrollable bleeding due to low platelet count. During the Accelerated phase increasing doses of chemotherapy are needed to attempt to control the disease. The Blast phase resembles an acute form of leukemia and is treated with an entirely different regimen to the chronic phase of CML. It is typically myeloblastic in 80% of patients, and lymphoblastic in around 20%. The average survival period for CML patients under conventional treatment is 5 years, but severe forms can prove fatal in months and patients with more chemoresponsive CML can live up to 10 years.
The complete cure for CML comes in the form of a bone marrow transplant (BMT). This procedure is coupled with treatment with powerful chemotherapy drugs. Two older, but still fairly common drugs used in the treatment of CML are Hydroxyurea and Busulfan, both synthetic molecules, and usually only used immediately before a BMT procedure. Both these drugs have severe side effects, including nausea, hair loss, anaemia, soreness of the mouth and difficulty swallowing, diahrrea and occasionally shortness of breath and lung damage.
A more recent drug is Interferon alpha, which is used to treat a variety of leukemias. The drug is an artificially copied protein produced naturally by humans during some viral infections, or in natural response to cancer. It interferes with cancer cell development and division, stimulating the marking of malignant cell membranes with molecules to attract an immune cell response, and stimulating killer T-cell response to such markers. Interferon a is used to control the majority of CML cases today, as its side effects are typically less severe and it is often more effective at controlling the spread of the cancer. Although still quite toxic, its side effects are less severe than those of the older chemotherapy agents. They involve flu-like symptoms of aches, low fever and nausea, as well as mild anaemia and low white cell and platelet counts.
Interferon a is, at present, undergoing a challenge as drug of choice in CML treatment. The response rates of a recently developed, revolutionary new drug, Gleevec, are currently being compared to Interferon a in a randomised clinical trial. No full statement of results has yet been published, but an early abstract announced at the May proceedings of the American Society of Clinical Oncology suggests that Gleevec is obtaining superior response rates.
Gleevec, or Imatinib Mesylate
, is an entirely groundbreaking drug. It is the clinical application of what promises to be a new wave of treatment regimes in oncology
, the targetting of pathogenic gene expression
with highly specific inhibitor
molecules. The characteristics that make CML the ideal candidate for research into this field need to be outlined.
CML, unlike many other types leukemias and cancers, including the related and more common Acute Myeloid Leukaemia, is a single, specific disease, instead of a bracket of related diseases. This characteristic made it an attractive subject for research into its trigger.
In 1960, it was discovered that not only was CML a single, uniform disease, it also appeared to have a single distinct cause. Genetic research made it clear that in all CML patients, a translocation had occurred between chromosomes 9 and 22. The genes that had been switched were designated ABL and BCR, both normal genes of unknown function. In CML cells, both genes are truncated in the process of the reciprocal 9-22 translocation. On the altered chromosome 9, now designated 9q+, there is a fused ABL-BCR gene. On chromosome 22q-, there is a fused BCR-ABL gene. It is this modified chromosome 22 that was identified in 1960 as being the key modification in all CML cells. Addition of the abnormal chromosome in mouse cells has been observed to induce a change in behavior to malignancy in that cell. Indeed, the modified chromosome is known as the Philadelphia, or Ph, chromosome, and proved so central in the function of the disease that CML is now defined in terms of the presence of this mutation.
Although the specific functions of normal genes ABL and BCR are unknown, it is known that ABL codes for a tyrosine kinase of very restricted function. Tyrosine kinases are protein complexes that receive cell communications ordering cellular growth and division. This is crucial to the actions of the chimeric gene produced during the translocation event, as the gene expression product retains the basic characteristics of a tyrosine kinase. The BCR-ABL gene’s expression as a tyrosine kinase was discovered in 1986 by a team led by Nobel laureate David Baltimore.
On the Ph chromosome, the BCR-ABL gene produces a chimeric RNA strand encoding the BCR-ABL oncoprotein. When this protein is produced, it operates as an abnormal tyrosine kinase, and messages ordering cell division begin to be received on multiple pathways, even where entirely inappropriate. Therefore the production of the oncoprotein results in rapid, uncontrolled and malignant increase in the number of affected myeloid cells.
CML was the subject of another milestone in molecular oncology when the BCR-ABL oncoprotein was modeled as a molecule in 1987, becoming the first cancer whose mechanism was precisely known and understood. This unique status meant that CML was the first cancer able to be targeted by drugs designed to alter or inhibit the mechanism of malignancy.
In the late 1980s, molecules that had the potential to inhibit the operation of abnormal tyrosine kinases were being studied extensively by research laboratories in the hope of turning up something useful. Dr Brian Druker, a haematologist who had given up work as a physician to conduct research into better drugs, and who had in 1992 discovered the molecular pathway that the BCR-ABL oncoprotein used to cause uncontrolled cell division, proposed to pharmaceutical company Ciba-Geigy that possible inhibitors to this protein be particularly closely studied. Although CML is rare and does not have the lucrative treatment market of other cancers, the potential for a breakthrough in drug design was fortunately decided to be worth the investment.
After two years of intensive research and molecular design, a research team had studied the atomic configurations that would be needed to be specific for the abnormal BCR-ABL tyrosine kinase, while leaving healthy, similar proteins unaffected. A selection of these molecules was submitted to Druker’s lab for screening tests, and one was clearly superior in terms of both specificity and effectiveness. The molecule, Signal Transduction Indicator (STI) 571, known as Imatinib Mesylate, was then studied for toxicity in preparation for a clinical trial that began four years later.
Initially, it was not known if STI 571 would kill the bone marrow stem cells that are the progenitors of the disease with much effectiveness. It was originally thought that patients would have to continue taking the drug for the rest of their lives to control the cancer. If they stopped their course when a single Ph chromosome stem cell was left, it would continue to produce floods of myeloid cells that would once more cause the symptoms of CML and eventual death.
In 1998, clinical trials of the drug began, using patients with the earlier, Chronic form of the disease who had not responded to standard treatment with Interferon a. Responses were extremely positive, with patients on a low dosage showing 50% reductions in white blood cell counts, and those on a high dosage showing a complete return to normal levels. It appears that the drug does not have to be taken indefinitely, but the number of years it is needed for is still a subject of debate. In 2001, the Imatinib was officially named Gleevec by Novartis, who had bought Ciba-Geigy in 1996.
The drug has relatively few side effects, particularly when compared to the earlier, more toxic chemotherapy treatment regimes. Most patients experienced no or very limited effects, but some work has recently been published indicating some liver toxicity at higher doses, edema, thrombosis, fever and, in one reported case, bone marrow necrosis and pain in the limbs. In addition, 3 of 10 000 patients experienced rupture of the spleen believed to have been related to Gleevec action on healthy platelet tyrosine kinases. Reports on side effects are still coming in from trials and hospitals across the world, as is typical with any new drug, and correspondence of this nature is frequently seen in haematological and medical journals.
Despite the most common references to Gleevec in current journals being reports of negative effects, the importance of the drug should not be underestimated. It represents the first successful product of an entirely new way of treating cancer. Current information suggests that it is drastically more successful than alternative treatments available, but conclusions must wait until the final results of the large-scale Interferon a / Gleevec comparison trials are published. It is not unreasonable to propose, however, that Gleevec may become the dominant treatment for CML a few years into the future. One factor that may inhibit this change in treatment regime is price: Gleevec is approximately twice as expensive as Interferon a, and has not been approved for Pharmaceutical Benefits Scheme subsidy in Australia, placing it out of the financial reach of most patients.
Gleevec is an impressive first success for specific protein inhibitor drugs treating cancer, and it is expected that other, similar drugs will follow in the next few years. However, most cancers are far more complex, or more poorly understood, than CML. It is the simplicity of CML and the depth of understanding gained into its mechanisms through groundbreaking science in the last few decades that allowed the revolutionary research into an entirely new class of drugs to be so successful.
Nature ( www.nature.com), New England Journal of Medicine, Blood, British Journal of Haematology, American Society of Clinical Oncology ( www.asco.com ), http://www.cancer.gov/clinicaltrials/developments/molecular-target-drug0400, http://www.newcmldrug.com/History.htm, http://www.tirgan.com/cml.htm
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