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Overview of CML
Chronic Myelogenous Leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells resulting in increases in myeloid and erythroid cells as well as platelets in peripheral blood, and marked myeloid hyperplasia in the bone marrow. CML accounts for 15% of leukemias in adults. The median age at presentation is 53 years, but all age groups, including children, are affected.
Molecular Basis of Disease
The molecular hallmark of CML is the Philadelphia (Ph) chromosome, a shortened version of chromosome 22 that is the result of a translocation between chromosomes 9 and 22, and is found in 95% of CML patients. The Ph translocation results in the recombination of segments from the BCR and ABL genes creating a hybrid BCR-ABL gene. This hybrid gene is transcribed and translated to produce the BCR-ABL fusion protein, an unregulated tyrosine kinase (TK) that alters cellular growth and function.
Diagnosis of CML
CML is confirmed by the presence of an elevated WBC count, splenomegaly, thrombocytosis, and identification of the BCR/ABL translocation. Cytogenetic karyotyping, which is the standard diagnostic test for CML, not only can detect the Ph chromosome in most CML patients, but can also detect the presence of other clinically significant chromosomal abnormalities.
Treatment of CML
Imatinib mesylate (Gleevec®) has emerged as the first-line therapy for CML. Imatinib is a TK inhibitor with high specificity for the BCR-ABL protein. While imatinib induces complete cytogenetic remission (CCR) in the majority of patients, a significant number of individuals do not respond and would benefit from alternative therapies earlier in the course of disease. Although the hybrid BCR-ABL gene is the molecular hallmark of CML, mutations to the ABL portion of the gene do not reliably predict response to imatinib therapy.
Imatinib is a molecularly-specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer. It has demonstrated remarkable clinical efficacy in patients with Chronic Myeloid Leukemia (CML) and malignant gastrointestinal stromal tumors. Imatinib was first made available to patients with CML in May of 2001. Imatinib is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (www.gleevec.com/hcp/page/hcp_prescribing_info). Follow-up is limited. Imatinib is also indicated for the treatment of patients with Ph+ CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Imatinib is also indicated for the treatment of pediatric patients with pH+ chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy. There are no controlled trials in pediatric patients demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.
Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low. Adverse effects most commonly include mild-to-moderate edema, nausea and vomiting, diarrhea, muscle cramps, and cutaneous reactions. Hepatic transaminase level elevations and myelosuppression occur less frequently and resolve with interruption of imatinib therapy. In general, the incidence and severity of adverse effects tend to correlate with imatinib dose and, in chronic myeloid leukemia patients, the phase of disease; patient age and other factors are also associated with some types of reactions. With prompt and appropriate intervention, adverse effects in imatinib-treated patients have proven to be manageable across the spectrum of severity and they seldom require permanent cessation of therapy. Dose reduction is not usually necessary and reduction to subtherapeutic levels is not recommended.
The majority of patients who received Gleevec® in clinical trials did experience adverse effects. Most adverse effects were mild or moderate. The most common adverse effects were fluid retention, nausea, muscle cramps, diarrhea, vomiting, muscle and bone pain, fatigue, rash, and abdominal pain. Serious and severe adverse effects such as liver problems, water retention in different parts of the body including the heart, muscle or bone pain, skin blistering, and low levels of certain blood cells have also been reported in some patients. Gleevec® was discontinued due to adverse effects in 4 percent of patients in the chronic phase of CML, 5 percent in accelerated phase, 5 percent in blast crisis, and 8 percent in GIST. Recently, reports of cardiotoxicity following initiation of treatment with GleevecŪ have been reported (Kerkela, et.al., Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nature Medicine, 12;8:908-916. 2006). Clinical trials of involving Gleevec® have reported a relatively high incidence of peripheral edema (63-66%), some of which have been classified as severe (4-5%). In addition, dyspnea has been reported in 12-16% of treated individuals and has been classified as severe in 4-5%. These symptoms have been interpreted to represent left ventricular dysfunction and even frank congestive heart failure.
Gleevec® has become recognized as the most effective non-transplant treatment available for patients with CML. However, it is an expensive drug. Costs of the drug range from $30,000 to $40,000 per year (USA Today, Cost of cancer drugs crushes all but hope. 7/11/06). The costs per quality adjusted life year are approximately $40,000 more than conventional therapy for patients treated in the accelerated phase and almost $60,000 more for patients treated in blast crisis (Gordois, et.al., Cost-utility analysis of imatinib mesilate for the treatment of advanced stage chronic myelogenous leukemia. British Journal of Cancer 2003;89:634-640).
Clearly, identifying patients with a low likelihood of responding to imatinib may avoid potentially serious adverse effects, hasten the initiation of potentially more beneficial treatment, and save considerable costs.
CLICK HERE for more information on the use of monitoring HAAH expression levels in the management of chronic myeloid leukemia.
As a health care professional, Panacea understands that you are committed to providing the best possible care to your patients. We're committed to helping you achieve that goal.