American Society of Hematology

Targeted Therapy for Chronic Myeloid Leukemia

Many advances in the treatment of cancer can be traced to the therapy of leukemia. The development of a specific therapy for chronic myeloid leukemia (CML) is a remarkable story of scientific discovery that proved that a precise understanding of the molecular cause of a cancer can lead to an effective and non-toxic "targeted" treatment.

CML is one of the four main types of leukemia, affecting approximately 5,000 people per year in the United States. The disease can occur at any age but is primarily a disease of adults. CML is characterized by a massive over-production of white blood cells. A normal white blood cell count ranges between 4,000 and 10,000; in contrast, patients with CML typically have white blood cell counts ranging from 100,000 to as high as 500,000. Because the white blood cells mature and function normally, infections are not a common feature of CML. Rather, symptoms include fatigue due to anemia or abdominal discomfort due to an enlarged spleen. Historically, patients with CML lived no more than three to five years, during which time the disease would quickly transform from a chronic leukemia to an aggressive and fatal acute leukemia.

CML has become the "poster child" for targeted cancer therapy, demonstrating that a precise understanding of the cause of a disease allows an effective therapy to be developed. To achieve this, however, required decades of scientific discovery to unravel the cause and develop a targeted therapy. In 1960, Peter Nowell and David Hungerford, working in Philadelphia, described a shortened chromosome in the blood and bone marrow of patients with CML. This was the first consistent chromosomal abnormality associated with a human cancer. Then, in 1973, Janet Rowley showed that this abnormal chromosome, now called the Philadelphia chromosome, came about because of an exchange of genetic material between two chromosomes. In the 1980s, it was demonstrated that the consequence of this chromosome exchange was the production of an abnormal gene called BCR-ABL. This gene acted like the gas pedal in a car stuck in the "on" position, fueling the excess growth of white blood cells in CML.

With the target identified, a drug discovery program was started, aimed at developing a drug to shut down the activity of BCR-ABL. The compound that became known as imatinib (Gleevec) was developed in 1992, and studies showed that this compound killed CML cells without harming normal cells. In 1998, the drug was tested in patients with CML who had exhausted standard treatment options and whose life expectancy was limited. Within six months of starting the clinical trials of imatinib, all of the patients had their blood counts return to normal. Remarkably, this once-a-day pill had minimal side effects. These unprecedented results were confirmed in much larger clinical trials, and imatinib was approved by the U.S. Food and Drug Administration (FDA) in 2001, less than three years from the start of the clinical trials. With longer follow-up, this once routinely fatal leukemia now has a five-year survival rate of 95 percent.

But imatinib is not perfect, and some patients have had their leukemia return. Once again, scientific discoveries into the cause of resistance have allowed new therapies to be developed. It has been determined that the major cause of resistance to imatinib is changes (or mutations) that occur in BCR-ABL, which is imatinib's target. These changes prevent imatinib from binding to the target to shut it down. If BCR-ABL was a lock and imatinib was the key, in the case of resistance, the lock has been changed, so the key no longer fits. These changes allow BCR-ABL to regain its foothold and once again drive the growth of white blood cells. Newer drugs (dasatinib and nilotinib) have been developed that can shut down most of the mutated forms of BCR-ABL, and have significant activity in patients with resistance to imatinib; these drugs are also FDA-approved. Thanks to these remarkable scientific advances, patients with CML now have numerous treatment options available and the prospect of a normal life expectancy.

This article was published in December 2008 as part of the special ASH anniversary brochure,50 Years in Hematology: Research That Revolutionized Patient Care.

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