Chronic Myeloid Leukemia and the Development of Gleevec

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• Why is the story of the development of Gleevec important?
• What were the early findings in the development of Gleevec?
• What is chronic myeloid leukemia and how has it been treated?
• What other advances were made in the development of Gleevec?
• What other treatments were developed for chronic myeloid leukemia?
• How was the development of Gleevec completed?
• What are the potential uses of Gleevec?

Why is the story of the development of Gleevec important?

Although I have not yet had the opportunity to have direct experience with the use of Gleevec, I am extremely excited by the development of this agent and look forward to having it available to treat my chronic myeloid leukemia patients. This article will focus on the extraordinary story of the development of Gleevec and how it has been intimately intertwined with our growing understanding of this rare type of leukemia (cancer of the white blood cells).

The development of this drug has been particularly satisfying intellectually, with direct benefits for patient care arising from several decades of basic science research. Furthermore, the story of this drug illustrates the promises of the human genome project and reflects the vast investment made in the basic science of human biology over the past four decades. The human genome project is a monumental international effort to identify all of the genetic information in the human chromosomes.

What were the early findings in the development of Gleevec?

Gleevec is a novel, specific BCR-ABL tyrosine kinase inhibitor. Its generic name is imatinib mesylate. The development of Gleevec began in the early 1960s with the identification of the so-called Philadelphia chromosome (after the city in which it was identified) in patients with chronic myeloid leukemia. This disease is one of those conditions whose impact on our general understanding of biology far outweighs the impact that the relatively small number of patients with the disease can have on our practice of medicine. (Of course, the disease has a tremendous impact on the afflicted individuals and their families.) Moreover, the treatment of chronic myeloid leukemia has undergone several revolutions over the past few decades. It turns out, quite remarkably, that each change in the management of this disease has had important applicability to other diseases. You will soon see what I mean by understanding of biology and applicability to other diseases.

The Philadelphia chromosome was first recognized as a shortened chromosome 22. (Chromosomes are thread-like structures in every cell nucleus. 23 pairs of chromosomes carry all of an individual's genes. The genes, in turn, carry the codes to produce the proteins that determine all of an individual's characteristics.) Anyhow, this chromosomal shortening was noted in 90% of patients with chronic myeloid leukemia. What's more, this abnormality was only found in the malignant (cancerous) cells, while the nonmalignant cells in the patients did not have the abnormality. Hence, this was the first consistently noted chromosomal abnormality that was associated with a malignancy. As a matter of fact, these observations led directly to the prevailing theory that most malignancies are the result of acquired genetic mutations (alterations of the genes).

To continue with the chromosome 22 part of the story: Subsequently, it was noted that the missing piece of chromosome 22 had in fact attached itself (translocated) to chromosome 9, while a portion of chromosome 9 had translocated to chromosome 22. Furthermore, it was found that the breakage on chromosome 22 consistently occurred (that is, clustered) in the same narrow region of the chromosome. This region, therefore, became known as the breakpoint cluster region, or BCR for short. During the time that these biological observations on the shortened chromosome 22 were being made, not much change was occurring in the treatment of chronic myeloid leukemia. Basically, the treatment at that time revolved around controlling the high white blood cell counts by using an agent named busulfan (Myleran).

What is chronic myeloid leukemia and how has it been treated?

Chronic myeloid leukemia is characterized by a chronic (long duration) phase that is relatively benign. This disease, however, has a constant risk and tendency to transform into an acute (short duration) phase that is rapidly fatal. As a result of this acute phase, the average time of survival from chronic myeloid leukemia was about four years, meaning that half of the patients died before the four years and half were still alive at that time. The first treatment that affected the natural history (course) of this disease was developed in the late 1960s and early 1970s. This treatment was bone marrow transplantation; initially from an identical twin, subsequently from a matched donor from within the family, and ultimately expanded to include matched donors from unrelated volunteers. The bone marrow is the primary place in the body where the blood cells, including the white blood cells, are made. The term matched donor refers to compatible tissue typing, which is needed to minimize the possibilities of the recipient's body rejecting the transplant (rejection), and the transplant rejecting the recipient's body (graft versus host disease).