Chronic Myeloid Leukemia and the Development 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).
Bone marrow transplantation is clearly curative. In fact, it is the only proven cure for
chronic myeloid leukemia, even now. However, only 30% to 40% of patients with
chronic myeloid leukemia have an appropriate donor. Beyond that, the mortality
(death rate) from the procedure ranges from 20% to 30%, depending upon the age
of the recipient. Finally, this procedure is extremely expensive.
Nevertheless, bone marrow transplantation has been the treatment of choice for
chronic myeloid leukemia since the 1970s. In retrospect, it is interesting to
recall that at the time this therapy was being developed, we thought the cure of this disease
was not a result of the transplantation itself. Rather, we believed the
cure came from the high doses of chemotherapy
and radiation that
were given to suppress the immune (protective) system and thereby prepare the patient's body
to accept the transplant. As I will discuss later, this belief was subsequently
proven to be erroneous.
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