- 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).
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.
What other advances were made in the development of Gleevec?
The next advance in the understanding of the biology of chronic myeloid leukemia came with the development of the techniques of molecular biology (a field that focuses on the genes) and the identification of cellular oncogenes. An oncogene is a cancer-causing gene. (Initially described in viruses, oncogenes actually came from mammalian cells and were then picked up by the viruses as they passed through various vertebrate hosts.) One oncogene, described below, is called the Abelson oncogene. This oncogene, located on chromosome 9, is on that part of chromosome 9 that, as I mentioned before, translocates to chromosome 22 in chronic myeloid leukemia. Thus, this translocation formed an abnormal gene in this disease that became known as BCR-ABL. (ABL is short for Abelson and remember that BCR is short for breakpoint cluster region.)
Now, what about the tyrosine kinase? Well, it happens that the Abelson oncogene codes for a protein that functions as a tyrosine kinase. This means that the gene itself works by attaching phosphate groups (a process called phosphorylation) onto tyrosine molecules that are on other proteins. (Tyrosine is one of the amino acid backbones of proteins.) Typically, the processes of tyrosine phosphorylation and de-phosphorylation are part of the cellular machinery for turning proteins on and off. In this manner, tyrosine kinases function as part of the internal communication network of the cell.
Consequently, in chronic myeloid leukemia, the BCR-ABL protein product results in the formation of a tyrosine kinase that is out of control. In other words, the tyrosine kinase is turned on all the time, somewhat like a thermostat stuck in the on position, driving cells to continuously reproduce (proliferate). Now you can see why the goal would be to find a specific inhibitor that turns off the BCR-ABL tyrosine kinase. Actually, a large amount of work went into mapping exactly which parts of this protein carried out which functions. Ultimately, each portion of the protein was assigned a function and, in fact, the active site on the protein that participated in the phosphorylation reaction was identified.
What other treatments were developed for chronic myeloid leukemia?
Meanwhile, other therapeutic advances were being made in the treatment of chronic myeloid leukemia. For one thing, alpha interferon (Roferon-A, Intron A) was developed and shown to have significant activity in this disease. With this treatment, a large number of patients had very good responses and some even lived much longer than would have been expected from the natural history of their disease. Interferon, therefore, became the standard therapy for patients who, either because they were too old or lacked an appropriate donor, could not be transplanted.
For another advance, it was discovered that the cures after bone marrow transplantations for chronic myeloid leukemia were, for the most part, not due to the high doses of chemotherapy given to patients along with the transplantation. Instead, the cure was actually brought about by the transplantation of the components of the immune system itself. Put another way, when we do a bone marrow transplant, we are, in reality, transplanting a healthy immune system from one person into another. Clearly then, we were curing these patients because the transplanted immune system attacked the chronic myeloid leukemia. As a result, the standard treatment today for a relapse (return of the signs and symptoms) of chronic myeloid leukemia following bone marrow transplantation is to boost the transplanted immune system. This boosting is accomplished by giving an infusion of white blood cells, which is known as a donor leukocyte infusion.
More recently, medication regimens for bone marrow transplantation have been developed that allow transplantation of the immune system to be done without major organ toxicities. The use of these relatively nontoxic regimens likewise demonstrates that chronic myeloid leukemia can be cured by the transplantation itself. This recognition of the beneficial immunologic effect of transplantation has now been generalized to the treatment of a variety of other malignant diseases, for example, renal cell carcinoma. Here then, is another example of how chronic myeloid leukemia has influenced our thinking about other malignant diseases.
How was the development of Gleevec completed?
In the meantime, the understanding gained about the way that BCR-ABL works led, as I indicated previously, to a search for specific inhibitors of this molecule. After screening many thousands of compounds, the drug eventually known as Gleevec was identified as having marked inhibitory effects specifically against BCR-ABL with only minor effects against other related normal molecules. This activity was shown first in the test tube and in animal models and then, almost miraculously, was completely confirmed in human studies.
What are the potential uses of Gleevec?
Because of this dramatic clinical activity of Gleevec in chronic myeloid leukemia, the drug was fast-tracked for approval by the FDA and is now available throughout the United States. In as much as Gleevec has been studied in patients for only two or three years, however, we cannot yet determine whether it has improved survival or cured any patients. These potential benefits remain to be seen. Therefore, I believe that bone marrow transplantation currently remains the treatment of choice for appropriately selected candidates having chronic myeloid leukemia, with Gleevec as an acceptable fallback option.
For me, the story of the development of this drug contributes to the excitement of being a clinician with an interest in basic science in these modern times. Beyond that, we have today an increasing emphasis on translational research. That is to say, scientific discoveries are occurring more frequently and are moving (being translated) more rapidly from the laboratory to the treatment of patients. As our understanding of the basic biology of malignancy continues to improve, we will see more and more specifically targeted therapeutic agents with marked activity and minimal toxicity developed in a similar fashion to Gleevec. Chronic myeloid leukemia is once more leading the way in advancing our understanding of the biology and treatment of cancer.
As an interesting footnote, Gleevec is currently being evaluated experimentally to treat a rare, otherwise difficult-to-treat tumor, called a gastrointestinal stromal tumor. Using Gleevec to treat this other tumor, however, seems to be a bit of a stretch, considering the intended specificity of Gleevec as an inhibitor of the BCR-ABL tyrosine kinase. You see, a different mutated gene that continuously turns on a different protein kinase from that in chronic myeloid leukemia causes the gastrointestinal stromal tumors. So, we have lots more to learn.
Medical Author: Michael Lill, M.D.
Medical Editor: Leslie J. Schoenfield, M.D., Ph.D.