1960: Peter Nowell reported that patients with chronic myelogenous leukemia (CML) consistently had an abnormally small chromosome 22, an alteration that became known as the Philadelphia chromosome. Because of the consistency of the finding, scientists speculated that this shortening might be related to the cause of the leukemia.

1973: New staining techniques allowed researchers to see that, in addition to the deletion in the long arm of chromosome 22, the long arm of chromosome 9 was lengthened by about the same amount in all the CML patients examined. This suggested that pieces of each chromosome were exchanged or translocated.

1982: One of the human cancer genes, the abl proto-oncogene, was shown to be located on chromosome 9 in non-CML patients and translocated to the Philadelphia chromosome in patients with CML. These findings raised the prospect that the abl oncogene was activated by this translocation.

1984-1987: During this period, several labs played a role in discovering how the translocation produces a cancer-causing protein. They found that in cancer cells, the abl translocation to chromosome 22 leads to the formation of an altered protein containing a piece of the Abl protein joined to a piece of a second protein, BCR. It is this fused protein product, called BCR-ABL, which is abnormally expressed in about 95 percent of CML patients.

1990: Several labs showed that bcr-abl alone causes leukemia in mice.

1993: The first laboratory studies of STI571 began when a scientist, now at Oregon Health Sciences Center in Portland, approached Ciba-Geigy, now Novartis Pharmaceuticals (Basel, Switzerland) requesting permission to test various compounds that would be likely to block the abnormal protein, BCR-ABL.

1996: One of these compounds, STI571, was shown to inhibit the growth of BCR-ABL-expressing cells.

1998: STI571 was first tested in a small study in people to determine whether it is safe. Doctors noticed that with higher doses, patients had dramatic positive responses to the drug.

1999: The preliminary results of this early study showed that 31 out of 31 patients who received at least 300 milligrams daily had their blood counts return to normal. In nine of the 20 patients who were treated for five months or longer, no cells with the Philadelphia chromosome could be found.

2001: February: Novartis submitted the New Drug Application for STI571, now known as Gleevec, to FDA for the treatment of the late phases of CML.

2001: April: Results of a larger study of STI571 in 83 patients were reported in New England Journal of Medicine. In the 54 chronic-phrase CML patients who were treated with doses of 300 milligrams or more, normal blood counts were restored in 53, and in 29 of the 54 patients, the Philadelphia chromosome disappeared. Most side effects were mild.

2001: May: U.S. Food and Drug Administration approved the sale of STI571/Gleevec for CML.

References:

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De Klein A, van Kessel AG, Grosveld G, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukemia. Nature 1982;300:765-767.

Gale RP and Canaani E. A 8-kilobase abl RNA transcript in chronic myelogenous leukemia. Proc Natl Acad Sci USA 1984; 81:5648-5652.

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Kelliher MA, McLaughlin J, Whitte ON, et al. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci U S A 1990;87:6649-6653.

Heisterkamp N, Jenster G, ten Hoeve J, et al. Acute leukemia in bcr/abl transgenic mice. Nature 1990;344:251-253.

Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996;2:561-566.

Deininger MW, Goldman JM, Lydon N, et al. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997;09:3691-3698.

LeCoutre P, Mologni L, Cleris L, et al. In vivo eradication of human Bcr/Abl-positive leukemia cells with an Abl kinase inhibitor. J Natl Cancer Inst 1999;91:163-168.

Druker BJ and Lydon NB. Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J Clin Invest 2000;105(1):3-7.

Mauro MJ and Druker BJ. Chronic myelogenous leukemia. Current Opinion in Oncology 2001;13:3-7

Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Eng J Med 2001;344:1031-1037.

Druker BJ, Sawyers CL, Hagop K, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Eng J Med 2001;344:1038-1042.

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