When Drs. Nowell and Hungerford first suggested a causal relationship between a chromosome abnormality and chronic granulocytic leukemia[1] (now termed chronic myeloid leukemia, or CML), an era of cancer genetics began. Over the course of the next 20 years, the Philadelphia chromosome, named after the city where it was discovered, became the hallmark of CML, and the focal point for many discoveries. In 1973, it was defined as t(9;22), a reciprocal chromosomal translocation.[2] A decade later, laboratories in the Netherlands and the United States localized the ABL proto-oncogene on chromosome 9 and the breakpoint cluster region (BCR) on chromosome 22 as focal points of the fusion gene product.[3-5]
Subsequent molecular discoveries and clinical advances have made the treatment of CML one of the great success stories of modern medicine. The development of therapy for CML in the clinic largely matches the scientific discoveries in the laboratory. Before the 1980s, the focus was on maintaining normal white blood cell counts, typically with hydroxyurea and busulfan(Drug information on busulfan) (Myleran). In the era of interferon, cytogenetic remission became the focal point of therapy. Targeted therapy was introduced in 1998 with the first studies of imatinib(Drug information on imatinib) mesylate (Gleevec), and since then, the objectives of therapy have rapidly shifted toward the achievement of molecular remission.
Interferon and Bone Marrow Transplantation
In 1983, interferon-alpha was first found to have activity against CML.[6] This finding was quickly expanded, and in early studies, hematologic and cytogenetic responses of 71% and 39%, respectively, were reached.[7] Randomized studies comparing interferon-alpha to traditional chemotherapy with busulfan and hydroxyurea echoed these findings; interferon-alpha prolonged the time to disease progression by 28 months and led to some long-term complete responses.[8] Dormant myeloid progenitors were seen in CML patients with interferon-alpha-induced remissions, and immunologic mechanisms leading to tumor dormancy were proposed as a cause of sustained remission with interferon-alpha therapy.[9] Indeed, long-term remissions off therapy, perhaps indicative of cure, were noted in 7.6% of the interferon-treated patients.[10]
Bone marrow transplant (BMT) is not intended to be a primary topic of discussion in this review (which focuses on nontransplant therapeutic approaches), but it is important to recognize the role of BMT in the management of CML. In some patients, BMT offered durable, long-term remissions, and in a significant proportion of patients who were candidates for transplant, the procedure was curative. The scope of BMT remained limited, given the restricted availability of matched-sibling and unrelated donors and the associated transplant-related morbidity and mortality.[11-13] A regimen of interferon alfa-2b(Drug information on interferon alfa-2b) (Intron A) plus cytarabine(Drug information on cytarabine) offered the first real survival advantage in the treatment of CML,[7,14] and this approach was augmented by judicious use of transplantation, which still provides benefit in select patients who fail targeted therapy.
