We have come a long way since the time when chronic myeloid leukemia (CML) was regarded as incurable except in a small minority of patients who were suitable for allogeneic transplant and were fortunate enough to have an HLA-matched donor. The introduction of imatinib(Drug information on imatinib) mesylate (Gleevec) and other tyrosine kinase inhibitors that specifically block the enzymatic action of the BCR-ABL fusion protein has been a major contribution to the management of CML and has heralded a new era of success with molecularly targeted therapy.In this issue of ONCOLOGY, Drs. Savona and Talpaz have elegantly summarized current advances in the management of CML. This is a comprehensive and authoritative review that will be helpful to every reader. The authors state that the treatment paradigm is now shifting toward the achievement of molecular remission in an attempt to prolong patient survival and to find a cure through medical management.
Before and After Imatinib
Savona and Talpaz have demonstrated that the goals of CML treatment have changed markedly in the past 10 years. Prior to the imatinib era, the treatment options for CML ranged from hydroxyurea and busulfan(Drug information on busulfan) (Myleran) to achieve a hematologic response to allogeneic stem-cell transplantation (ASCT), which was curative in selected patients. Interferon-alpha, although shown to achieve a long-lasting cytogenetic response in some patients, did not prove to be the answer we sought.The introduction of imatinib has redefined the management of CML. Imatinib demonstrated superior activity compared to other agents currently used in the treatment of this disease. But, unfortunately, resistance to this "magic bullet" is emerging. As noted by Savona and Talpaz, about 2% of patients annually will have progressive disease while on imatinib. Also, evidence suggests that discontinuation of imatinib leads to recurrence of the disease, revealing that imatinib is not a curative therapy. The quandary that clinicians are facing now is how to identify patients early during imatinib therapy who are at a greater risk of developing resistance or relapse.
Some of the new prognostic markers that have been looked into in the International Randomized study of Interferon alpha plus cytarabine(Drug information on cytarabine) vs STI571 (IRIS) trial or its companion studies are worth mentioning here:
(1) Achievement of a complete cytogenetic response after 12 months or of at least a major cytogenetic response after 6 months of imatinib therapy appears to be a significant predictor of improved progression-free survival.
(2) It also appears that attainment of a major molecular response, which is defined as at least a 3-log reduction of BCR-ABL fusion mRNA anytime while on imatinib or the attainment of a 2-log molecular response at the time of complete cytogenetic response is a significant and independent prognostic marker of subsequent progression-free survival.