CML yields a few more clues

The popular, though not necessarily correct, interpretation of molecular events in chronic myeloid leukemia (CML) assumes that the acquisition of a BCR-ABL fusion gene is the critical event in generating chronic phase (CP) disease and that other genetic events then occur that underlie disease progression. Thus interferon-alfa, until recently the agent most active in inducing cytogenetic remissions in CML in chronic phase, has little activity in advanced phase disease. If then the new kinase inhibitor imatinib (STI571, Gleevec) targets mainly the Abl kinase activity of the Bcr-Abl oncoprotein, it should have little or no activity in advanced phase disease. It came therefore as something of a surprise that the compound was active in CML cell lines, all derived from patients with CML in transformation, and in treating patients with blastic phase disease. The papers by Sawyers et al (p 3530) and Kantarjian et al (p 3547) in this issue ofBlood confirm this impressive clinical activity. There are only 2 logical explanations: either BCR-ABL continues to play a major role in at least some patients with advanced phase disease, or imatinib also inhibits other kinases not yet identified that are involved in blastic transformation. Some extra support for the notion that Bbl-Abl is no benign bystander in advanced phase disease comes from the observations reported recently that imatinib-resistant cell lines over-express Bcr-Abl and patients who respond and then become resistant to imatinib may have acquired mutations in the Abl ATP binding domain that interfere with imatinib binding. One feels however that this cannot be the whole story, and non–Bcr-Abl mechanisms must be playing a role in other cases of primary or secondary resistance to imatinib. In the past lymphoid transformations have been more amenable to treatment than myeloid transformations, though the reverse seems to apply with imatinib. Overall median survivals are 6 to 8 months, which seems no great improvement on results achieved in the pre-imatinib era. What does seem important is that hematologic and indeed cytogenetic responses can be achieved frequently with a relatively nontoxic oral agent, which can then set the scene for more intensive chemotherapy or allogeneic stem cell transplantation. Both papers end their summaries with reference to the future use of imatinib in combination with other agents, and here indeed lies the best hope for substantial prolongation of life for CML patients unfortunate enough to proceed to blastic transformation.