Advances in the treatment of chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by BCR-ABL, a chimeric gene generated as a result of a reciprocal translocation [t(9;22)(q34;q11), cytogenetically visible as the Philadelphia chromosome (Ph)] that places sequences from the ABL gene from chromosome 9 downstream of the BCR gene on chromosome 22. The fact that tyrosine kinase activity of BCR-ABL is conditio sine qua non for the protein's ability to transform cells led to the development of small molecule tyrosine kinase inhibitors (TKIs) [1]. It is a little more than ten years ago that the first TKI, imatinib, was approved for the treatment of chronic myeloid leukemia (CML) patients who had failed prior therapy with interferon-α (IFN). Two years later, the International Randomized Study of Interferon and STI571 (IRIS) study demonstrated the superiority of imatinib over IFN/cytarabine (the standard drug therapy at the time), in newly diagnosed chronic phase patients, and led to its approval for first-line therapy [2]. Prior to the development of imatinib, effective treatment for CML was limited to a minority of patients. IFN-based regimens prolonged survival compared to hydroxyurea, with induced durable responses in 10-30% of patients [3,4]. However, this benefit was largely limited to patients with low risk according to Sokal and came at the expense of significant toxicity. Allogeneic hematopoietic stem cell transplant in first chronic phase from a matched related donor produced five-year disease-free survival rates of approximately 50%. However, transplant-related mortality and morbidity were considerable and many patients were not eligible due to co-morbidities or lack of a suitable donor [5]. All this changed radically with the advent of imatinib. We now have the luxury of asking questions that would have seemed presumptuous just ten years ago, foremost whether we can safely discontinue imatinib in patients whose disease is consistently undetectable by RT-PCR. The logical exten