Author reply

Abstract

We appreciate the thoughtful comments of Drs. Drummond and Holyoake, which have highlighted several important issues in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML) with imatinib mesylate. The first issue is when to advise patients receiving imatinib that the treatment is unlikely to benefit them, and that they should consider allogeneic stem cell transplantation (SCT). Our concern is that such patients currently are often advised to consider allogeneic SCT if they have not achieved a major cytogenetic response after only 6–12 months of imatinib therapy or if they demonstrate persistence of residual disease by polymerase chain reaction (PCR). To our knowledge, there is little evidence to support such opinions. Our analysis in patients with chronic phase CML after interferon failure (with a median duration of 33 months) is, to our knowledge, the first to indicate that even if a minor cytogenetic response is obtained after 3–12 months of treatment with imatinib, 35–54% of patients may later achieve a complete cytogenetic response with continuation of imatinib.1 This information pertains not only to considerations of allogeneic SCT but also to the interpretation of data from investigational trials (e.g., vaccines, decitabine). In a study using a vaccine strategy, patients were categorized as having “resistant CML” based on the lack of a major cytogenetic response after only 6 months of imatinib therapy.2 The information in our analysis was derived from patients in chronic phase CML after interferon failure. In our experience in 167 patients with early chronic phase CML who were treated with imatinib, 131 patients (78%) had achieved a complete cytogenetic response at last follow-up. The prediction of later response based on initial response is preliminary but suggests similar trends (Table 1). Current data suggest that a complete cytogenetic response with different levels of quantitative PCR cannot be considered to be an indication for a change in imatinib therapy.3 The second issue is the significance of persistent PCR positivity during imatinib therapy. Only 10% of patients with newly diagnosed CML have been reported to achieve PCR negativity while receiving standard-dose imatinib, and this number increased to 30–40% with high-dose imatinib.4, 5 These low rates often are used to argue against the curative potential of imatinib. However, cures have been observed in other malignancies despite persistent minimal residual molecular disease (e.g., acute lymphocytic leukemia, acute promyelocytic leukemia, and lymphoma). Thus, long-term event-free survival perhaps depends not on the absolute presence or absence of molecular residual disease, but on reaching a critical threshold. This threshold in CML may be below a quantitative PCR value of 0.045% based on the interferon experience.6 Such levels reportedly are achievable in > 50% of patients with newly diagnosed CML who are receiving imatinib therapy.4, 5 Historically, the advice to consider upfront allogeneic SCT in patients with CML was based in part on an expected median survival of 3–7 years. The preliminary experience with imatinib suggests a reduction of the annual mortality in patients with chronic phase disease after interferon failure from approximately 15–20% to < 5% (estimated 2-year mortality rate of 8%).7 In newly diagnosed patients treated with imatinib, the estimated annual mortality rate has been reported to be < 2% in the first 2 years.8, 9 If this encouraging experience persists with longer follow-up, the expected 10-year survival rate in CML patients may exceed 50%.10 Finally, we agree that ultimately, the choice of therapy is the patient's, after considering the potential risks and benefits of each approach based on timely objective presentations of the updated results of different therapies.