Chronic Myelogenous Leukemia
An important question is the impact of imatinib mesylate treatment on outcome for patients who subsequently proceed to allogeneic HSCT. A retrospective comparison of 145 patients who received imatinib mesylate prior to transplant compared with a historical cohort of 231 patients who did not, showed no difference in early hepatotoxicity or engraftment delay. In addition, overall survival, disease-free survival, relapse, and nonrelapse mortality were similar between the two cohorts. The only factor associated with poor outcome in the cohort that received imatinib mesylate was a poor initial response to imatinib mesylate. Further evidence for a lack of effect of pretransplant imatinib mesylate on posttransplant outcomes was supplied by a report from the Center for International Blood and Marrow Transplant Research. This report compared outcome for 181 pediatric and adult subjects with CML in first chronic phase treated with imatinib mesylate before HSCT with that for 657 subjects who did not receive the agent before HSCT. Among the patients in first chronic phase, imatinib mesylate therapy before HSCT was associated with better overall survival. Better HLA-matched donors, use of bone marrow, and transplantation within 1 year of diagnosis were also associated with better survival.
Imatinib has shown a high level of activity in children with CML that is comparable to that observed in adults.[21,22] The pharmacokinetics of imatinib in children appears consistent with prior results in adults. The target oral dose in children, determined from the COG-P9973 and COG-ADVL0122 trials, is 440 mg/m2 /day.[21,23]
Although imatinib mesylate is an active treatment for children and adults with CML, there is little evidence that it is curative. Most adults with CML treated with imatinib mesylate continue to have bcr-abl transcripts detectable by highly sensitive molecular methods, although the rate of molecular complete remission does increase with duration of therapy.[24,25] Six of 12 adults with molecularly undetectable disease who stopped imatinib mesylate lost their molecular remission within 18 months of treatment cessation. At this time, therefore, imatinib mesylate cannot be viewed as a replacement for allogeneic HSCT in children for whom there is a suitable HLA-matched donor.[27,28]
In patients who develop a hematologic or cytogenetic relapse on imatinib, alternative kinase inhibitors, such as dasatinib or nilotonib, should be considered.[29,30,31] Patients on kinase inhibitor therapy should be monitored approximately every six months by quantitative retrotranscriptase polymerase chain reaction on peripheral blood. A persistently rising bcr/abl to abl transcript level indicates the likely need to change therapy, usually increasing the dose of imatinib or changing to a different kinase inhibitor. Patients who show resistance to imatinib should be tested for the presence of the T315I mutation, and, if positive, strong consideration should be given to performing an allogeneic transplant.