Newly Diagnosed Patients
The only other areas that Savona and Talpaz might have emphasized would be how to approach a newly diagnosed patient who is in chronic phase CML and how to monitor the disease during imatinib(Drug information on imatinib) therapy. The standard therapy of a patient with newly diagnosed CML in chronic phase is to start imatinib at 400 mg daily. The use of higher doses of imatinib in the early chronic phase appears promising in small single-arm trials, but that strategy needs to be validated in larger, randomized trials. Current recommendations for disease monitoring in patients who are in complete cytogenetic response include a peripheral blood reverse transcriptase polymerase chain reaction (RT-PCR) assay every 3 months and measurement of bone marrow cytogenetics every 12 to 18 months. Patients, who are not in a cytogenetic remission, should have bone marrow cytogenetics every 3 to 6 months and peripheral blood RT-PCR every 3 months.Any patient with a suboptimal response or signs of resistance should be considered for a clinical trial. Second-generation tyrosine kinase inhibitors such as AMN107 or dasatinib(Drug information on dasatinib) appear quite promising. However, it should be noted that these agents do not overcome the resistance conferred by BCR-ABL/T315I mutation (seen in a small number of CML patients). Outside of a clinical trial, the most reasonable approach in this setting is dose escalation, which may be effective in 30% to 50% of patients. Lastly, the option of ASCT should be revisited in appropriate patients.
The following questions need to be answered in future trials: What is the best dose of imatinib? Should imatinib be combined with other agents such as interferon-alpha or chemotherapeutic agents? What is the role of allogeneic bone marrow or stem cell transplantation for younger, eligible patients, and when should it be offered? What is the most effective dose and schedule, and what is the long-term efficacy of the newer agents? Given the heterogeneity of imatinib resistance, it is possible that a combination approach will be necessary for maximal antileukemic effect. Whether this will lead to improved progression-free and overall survival remains to be seen.
This is an exciting time for both researchers and clinicians who treat patients with CML or gastrointestinal stromal tumor (GIST), which is also responsive to imatinib. A recent report that GIST cells refractory to imatinib in vitro were responsive to the drug in vivo has led to the observation that there might also be an immune-cell-based mechanism for the total therapeutic effect of imatinib. In mice, a new type of cell has been discovered that may be the basis of the immune effect of imatinib. This new cell, considered a cross between a dendritic cell and a natural killer cell, has been named interferon-producing killer dendritic cell, or IKDC. It would not be too optimistic to believe that it is perhaps only a matter of time before an IKDC equivalent cell is identified in humans. Once that is achieved, the potential of imatinib therapy in CML might be significantly enhanced with appropriate manipulations of the immune system.The success in understanding and treating CML represents a milestone in the history of medicine. We look forward to the upcoming results of trials investigating newer agents. -Finally, we congratulate Drs. Savona and Talpaz on their extremely
well written and balanced overview of CML.
Rajasree Roy, MD
Kanti R. Rai, MD