The daunting task of modeling response to imatinib therapy in patients with chronic myelogenous leukemia

An attempt at modeling the dynamics of BCR – ABL1 transcripts in patients with chronic myelogenous leukemia (CML) receiving standard dose imatinib (i.e. 400 mg daily) has been recently reported [1]. Albeit this kind of strategy is certainly desirable as it may provide valuable insights into the kinetics of CML, we must refrain from generalizing the results of this rather deterministic system as this is based on rigid assumptions and does not account for a series of variables frequently encountered in clinical practice. For instance, one such variable is that of imatinib dose intensity. The authors present 69 patients who received treatment with imatinib 400 mg daily in the context of the IRIS trial [1]. Imatinib dosage is predicated upon tolerability, which unfortunately, leads to frequent dose modifications. Assuming a fixed dose of 400 mg daily, most patients receiving imatinib will experience a biphasic exponential decline in BCR – ABL transcript levels, with a steep first slope due to leukemic differentiated cell killing, and a second slope reflecting a slow and incomplete leukemic progenitor death. However, the differences in molecular outcomes vary remarkably with imatinib dosing and overall dose intensity. Approximately 5 – 15% of patients will exhibit undetectable transcript levels by PCR, in stark contrast with 35 – 40% of those receiving therapy with high-dose imatinib (i.e. 800 mg daily) [2]. This difference might suggest the rather appealing possibilities of either ‘‘leukemic stem cell exhaustion’’ or persistence below the threshold of detection of currently available PCR techniques. Alternatively, exposure to low imatinib dose intensity (less than 300 mg daily) has been associated with suboptimal cytogenetic outcomes. Neither of these scenarios nor the plausible existence of variability in imatinib-sensitivity and proliferation rates of leukemic stem cells have been taken into consideration in the proposed model. Furthermore, the timing at which imatinib therapy is initiated may be critical. Although some leukemic stem cells may eventually respond to tyrosine kinase inhibitor therapy, these cells, while viable, are subjected to the impending fate of acquiring Abl kinase domain mutations that lead to resistance and/ or insensitivity to imatinib. Undoubtedly, this risk increases over time, hence suggesting that early intensive therapy may prevent the development of resistance. A crucial aspect in the dynamic of BCR – ABL transcripts in patients with CML is the distinct dynamics of the molecular responses observed between patients in chronic phase and those in more advanced stages of the disease (i.e. accelerated and chronic phase), as well as the tyrosine kinase inhibitor employed. This latter aspect is becoming more critical as new agents with superior Abl kinase inhibition potency compared with that of imatinib are introduced in the clinic. We have recently analyzed the dynamics of BCR – ABL transcript levels in 53 patients who had failed imatinib while receiving therapy with the Src/Abl kinase inhibitor dasatinib [3]. Dasatinib is approximately 300-fold more potent against Abl kinase relative to imatinib and has been recently approved by the Federal Drug Administration for the treatment of adult patients in all phases of CML with resistance or intolerance to prior therapy. Patients in