Minimizing Treatment Failures
As relapse to accelerated phase or blastic crisis is associated with incomplete cytogenetic response, increasing the rates of complete cytogenetic and molecular responses has been the goal. First attempts at this were done with imatinib(Drug information on imatinib) dose escalation. The maximal tolerated dose of imatinib was not reached in the initial phase I trial of the drug, and standard 400-mg once-daily dosing has not been established as the optimal therapeutic dose. In a recent single-arm study, high-dose imatinib (400 mg twice daily) led to a 38% complete molecular response rate. This represents a sixfold increase over historical data in patients treated with 400 mg once daily, and has led to the design of a multicenter randomized study comparing the two dose schedules.
Overcoming resistance to imatinib was also shown in a study incorporating dose escalation to 1,200 mg, and a recent phase II study showed greater than a 40% improvement in major molecular response at 24 months' follow-up among patients receiving imatinib ≥ 600 mg daily vs those receiving imatinib ≤ 600 mg daily over the course of the initial 12 months of therapy. Early utilization of high-dose imatinib may improve the overall molecular response rate, reduce the risk of the emergence of imatinib-resistant clones, and overcome relatively resistant cell clones, which seem to respond in a dose-dependent manner. The gains need to be weighed against the increased toxicity profile and rates of compliance.
Some imatinib resistance cannot be overridden by increasing imatinib doses, however, and these resistant clones are commonly seen in relapsing and progressive disease. Imatinib resistance has most commonly been associated with a rise in BCR-ABL protein products, loss of complete cytogenetic response, and increase in white blood cell counts.[31,32] This resistance is frequently due to point mutations within the ABL kinase domain. Over 30 such mutations have been identified, and they lead to mutant ABL kinase that adopts a conformational change in the kinase domain and subsequent destabilization of the binding complex, which may sterically block imatinib from the binding site.[30,33] These mutant BCR-ABL clones have led to the development of more potent, "second-generation" selective kinase inhibitors.
Two of these agentsnilotinib (AMN107) and dasatinib(Drug information on dasatinib) (BMS 354825)are currently under clinical investigation. Nilotinib(Drug information on nilotinib) is a relatively selective BCR-ABL tyrosine kinase inhibitor, which binds to the inactive conformation of the ABL kinase with 30-fold more potency than imatinib. In contrast, dasatinib is a dual SRC kinase and ABL kinase inhibitor that binds to the ABL kinase in its inactive and active conformation with 325 times the inhibitory capacity of imatinib. Both of these agents have exhibited activity in in vitro and in vivo preclinical cell proliferation and phosphorylation studies against all imatinib-resistant BCR-ABL mutants, with the exception of T315I.[34-36] Dasatinib also inhibits SRC kinases, which are cell-signaling molecules that have independent oncogenic potential in CML.
In separate phase I trials, the use of nilotinib and dasatinib in imatinib-resistant (or intolerant) CML patients has revealed nearly 90% hematologic response rates in the chronic phase of CML, and substantial activity in the advanced stages of the disease.[38,39] The phase II trials (SRC-ABL Tyrosine kinase inhibition Activity Research Trials, or START studies) of dasatinib for imatinib-resistant chronic phase, accelerated phase, myeloid blast crisis, and Philadelphia chromosome-positive acute lymphocytic leukemia show similarly positive preliminary results.[40-42] BCR-ABL mutant T315I confers a particular conformational change and subsequent hindrance to imatinib, nilotinib, and dasatinib from their shared target within the ATP-binding pocket. A search for new inhibitors that overcome or avoid this hindrance is underway, and early potential successes are described below.
Further Considerations of Imatinib Resistance
Although the data suggest a marked prolongation of survival with imatinib therapy, there is growing evidence that the malignant clone is not fully eradicated in the majority of patients.[23,43-45] Furthermore, the cessation of imatinib therapy, although not extensively studied, seems to lead to molecular and cytogenetic recurrence.[46,47] Given the frequent relapse after cessation of imatinib therapy in patients with a complete molecular response, imatinib seems unlikely to be a curative therapy for CML. Rather, when given as single agent, imatinib appears to be more precisely a suppressive therapy.
Although greater than 90% of CD34+ cells are sensitive to imatinib in a dose-dependent manner, the primitive CML self-renewing stem cells are refractory to the inhibitory effect of imatinib.[43,48] Holyoake et al recently demonstrated that CD34+ cells are more sensitive to dasatinib than to imatinib. In these experiments, however, the most primitive, quiescent CD34+/CD38 cells were not affected. This work provides an explanation for the presence of a residual imatinib-refractory population of cells, and it suggests a lack of sensitivity of BCR-ABL kinase to the effect of kinase inhibitors in these cells. Further investigation of the CML stem cell should lead to additional clinical advancements.
Imatinib has altered the natural history of CML. It is probably the most cogent example of therapy directed against a dominant, oncogenic target. Challenges today concern CML that escapes suppression via imatinib (ie, resistance) and how to deal with minimal residual disease. As discussed above, second-generation ABL kinase inhibitors can overcome imatinib resistance in most patients with chronic phase CML and in some patients with advanced stages of the disease. Clinically, their effect on primitive CML stem cells remains in question. Further, the limited experience with these agents prohibits conjecture as to disease response when therapy is stopped after complete molecular response is reached.
The tyrphostin kinase inhibitor adaphostin (NSC680410) was originally developed to compete with substrate, rather than ATP at the BCR-ABL tyrosine kinase binding site, but it has also been found to have BCR-ABL-independent efficacy through reactive oxygen species. It has been found effective against wild-type BCR-ABL and all known mutations including T315I. GNF-2, which inhibits the Abl-kinase via an allosteric, non-ATP-competitive mechanism, may be another agent with potential to overcome resistance induced by T315I mutations. Additional small molecules targeting the BCR-ABL-signaling pathway are under development as well.
In conclusion, targeted therapy has provided a minimally invasive mechanism to suppress CML in most patients, but for the reasons mentioned above, cure has not been seen with this treatment. Given a developing armamentarium of targeted therapies to quiet active disease, new clinical focus should be on the development of therapy to cure CML. Exploring the nuances of allogeneic stem cell transplant and interferon-alpha therapies against the CML stem cell requires rigorous study. These therapies have yielded the only reported cures of this disease. Clinical trials combining the use of targeted therapy to achieve a complete molecular response, followed by interferon alfa-2b(Drug information on interferon alfa-2b) to eradicate the malignant CML stem cell, are now underway.