TIDEL-II Trial for CML

Transcript:Kendra Sweet, MD: The TIDEL-II trial looked at newly-diagnosed CML patients and started them on treatment with imatinib, 600 mg daily. And the patients were divided into 2 cohorts. One cohort was patients who would be dose-escalated with imatinib, up to 800 mg daily, if they failed to meet milestones or early molecular response—3 months or 6 months—or failed to achieve a major molecular response by 12 months on imatinib at 600 mg. The other cohort was switched to nilotinib, 400 mg twice daily, in the setting of failure to achieve specific milestones, again, the same 3-, 6-, and 12-month milestones. There was also a component of looking at imatinib trough levels on day 22, and, at that point, anyone with a trough level less than 1000 was dose escalated to 800 mg a day of imatinib. The rationale for this study was really to determine if the switch to nilotinib could salvage patients who had failed imatinib or if escalating the dose of imatinib was equally as effective in salvaging those patients.

In the TIDEL-II trial, they enrolled 210 patients at the beginning of the study. By 2 years, 75 patients had been switched to nilotinib and 55 of those patients were switched because of failure to meet milestones. The remaining patients were switched because of intolerance to imatinib. Overall, what they found was that those patients who switched from imatinib to nilotinib, because of failure to meet their milestones at 3 months or at 6 months, had a much lower incidence of major molecular response or MR4.5 at 5 years compared to those who switched because of a failure to meet the 12 months’ milestone or those who switched because of intolerance to imatinib. In those 2 settings, patients had relatively good outcomes by 5 years. I think these data really signify that those deep early molecular responses are really crucial to improving long-term outcomes. So, it’s essential to identify those patients who are at high risk for failing to meet early molecular response, so that we can either dose escalate early on, start with more potent therapy, or consider clinical trials in someone in that situation.

These data can apply to routine clinical practice by really telling us that we need to try to identify patients who are at high risk of failing to achieve an early molecular response. By identifying those patients either based on the Sokal risk score, EUTOS risk score, or some other scoring system or other factors, then we can use that information to affect our decision making as far as first-line therapy is concerned. Because we need to figure out who are these patients who are most likely to fail those early milestones, and, in that situation, we need to try and either dose escalate or start with a more potent therapy.

The switch from imatinib to nilotinib should likely be made early based on the data that they’re presenting from the TIDEL-II trial. The data indicate that these people who are not responding early on are the people who are going to potentially get into trouble down the road. Switching to more potent therapy early is hopefully going to benefit these patients in the long run. I would not wait to see if they catch back up again. If they failed an early milestone, that’s the time you want to switch. When switching from imatinib to nilotinib, the monitoring is going to be similar to what you would want to do if you were starting someone on nilotinib in the very beginning. You want to watch someone’s blood counts on a regular basis in those first few months on the drug to make sure that their neutrophils aren’t dropping too low, that their platelets aren’t dropping too low, and assess the patient for tolerance because there’s a different set of toxicities that can occur with nilotinib compared to imatinib. So, monitoring those patients a little more closely in the very beginning is going to be very important. In regard to molecular monitoring and response assessment, that would be the same as what you would do with imatinib or any other TKI where you want to check again at 3 months, check the PCR to determine the molecular response and then go forward based on whatever that response is.

Transcript Edited for Clarity