Data suggest that the cytogenetic response to second-line therapy at 3 months predicts how patients will fare longer term (ASH 2008. Abstract 332).
“That ends up being a pretty good time point because if you have a patient who’s resistant and you start the search for a donor, for an HLA match, the median time to finding a donor is about 4 months,” Dr. Radich commented. “So a practical point is if you have to switch to a second-generation drug, you start a search. You find a donor, you evaluate again. If the patient had a great response, you say fine, we’re going to follow you; if they don’t, that’s a good time to move to transplant.”
In the guidelines, the Evidence Blocks for second-line (and later-line) therapies generally show what one might expect from clinical practice, Dr. Radich said. “As you march from primary therapy to secondary therapy to tertiary therapy, what happens? You all know, toxicity increases in those settings, efficacy goes down. And that’s exactly what happens here. And if you match up all these drugs, we say there is no difference in which one you pick.”
Can you discontinue therapy?
“The other issue that is really driving a lot of CML strategy these days is the issue of discontinuation,” Dr. Radich commented. Conventional belief has been that TKIs do not eliminate CML stem cells; therefore, patients will need to be on therapy lifelong.
“Turns out, like many things, we were wrong,” he said. “There have been a number of studies now showing that if you are PCR negative for a number of years and get off therapy, about 60% of patients will relapse usually within the first 3 months, but about 40% of patients will actually remain negative for BCR-ABL up to 2-3 years.”
“Now the good part is that all the patients pretty much who have relapse and get put back on drug go back to getting a response; they don’t go into complete molecular remission, however. And the reason that we worry that all these patients should still be [discontinued] on a clinical trial as opposed to doing it at home is we don’t know the long-term consequences of this,” Dr. Radich said.
A period of unopposed BCR-ABL activity may allow emergence of resistant clones that take years to become clinically evident, he noted. In fact, data from Hiroshima survivors show that CML can have “an amazing dormancy,” possibly 70 years.
“So I think you have to approach any discontinuation with some caution. The risk is probably very low, but it’s actually probably a number,” he said. The guidelines therefore recommend that in patients whose disease is responding to TKIs, discontinuation should be undertaken only in a clinical trial.
“How this weighs in, I think, is if you look at CMR [complete molecular response] rates, they are higher with second-generations than with imatinib. So if you have a patient who you some day want to get to a discontinuation trial, a younger person who wants to have children and the like, then second-generations might be your best option for getting them there,” Dr. Radich proposed.
Take-home message
The guidelines, with all of their algorithms and the new Evidence Blocks, are helpful but do not replace clinical wisdom and experience, Dr. Radich asserted in closing.
“You have to kind of use your clinical judgment, and that trumps everything else,” he said. “The other thing that’s important is all of you have different experiences with using these drugs, and nothing replaces that. If you are someone who uses drug A all the time, you know how to anticipate the complications, you know what to look for. It’s a lot better [to use that drug] than just jumping to drug C when you have never used it or have little experience, because really experience is the main thing.”
Dr. Radich disclosed that he has consulting and/or research funding relationships with Ariad Pharmaceuticals, Gilead Sciences, and Novartis.