Key opinion leader perspectives on assessing a patient’s response to therapy for chronic myeloid leukemia.
Jorge E. Cortes, MD: There are many methods to monitor the response. It’s still important to do a cytogenetic analysis at some point. I always do it at baseline because you want to know whether there are additional chromosomal abnormalities. Once or twice after a year or 2 you’ll see additional chromosomal abnormalities in the Philadelphia-negative metaphases as the patients start responding. That’s important to know because these can translate into additional issues. For example, a small percentage of those patients can develop a second AML [acute myeloid leukemia] or MDS [myelodysplasia]. But for the most part, the monitoring is done for most patients with PCR [polymerase chain reaction]. It’s very important to get a PCR at baseline. The value doesn’t tell you much, but it’s important to know that the PCR detects the transcripts the patient has. An atypical transcript is not common, but if the patient has an atypical transcript, it will not be detected by PCR. At diagnosis, you’ll know the patient will be Philadelphia-positive, PCR-negative. And you’ll know that you cannot count on the PCR.
After that, they do PCR every 3 months during the first year, year and a half, until the patient gets to a major molecular response. After that, every 6 months. I don’t recommend, and none of the guidance recommends, doing the PCR more frequently than every 3 months. There’s a lot of variability in the test, and it can lead to confusion and concerns. I do a mutation analysis every time I diagnosis a resistance, based on the recommendations and definitions. At that time, it’s important to do mutation analyses. There’s no need to do mutation analyses at diagnosis or during therapy if the patient is responding. If PCR doesn’t work because of these atypical trials, then FISH [fluorescent in situ hybridization] becomes your most valuable test. It’s the most sensitive test you can do to get an assessment of response. But you cannot assess the deep molecular responses.
The levels of the transcript are what tell us how deep the response may be. There’s some correlation with the cytogenetic response. Usually, when a patient gets to about 1% or less, you know that patient has a complete cytogenetic response, approximately. That’s important because that’s the level of response that correlates with improved survival. Then the deeper molecular responses have additional value. For example, major molecular response correlates with improved progression-free survival. The deep molecular responses [MRs] that we call MR4 and MR4.5 are the responses that we look for when we’re considering treatment discontinuation. It’s very important that these tests are done on the international scale and in a reliable laboratory. Fortunately, most of the available laboratories do a good test nowadays. But those are the additional levels. Importantly, not every patient gets to a deep molecular response. About 50% to 60% of patients will ever get an MR4.5. And MR4.5 is 0.0032 or less. Not getting to that level, not becoming undetectable, is not a failure, and it’s not a reason to change therapy in most patients.
Assessing a mutation is very important when we’re considering a change of therapy. When a patient has the criteria for a resistant disease, for failure, you need to assess mutations. They’re identified in approximately 30% to 50% of all patients who developed a resistance. You won’t find it in every patient. But when you find it, it may guide you on what treatment options you have available, and that may work on a given patient. For example, there are mutations where we know that certain TKIs [tyrosine kinase inhibitors] don’t work, like V299L. We know that dasatinib or bosutinib cannot work. For F359, we know that nilotinib doesn’t work. For T359, we know that none of the second-generation TKIs works; only ponatinib and asciminib work. So it’s very important to understand what mutation a patient may have. In some patients, you won’t find a mutation, but it’s important to look for those mutations because when you find them, they can be very informative.
Transcript edited for clarity.