Transcript: Javier Pinilla-Ibarz, MD, PhD: The switching to an alternative TKI in the treatment of chronic myeloid leukemia is always based on obtaining a milestone—so, the early and later milestones that need to be achieved in any patient who starts therapy with a TKI. So, the classical minds of the NCCN and ELN always provide the 3 or 6 months' molecular, or even cytogenetic, response. And we know, as we discussed previously, that the lack of less than 10% of pCR by 3 months is a sign and, more or less depending on the reason of the patient, may be a red flag that really allows us to follow the patient more closely. In some cases, it really introduces a switch of TKI early on in other patients; maybe follow closely to truly see if they achieve these milestones later on. However, the second important milestone, of course, is the 12 months. We know that most of the patients consistently need to be in a complete cytogenetic response and in an ideal place where they achieve major molecular response. We know this it is not really a criteria for NCCN; it is more for ELN. But definitely, we know that at least obtaining complete cytogenetic response at 1 year guarantees that those patients are going to do better later on. And, obviously, the deeper the molecular response the patient achieves at 1 year, the better the outcome and the most likely, or the more likely, for consideration of discontinuation of the drugs in the future.
The main reason why we switch therapies with TKIs in patients with chronic myeloid leukemia is intolerance. Intolerance is a more common situation than resistance. We know that, mainly with second-generation TKIs, it is really rare to see resistance in the first 3 months. However, we know that second-generation TKIs, even first-generation TKIs, may be associated with chronic or acute side effects that some patients may not be able to continue because they are bothersome, because they really have a pleural effusion, or because they may have any other condition that will require a switch of therapy. So far, and for the last year, we have seen that the most common reason why we switch therapies is intolerance. It is true that because of the plethora of drugs that we have in our practice, sometimes you see a practitioner who switches these drugs very fast without trying to really intervene with supportive care and trying to keep the drug as long as we can. We always say that the degree of intolerance in patients with TKI is directly proportional to the amount of TKIs available outside of the one the patient is taking. It's sometimes a tendency to switch too early, and I think it's not really a good practice for our patients because we need to at least consider as much as we can when optimizing the supportive care. And, of course, after failure of optimization of the support of the symptomatology, consideration of switch may be done.
Naval Daver, MD: In general, I think that switching of therapies is something that, in the past, we have had problems with, especially in patients on protocols where, unfortunately often, the therapies were switched very early. So, we're very happy that there are multiple tyrosine kinase inhibitors—5 of them at this time—that are available and potentially more that are in trials. But one of the negative consequences of this has been a comfort level in switching early because there are so many drugs approved. And, in general, that has been something that a lot of the CML experts have been pushing back on. We don't want to have the patients switching therapy early. There are standardized guidelines by Sokal, as well as by the NCCN, that say that, in general, you monitor the pCR for BCR-ABL every 3 months in the first year, then every 3 to 6 months for the next 2 years, and then you can drop it to every 6 months or 1 year.
If you start seeing a rise in the pCR for BCR-ABL confirm that the patient is compliant, then you have to do a repeat pCR for BCR-ABL in 4 weeks. If the repeat pCR for BCR-ABL continues to show a one log or more increase, then that would be an appropriate indication to switch either from a first-generation TKI to a second-generation or from one of the second-generation TKIs to another second-generation TKI, or a third-generation. That is probably the most common scenario where one could switch, but what we don't want is that the switch happens after only one reading without any confirmation. If there's an increase, for example, from 0.21 to 0.28, we don't consider that very significant. That's not 1 log increase. So, that's not usually a scenario where we would make this switch.
The second scenario where we think it's obviously very important to make the switch in therapies is in somebody who is having a full blown refractoriness or relapse that's morphologically apparent. So, either their white blood cell count is going up, they're having a spleen enlargement, they're have worsening cytopenias, or they're having increased blasts in the peripheral by their bone marrow. In that situation, one would definitely be switching. But those are actually the patients that are ideal for clinical trials, and those are the patients we would strongly recommend, at least, consulting or discussing with your local hematology-oncology or leukemia experts. There are now a number of trials that are combining tyrosine kinase inhibitors with other active standard therapies, such as hypomethylators or high-dose chemotherapy, and also other novel therapies, such as immune agents, JAK inhibitors, and BCR2 inhibitors. Such patients would have very poor outcomes by just switching from one tyrosine kinase inhibitor to other. There's hope that by combining approaches, we may be able to improve these outcomes. So, I would really recommend that you consider those patients for clinical trials. -