Treatment Choice in CML

Transcript:Javier Pinilla-Ibarz, MD, PhD: The role of next-generation sequencing in the management of chronic myeloid leukemia still is not very clear. We understand that there is recent evidence in publication that investigates the possible mutation that may transform in patients later on. However, it still is not really a clear utility of this technique in the regular management of CML. I would like to make the point, however, that in order to address the ABL mutations that have sometimes been seen in the treatment with a tyrosine kinase inhibitor (TKI), it’s important to remember that next-generation sequencing is only going to address mutations in, most of the time, normal ABL and not in the BCR-ABL. So, it’s important to specifically order a kinase domain mutation that needs to be performed after amplification of BCR-ABL. That will be an important point to consider when people in the community and other institutions can’t have access to these panels of next-generation sequencing that include ABL.

In order to choose a first-generation or second-generation TKI in our patients with newly diagnosed chronic myeloid leukemia, we always have to consider several factors, including age and risk of disease at diagnosis. In terms of when I use a first-generation TKI, I keep these options for patients who have multiple comorbidities. Most of the time, they are old age and are low-risk disease, and the reason is because the importance of early molecular response of the control, in the long run, is not as important in another group age.

So, the use of a second-generation TKI in the treatment of chronic myeloid leukemia is a topic that has been in the area for many years, and there is no doubt that the second-generation TKIs—in this case, dasatinib and nilotinib—have an important role in multiple areas in this setting. In my practice, most of the time I use these second-generation TKIs, dasatinib and nilotinib. And, in general, I use these in a younger population of patients, specifically in people who have high or intermediate risk. However, we can also offer these drugs in people who have low-risk disease, with the goal to achieve this complete molecular response that will be open to the possibility to this continuation of the drug after a number of years—most of the time for 2, 3, or 4 years—and, of course, after at least 2 years of complete molecular response.

When I use dasatinib or nilotinib is really a matter of performance status and comorbid conditions. It is true that dasatinib and nilotinib have a different pathology and, of course, dasatinib sometimes is more adapted to a younger population with active lives. It may be a little harder for them to have a twice-a-day drug with fasting requirements. However, there is another population that may be in-between or they are not too old, who are not really bothered by this pathology, and they really may be a very good candidate for this drug. Besides this pathology of administration, comorbid conditions are really an important part of choosing these 2 second-generation TKIs. And we always discuss that in patients who have pulmonary conditions or chronic obstructive disease. We try to avoid as much as we can with dasatinib. In a patient who has severe history of diabetes or very strong cardiovascular history, we may shy away off nilotinib due to the described side effects.

On the topic of personalized dosing of a different TKI, I have to really say that we used to have access to imatinib levels a few years ago. Unfortunately, we don’t really have this anymore. There is some evidence from the Australian, and also from the French group, that optimizing the dose of imatinib in the first to second months from 400 mg to 600 mg—an even higher dose, depending on the level—may really improve outcomes and is something that was studied. However, these days, we don’t have an easy access to dosing of levels and these make it extremely difficult to perform this personalized dosing. The truth is that, in general, in the history of CML, we have seen that most of the drugs that we have been using as a frontline, or as they’re being studied with subsequent studies, have been shown that the dose was too high. And these examples with dasatinib—initially 140 mg, now we are using 100 mg based on the data—show a lower dose can really be efficacious. The same thing with nilotinib, 400 mg twice a day, was explored initially. They were lowered to 300 mg twice a day, and the lower dose also can be efficacious later on. However, unfortunately, we still don’t have really good information about how to measure levels and how to really specifically personalize these therapies.

Transcript Edited for Clarity