Transcription:

Daniel J. DeAngelo, MD, PhD: My advice to oncologists on treating patients with chronic phase CML (chronic myeloid leukemia) is that the gain is high. Patients should have a normal life expectancy. It is the responsibility of the physician to find the most appropriate treatment to maximize survival, which can be achieved with any of the agents. What you want to do is maximize quality of life and minimize toxicity. Part of what I do in spending my time with my patients is to look at toxicities, not only focusing on the major toxicities, but also focusing on the small toxicities and trying to lessen them with supportive care. and lifestyle adjustments. For patients who respond, a dose reduction may sometimes be an option. Going from 400 mg to 300 mg of imatinib can sometimes eliminate many low-grade toxicities in some patients and not in others. Pay really close attention to [reviewing and managing toxicities]. The other thing I watch is how often I refill my prescriptions. If a patient’s refills are not done consistently, the patient is missing pills. I always ask, “How many pills have you missed in the last week, last month, or last 2 months?” Sometimes I get, “Oh, I forgot because of the trip.” However, less than 10% compliance is important. Anything the physician can do to maximize compliance/adherence and minimize toxicities is really the goal of care and therapy. It’s also important to be realistic about what these milestones mean. More isn’t always better, as it’s pretty easy these days. The bar is low enough to achieve cytogenetic remission. Most of these agents will and [give a patient] normal life expectancy. I think in my practice I’ve seen mistakes in pushing a dose on a patient that’s inappropriate. As a result, patients get cumulative toxicities that they really didn’t need.

Jorge E. Cortes, MD: Combination therapy is going to be important. It was a bit difficult to develop, but, in the chronic phase, we have to remember that TKIs (tyrosine kinase inhibitors) alone were not able to eradicate the first progenitor. This is why most patients either have residual disease or, even if undetectable when treatment is stopped, at least half of them relapse. Several studies have shown that combining it with agents (eg, MCL2 inhibitors and other approaches) can give us a better chance of eradicating these early progenitors. An interesting consideration is a combination, now that we have a TKI that works, that binds in a different site like axitinib does – combining 2 TKIs that have slightly different mechanisms of action. The in vitro data are very interesting, suggesting that it prevents the emergence of resistant clones. So even this type of combination can be useful. Certainly, the more advanced stages of the disease, especially in the blast phase, will depend on a combination. Single-agent TKIs are not enough, so we combine them. There have been associations with some chemotherapies, but there are emerging associations (eg monoclonal antibodies with all targeted therapies).

There are a few other TKIs emerging that may have niche indications. Ponatinib is an important TKI with a very good safety profile; it does not work against [BCR-ABL1] T359 mutation, but early data was very interesting in patients who developed resistance to ponatinib. HTP1351, another very attractive drug, is particularly beneficial against [BCR-ABL1] Mutation T359, but a little less against other mutants or mutations, so this may be another alternative for patients with this mutation. There’s PF-114, which is a drug in development that’s structurally very similar to ponatinib but made in a way that it doesn’t inhibit EGFR. Early data from phase 1 and phase 2 studies suggest that it is very effective, but has none of the events or problems of arterial occlusion. Again, it’s early, but it’s interesting in that regard. eradicate these early progenitors. There are good options ahead, and we will continue to try to improve outcomes for most patients. We’ve touched on a good number of patients, but there are still, unfortunately, patients who don’t respond well or patients who don’t get those deeper molecular responses. This is where we need to focus now.

Transcript edited for clarity.