Future Management of Chronic Myeloid Leukemia

Transcript:

Daniel J. DeAngelo, MD, PhD: My advice for oncologists on the treatment of patients with chronic-phase CML (chronic myeloid leukemia) is that the gain is high. Patients should have a normal life expectancy. It behooves the physician to find the most appropriate therapy to maximize survival, which can be achieved with any of the agents. What you want to do is maximize the quality of life and minimize toxicity. Part of what I do in spending my time with my patients is reviewing toxicities—not just focusing on the major toxicities, but also focusing on the little toxicities and trying to mitigate that with supportive care and lifestyle adjustments. For patients who are responding, sometimes lowering the dose may be an option. Moving from 400 mg down to 300 mg of imatinib sometimes can eradicate a lot of low-grade toxicities in some patients and not in others. Really being very careful about [reviewing and managing toxicities]. The other thing that I keep track of is how often I refill prescriptions. If a patient’s renewals are not being done routinely, the patient's missing some pills. I always ask, “How many pills did you miss in the last week or the last month or the last 2 months?” Sometimes, I get, “Oh, I forgot because of travel.” However, compliance of less than 10% compliance is important. Whatever the physician can do to maximize adherence/compliance and minimize toxicities is really the goal of care and therapy. It’s also important to be realistic as to what these milestones mean. More is not always better, because it's pretty easy these days. The bar is pretty low in terms of achieving a cytogenetic remission. Most of these agents will do that and [give a patient] a normal life expectancy. I think in my practice, I've seen errors 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’s been a little challenging to develop, but, in the chronic phase, we need to remember that the TKIs (tyrosine kinase inhibitors) alone have not been able to eradicate the earliest progenitor. That is why most patients either have residual disease, or, even if it's undetectable when you stop therapy, at least half of them relapse. Several studies have shown that combining it with agents (eg, inhibitors of MCL2 and other approaches) may give us a better probability of eradicating those 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. In vitro data are very interesting, suggesting that it prevents the emergence of resistant clones. So even that type of combination may be valuable. Certainly, the more advanced stages of the disease, particularly in the blast phase, will depend on a combination. Single-agent TKIs are not enough, so we combine them. There have been combinations with certain chemotherapy, but there are emerging combinations (eg, monoclonal antibodies with all the targeted therapies).

There are a few other TKIs that are emerging that may have niche indications. Ponatinib is an important TKI with a very good safety profile; it doesn't work against the [BCR-ABL1] T359 mutation, but the early data have been very attractive in patients who have developed a resistance to ponatinib. HTP1351, another very attractive drug, is particularly beneficial against the [BCR-ABL1] T359 mutation, but a little bit less so against the other mutants or mutations, so it may provide another alternative for patients with this mutation. There is PF-114, which is a drug being developed that is structurally very similar to ponatinib but manufactured in a way that it will not inhibit the EGFR. Early data from phase 1 and phase 2 studies suggest that it is very effective, but it does not have any of the arterial occlusive events or concerns. Again, it is early, but it is attractive in that regard.There are other compounds that are being developed, particularly for combinations with the TKIs, such as the monoclonal antibodies, the EB2 inhibitors, and a few others that may help in terms of eradicating those early progenitors.There are some good options coming, and we'll continue trying to improve the outcome for most patients. We've addressed a good number of patients, but there are still, unfortunately, some patients who don't respond well or patients who do not get to those deeper molecular responses. That's where we need to focus now.

Transcript edited for clarity.