Treatment Free Remission: Approaches

Dr. Kalaycio: Very interesting discussions. As we wind down the conversation, I want to get to the idea of stopping therapy. We're all aware of data that suggest it's at least possible for a proportion of patients to stop treatment.⁵

However, the guidelines^3,4 such as they are, suggest that stopping should not be done outside the context of a clinical trial. I think most of us would agree with that. I wonder in a practical sense, Dr. Mauro, in your practice, do you have your own set of internal criteria for stopping a TKI and observing patients in the absence of any therapy?

Dr. Mauro: I think I try to incorporate all the experience we have to date when considering this question. That being said I'm a little hesitant to agree entirely with the current thinking regarding retreatment during a Treatment Free Remission trial, which is waiting until patients lose MMR in order to resume treatment but agree it might be hard to retreat based on lesser degrees of molecular relapse. I just worry a little bit about that amount of proliferation without treatment.

On the other hand I think we're coming to the realization that TFR may be feasible in patients who are simply nonproliferative and have low volume of disease based on newer data that patients may not need to have consistent "complete molecular response" or disease reduction below 4.5 logs in order to consider TFR. This will mean more patients may be eligible for such a strategy.

With that being said, I strongly advocate for discontinuation occurring in trials still, especially in the United States. I think we still have to ensure regular monitoring and not run the risk of loss of CML remission as a result of this endeavor. I think we have to have a clear message that this is still an investigational approach.

As we apply TFR strategies more broadly and explore it in patients with different circumstances, rather than those already studied in clinical trials, we may see slightly different results. We may need to exercise more caution.

Outside of a trial I don't discontinue TKI therapy unless there's a clear medical indication and there's no way around it, such as pregnancy or other illness that precludes TKI treatment. I would still pursue TFR only in a clinical trial.

Dr. Kalaycio: Dr. Deininger, I'll give you the last word for your thoughts regarding both treatment discontinuation and the future of CML therapies.

Dr. Deininger: As far as TFR is concerned, I agree with Dr. Mauro. Unfortunately, in the United States we're not quite as far advanced as the Europeans at monitoring diligence. There's a bit of a concern that if we elevate that into daily practice, we may see that patients are not monitored frequently enough and then relapse, but that doesn't get caught. You could imagine a scenario where we're actually seeing a decline in outcomes because people are discontinued and then not restarted if they have a recurrence at the molecular level.

All in all, where this is going, I think it will be really interesting to see more confirmatory data for second-generation TKIs. Let me put that differently: whether a similar proportion of patients in deep molecular response can maintain responses and have TFR if they needed a second-generation TKI to get there rather than just imatinib.

If so, this would be very promising. That would mean that second-generation TKIs actually somewhat impact the natural history of the disease and its biology. Then TFR may become a reality for a substantial proportion of our patients.

I don't think we have the data yet, but at least there are some suggestions that this may be the case. If you do the math, you will still see that many patients with CML will never reach a state where they can consider TFR.

They'll never get into a deep molecular response or they will have been diagnosed with accelerated phase. For all these patients who are not candidates for TFR, we still have to think about treatment optimization in order to make them catch up with the rest.

Now I have a couple of interesting developments. One is clearly to see whether ponatinib administered at a lower dose will have a more practical, therapeutic window in terms of toxicity and yet maintain the excellent efficacy that it has in the setting.

These data need to be produced. Another scenario would be that people would get started on intense induction treatment with higher-risk drugs such as ponatinib. Then if they are a good responder, they can switch to something that is lower-risk and that may be better tolerated.

Actually some of these trials are underway in Europe. Of course there's the question, are there still other drugs that will enter the CML space. There's one promising molecule called ABL001, a TKI with a different mode of action, which exploits an allosteric site rather than the catalytic center of the kinase.

It’s really conceptually very interesting. The expectation would be that this molecule has fewer side effects but still may be quite potent. This could be a very interesting development and add something to the armamentarium that we currently don't have.

I also think there will be patients whose diseases are just beyond the reach of a TKI alone for many reasons, maybe additional mutations or things that have to do with the host and metabolism.

In these cases, we'll still have to think about combination treatments and non-TKI treatments. Here, I think an honest answer is the labs have pulled out a lot of interesting leads, but so far, nothing has really made it into a serious clinical context, either because of side effects or because the target may not be as good in humans as it seemed from mouse models.

I think a lot more work is required here to find the best combination therapies and to define those pathways that need to be inhibited together with BCR-ABL. I think there's a field that we'll develop further and that will be the cutting edge.