ONCAlert | Upfront Therapy for mRCC

Challenges in Management of Chronic Phase CML

Targeted Oncology
Published Online:12:00 PM, Mon August 5, 2019

Harry Erba, MD, PhD: Well Jorge, I’ve been driving the discussion with all of these questions. I’m going to give you an opportunity to wrap it up with what you think are a few of the outstanding questions or challenges that remain in the management of chronic phase CML [chronic myeloid leukemia].

Jorge Cortes, MD: One of the important questions is…we’ve been talking a lot about arterial occlusive events. I don’t think we’ve done a good job understanding why. And the more we understand why, the better we’ll be able to prevent it, to manage it, and of course it can help us to better use these drugs, because they’re good. We’ve been talking about how good ponatinib is, but we are concerned about these adverse events. We need to do better.

We talked about the treatment-free remission, the treatment discontinuation. That’s becoming increasingly a goal of therapy, but the reality is that it’s effective in only about 25% of patients. Only about 50% of patients get to sustained deep molecular responses. And of those, only about half of them remain free of therapy. So really, only 25% can stop therapy without a relapse. Now that’s great compared to what we thought some years ago, but the majority can’t.

So we’re trying to see how we can increase the number of patients who have a sustained molecular response. And how can we reduce the risk of relapse? We know TKIs [tyrosine kinase inhibitors] alone can’t eradicate the stem cell. That’s preclinical work. So there’s a lot of work going into what combinations we can use. There’s been some work with interferon therapy. In Europe, there have been several studies combining different TKIs with interferon. There is very nice preclinical work with venetoclax.

There are studies that are starting to incorporate that to see if that can help. There’s this new tyrosine kinase inhibitor called asciminib. It is very effective in the salvage setting. There’s an ongoing randomized study against bosutinib in third-line therapy to see if it can gain approval in that context. But it also binds in a different place. It’s an allosteric inhibitor of BCR-ABL. So there are good data, preclinical, that it synergizes with the different TKIs and prevents emergence of resistant clones. There’s also a study looking at that combination. So there are a few combinations investigating that to see if we can get to treatment-free remission. It’ll be fantastic if at least half or more of our patients could have that as a reality.

Harry Erba, MD, PhD: Yes, that last one you mentioned, that’s ABL001?

Jorge Cortes, MD: That’s correct.

Harry Erba, MD, PhD: OK. And actually, based on some of the work that was done at The University of Texas MD Anderson Cancer Center and at Moffitt Cancer Center, SWOG is actually looking at a randomized phase II study where we add in ruxolitinib with dasatinib or nilotinib in patients who’ve achieved a CCyR [complete cytogenetic response] but not a major molecular remission.

Jorge Cortes, MD: That’s true. That’s because there are some good data that suggest that these leukemic stem cells, the CML stem cells, are very dependent on JAK2. And at least in vitro it worked well, that combination, to eradicate the disease. Both, as you mentioned, Moffitt and ourselves did some piloting and there are some intriguing responses. They were both small studies, so I think this study will be very valuable to give us an idea of whether that could be another way to go.

Harry Erba, MD, PhD: Well Jorge, I’ve kept you longer than I promised I would, but I’ve enjoyed this conversation. Thank you, Dr Cortes, for this insightful discussion. And thank you to our audience, for watching this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.

Harry Erba, MD, PhD: Well Jorge, I’ve been driving the discussion with all of these questions. I’m going to give you an opportunity to wrap it up with what you think are a few of the outstanding questions or challenges that remain in the management of chronic phase CML [chronic myeloid leukemia].

Jorge Cortes, MD: One of the important questions is…we’ve been talking a lot about arterial occlusive events. I don’t think we’ve done a good job understanding why. And the more we understand why, the better we’ll be able to prevent it, to manage it, and of course it can help us to better use these drugs, because they’re good. We’ve been talking about how good ponatinib is, but we are concerned about these adverse events. We need to do better.

We talked about the treatment-free remission, the treatment discontinuation. That’s becoming increasingly a goal of therapy, but the reality is that it’s effective in only about 25% of patients. Only about 50% of patients get to sustained deep molecular responses. And of those, only about half of them remain free of therapy. So really, only 25% can stop therapy without a relapse. Now that’s great compared to what we thought some years ago, but the majority can’t.

So we’re trying to see how we can increase the number of patients who have a sustained molecular response. And how can we reduce the risk of relapse? We know TKIs [tyrosine kinase inhibitors] alone can’t eradicate the stem cell. That’s preclinical work. So there’s a lot of work going into what combinations we can use. There’s been some work with interferon therapy. In Europe, there have been several studies combining different TKIs with interferon. There is very nice preclinical work with venetoclax.

There are studies that are starting to incorporate that to see if that can help. There’s this new tyrosine kinase inhibitor called asciminib. It is very effective in the salvage setting. There’s an ongoing randomized study against bosutinib in third-line therapy to see if it can gain approval in that context. But it also binds in a different place. It’s an allosteric inhibitor of BCR-ABL. So there are good data, preclinical, that it synergizes with the different TKIs and prevents emergence of resistant clones. There’s also a study looking at that combination. So there are a few combinations investigating that to see if we can get to treatment-free remission. It’ll be fantastic if at least half or more of our patients could have that as a reality.

Harry Erba, MD, PhD: Yes, that last one you mentioned, that’s ABL001?

Jorge Cortes, MD: That’s correct.

Harry Erba, MD, PhD: OK. And actually, based on some of the work that was done at The University of Texas MD Anderson Cancer Center and at Moffitt Cancer Center, SWOG is actually looking at a randomized phase II study where we add in ruxolitinib with dasatinib or nilotinib in patients who’ve achieved a CCyR [complete cytogenetic response] but not a major molecular remission.

Jorge Cortes, MD: That’s true. That’s because there are some good data that suggest that these leukemic stem cells, the CML stem cells, are very dependent on JAK2. And at least in vitro it worked well, that combination, to eradicate the disease. Both, as you mentioned, Moffitt and ourselves did some piloting and there are some intriguing responses. They were both small studies, so I think this study will be very valuable to give us an idea of whether that could be another way to go.

Harry Erba, MD, PhD: Well Jorge, I’ve kept you longer than I promised I would, but I’ve enjoyed this conversation. Thank you, Dr Cortes, for this insightful discussion. And thank you to our audience, for watching this Targeted Oncology presentation on precision medicine.

Transcript edited for clarity.
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