Targeting JAK2 in Myeloproliferative Neoplasms - Episode 13

Searching for a Cure for MPNs

The doctors discuss new discoveries that may lead to a cure for MPNs.

Srdan Verstovsek, MD: What thoughts do you have on the future?

Andrew Kuykendall, MD: I think the duration of response and disease modification is what it comes down to. What we have done so far is transform patients’ lives as far as their quality of life goes, and we have been able to induce a survival benefit in the case of ruxolitinib, but I think there is a lot more to do. We are not meaningfully impacting the disease in many ways. When looking at things like pelabresib and momelotinib, we are at least starting to think more 3 dimensionally about these diseases, especially when talking about myelofibrosis. We are not just saying, “Hey, we are focused on the spleen and symptoms. Anemia is going to be bad; we are going to have to deal with it.” We are talking about getting triphasic responses, or whatever term you to want to use, saying we are going to help with 3 different aspects of the disease. One would have to impact all the different aspects of the diseases to modify the underlying disease, get rid of the stem cell, to target that.

For all the benefits of the ongoing phase 3 studies, very few right now are really hoping for that type of impact. I think that is going to be something we see that will be emerging out of phase 1 and phase 2 studies if we are able to find a way to selectively target that. That comes from the laboratories and that comes from the folks who are researching that, who are identifying these novel targets.

If you go back 5 years ago, I think in 2016, we still did not really understand how calreticulin did what it did. Then, five years before that, we did not know calreticulin existed. Things happen very quickly within 5 years. Drug approvals are probably the things that happen the slowest within this realm, but drug approval occurs after we reach an understanding of a disease. The amount we have understood the disease has increased so much in the last decade that it is not surprising that we are on the precipice of having multiple different drugs being approved.

Srdan Verstovsek, MD: That is very well said, but now you are bringing up a possible cure, right? It is a very high bar. We have an opportunity to develop and use a lot of different medications, hopefully as we just said, with different modes of action, in combinations. Realistically, the goal is to control the disease signs and symptoms and make our patients live longer. I think that evolution of the role of the transplant may happen as well. When we saw with ruxolitinib such a massive improvement in a good number of patients, in their livelihood and physical condition, we said, “Oh, now we can maybe do the transplant in them. We can make them transplant eligible and cure them, right?” In my own practice, this is what we are trying to do, in a sense. When we see the patients and they are not doing well, even if they do have a donor, we would give them JAK inhibitors for a few months to get the maximum possible benefit, to improve their condition. If they do not have a donor, you treat them with JAK inhibitors, you improve their condition, you find a donor, and then you tell them, “Let’s go for it because you are in good shape. You can do it.”

With the combinations and with new therapies, that type of success might be much more common. We may have much better results overall in controlling signs and symptoms in a large group of people for much longer. Then there would be a role—a much larger role, possibly—for a bone marrow transplant even as this procedure improves on its own over the next few years. The combination of the pills or injections plus the high appreciation of the transplant as a possibility may click much better than these days.

Andrew Kuykendall, MD: Definitely; I think you have the ability to provide better therapy for patients in the later stage of the disease or perhaps provide more targeted therapy in earlier stages of the disease. I think there are a couple different ways that we can meaningfully impact the disease progression, and that is what makes this an exciting time. Just the idea of early intervention, I think, is something that has not really been touched upon. We talk about most of our therapies are for patients with higher-risk myelofibrosis. When we talk about therapies for ET [essential thrombocythemia] and PV [polycythemia vera], it is a much shorter conversation. But that might be the area where intervention has the potential to make the most difference, and we will have to see.

Srdan Verstovsek, MD: Well, this was extremely informative. Andrew, thank you much for this insightful discussion on multiple levels. I would like to thank our audience for watching this Targeted Oncology™presentation on precision medicine. We hope you found this discussion to be useful and informative, and hopefully you learned a lot from our experience here to apply in the treatment of patients with MPNs [myeloproliferative neoplasms] in your practice. We appreciate you listening, and I hope you have a nice day. Thank you so much, until next time.

Andrew Kuykendall, MD: Thank you.

Transcript edited for clarity.