Emerging Therapies in Essential Thrombocytopenia

Transcript:

Harry Erba, MD, PhD: I’m going to give it to a clinician here. Mary Frances, we heard higher age, prior thrombotic event associated with higher risk. As I remember, the ELN [European LeukemiaNet] criteria now includes a platelet count of 1.5 million as high risk. Your patient is completely asymptomatic or a young woman with headaches, migraine headaches. Do you have to give that patient cytoreductive therapy? Can you give them aspirin, or are there any specific things you have to worry about with that?

Mary Frances McMullin, MD: With a platelet count over 1.5 million, I would put them on interferon because they’re also at risk of bleeding. Following those patients up and seeing them once the platelet counts go over that level, they clinically run into problems.

Harry Erba, MD, PhD: So that is the level, 1.5 million.

Mary Frances McMullin, MD: The PT-1 [primary thrombocythemia-1] story was interesting because when it started, the cutoff was 1000. But the data came right from the Italians, and the level was moved up to 1.5 million. In that group, which are really a low-risk group because they were between ages 40 and 60, and with no previous thrombotic events, not on pharmacological therapy for diabetes or hypertension.

John Mascarenhas, MD: Just to clarify, the risk really with extreme thrombocytosis is really bleeding.

Mary Frances McMullin, MD: Bleeding.

John Mascarenhas, MD: It’s not really thrombosis. Just to comment on the scenario you painted, I worry about women or men for that matter that have headaches, because to me that’s a microvascular disturbance and that’s the difference. Those patients I actually do think need to be cytoreduced. I still struggle with what the goal platelet count is, but I do put them on cytoreductive therapy. To me there are 2 scenarios you’re trying to address.

Harry Erba, MD, PhD: The question was 1 to beat you. No, you do not give them aspirin. There’s a pseudo-Von Willebrand disease situation that you can run into, so thank you for taking the bait. Before we finish this, you guys are getting into some pretty fancy stuff. How are type 1 mutation? Well, there’s type 2. John, what’s the difference between those, and is the effect the same in MF [myelofibrosis] as it is in ET [essential thrombocythemia]?

John Mascarenhas, MD: The real answer is that we probably don’t really know. Mechanistically and biologically, I don’t understand why there’s a difference, because they end up in the same frameshift mutation. There’s a concept that there’s a differential in terms of progression to myelofibrosis in ET between type 1 and type 2 and survival. The type 1 is a 52-base paired deletion. Type 2 is a 5-base paired insertion. In primary myelofibrosis, if you have a type 1, that’s considered a favorable-risk mutation. In ET, that may be the opposite. In my humble opinion, I’m not quite sure that’s crystal clear. I don’t necessarily treat patients differently based on the type of mutation.

Harry Erba, MD, PhD: Moshe, does the JAK2 mutation mean anything to you when treating ET?

Moshe Talpaz, MD: No. I treat it. Well, I’m a little more aggressive than what was discussed here, so I wouldn’t get into it.

Harry Erba, MD, PhD: No, please, that’s the purpose.

Moshe Talpaz, MD: I have a large collection of young patients with ET, and they can have platelets come between 700,000 to 1 million, and I do treat them typically with interferon with the objective that was described here—long-term therapy, not just controlling the counts. Maybe that’s a different aspect of this management. Now I want to interject 1 point of...

Harry Erba, MD, PhD: Before you do that, don’t forget your point. If you achieve a JAK2-negative mutant allele burden, will you stop the interferon?

Moshe Talpaz, MD: I have done it in the past. I’ve seen patients that have a remission of 2 or 3 years without recurrence, and then I see a recurrence. The experience is anecdotal. I don’t have 200 patients that I can comment from. I can comment on single numbers, but in reality I cannot comment. Even people who have no experience, it would be interesting to hear. It does happen if this is true remissions. The question is, do we get a situation of treatment discontinuation without the disease coming back?

Harry Erba, MD, PhD: Given the cost and the symptoms with the drug…

Moshe Talpaz, MD: It’s an untested question. One comment, and I want to say I’m not aware, is next-generation sequencing that we have done. ET is the disease with the best outcome for a very simple reason: it has the lowest number of mutations. On the average, only 1. Prefibrotic myelofibrosis, about 1.5; PV [polycythemia vera] has more than 2; myelofibrosis, on average, 5. So you see this transition of mutation as it relates fairly nicely to the outlook and survival.

Harry Erba, MD, PhD: Well, I want to thank OncLive®, because I’ve had a lot of fun this afternoon with the 4 of you and learned a lot. This has been a fantastic discussion. Before we conclude, I’d like to get final thoughts from each of our panelists. We’ll start with you, Mary Frances.

Mary Frances McMullin, MD: We live in exciting times. Myelofibrosis remains a major problem, but I’m old enough to have been around when we had nothing to offer them. Now we’re looking at all these different drugs. I’m also excited about what’s happening in polycythemia vera. Again, we have ruxolitinib, but there are more things coming into this realm as well. We’re looking at up-front trials in the future of new treatments in polycythemia vera.

Harry Erba, MD, PhD: Robyn?

Robyn Scherber, MD: One of my big thoughts in seeing patients very frequently is just the idea that I don’t know that we do enough in terms of prevention. We have so many drugs that are really doing amazing things and so much more in our arsenal. I’d like to see us move more until potentially lower-risk therapies that we might be able to help with prevention of progression. But we’ll see how that goes. I mean, it’s very hard to find low-risk therapies. Certainly in terms of myelofibrosis, things are moving at an unparalleled pace with lots of exciting, new advancements and options for patients in the future.

Harry Erba, MD, PhD: John?

John Mascarenhas, MD: To me, and I tell fellows all the time, I think MPNs [myeloproliferative neoplasms] are probably the most exciting hematologic malignancy perhaps of all malignancies because the science really informs the clinical development of therapy, probably more so than anything. Moshe knows better than anyone, the first targeted therapies really came from myeloproliferative neoplasm. To me it’s the melding between the scientific discovery and the translation to the clinic that’s very exciting as a clinical investigator, but I’m hoping it’s going to change our patients’ lives in the near future.

Harry Erba, MD, PhD: Finally to the man who put up with me at the University of Michigan, Moshe.

Moshe Talpaz, MD: Actually, we got along.

Harry Erba, MD, PhD: We did.

Moshe Talpaz, MD: Well, considering the other things that influenced us.

Harry Erba, MD, PhD: That’s a different discussion.

Moshe Talpaz, MD: That’s a different discussion. As you know, I’ve been a spoiled person. I developed treatments in CML [chronic myelogenous leukemia], and we have seen linear transition improvement. It was elegant, nice targeted therapy and all that, and then I decided to move. I needed some punishment, so I moved to myelofibrosis. It clearly is not a linear story, and clearly it’s complex. I said maybe we should set goals. At this point, we didn’t have tools to eliminate the malignant clone. We don’t know what drives it. It’s not a single driver. It’s not a JAK2 only and we know it. It’s much more complex than that.

Maybe we should focus at this stage in things we can affect, the interplay between the malignant clone and the stroma. As it turns out, if we change fibrosis in this disease, we change the outcome in about three-quarters of patients. Only a quarter to a third of the patients will die of transition to leukemia over the years. Many of the patients will die because they have liver failure, because they have pulmonary hypertension, because are they just wasted. If we can affect those processes, we change the disease. So maybe perhaps we should focus on things that we can affect. Cytokine interplay, cell to cell interplay before we go and say how to eliminate the clone.

Harry Erba, MD, PhD: This has been a great discussion. Thank you so much for joining us. On behalf of the panel, we hope you found this Peer Exchange® discussion to be useful and informative.

Transcript Edited for Clarity