Dr Fleischman explains the clinical course she would take with MF treatment and what it would take to change therapies.
Ruben Mesa, MD: So, we have these patients, we’ve started them on therapy, at the current time with MF [myelofibrosis] we have ruxolitinib or fedratinib, likely soon pacritinib. Angela, what does that course typically look like? When might you expect to see a response? How durable does that tend to be in your experience?
Angela Fleischman, MD, PhD: With anything, it varies from patient to patient, but in general I think JAK inhibitors are a really satisfying drug to use because patients feel better quite quickly. It’s satisfying to see a significant improvement in people’s lives and pretty quickly. That’s a great feature, it has a quick onset. In terms of durability of response, again it differs from person to person.
Then also another level of complexity is if you need to change the dose because of the blood counts. Maybe on a certain dose of ruxolitinib that the patient had been on for a while they had a great symptom response and a great spleen response, but now unfortunately, you need to bring down the dose. It’s likely that if you have to bring down the dose, you will dampen their response in terms of their symptoms and their spleen.
There are people who have enjoyed a really great response with ruxolitinib, and I guess you could say that the drug is slowly losing its oomph. It is petering out; the person just isn’t getting that same bang for their buck. And usually, in my experience, over a period of time they’re just not deriving the same benefit from it in terms of durability of response.
Ruben Mesa, MD: So they’ve now had another losing response, and that in my mind is kind of a continuous variable. People have asked me frequently over the last 10 years, define ruxolitinib failure, and I share with them, failing any therapy really depends on what is your alternative. Which, up to the approval of fedratinib, it was transplant or a clinical trial, and not many patients have the ability, the resources, the energy to participate in a clinical trial.
That’s kind of a key piece, it’s always balanced against what are my other options, and I go through those with the patient. Jamile, in your mind, and maybe I’ll make it simple, because we truly only have 2 approved drugs right now. And let’s say pacritinib is also out on the table, how might you choose between those drugs? What might cause a change? Let’s say pacritinib is available for you, you’ve got a patient, what might make you make a change from ruxolitinib, and what might drive that?
Jamile Shammo, MD, FACP, FASCP: I think the clinical trials that are taking place in that agent are focusing on a huge area of need, which is platelets, patients with platelet counts below 50,000. And as the MF progresses, you’re likely to see patients with low platelet counts. I think that would be the low hanging fruit, this would be the patient population I’d use.
The other point is that we don’t have many options, excluding transplant. It would be nice to figure out a way, maybe that would be one area of need. What other pathway can I actually block so that this patient’s disease could get better, but we’re not there yet. I would say patients who may be more cytopenic, low platelet count, could benefit from a spleen volume reduction, would be the patients I would consider.
Ruben Mesa, MD: Based on some of our experiences we’ve had with other drugs, let’s say we could prescribe that tomorrow and you’ve got a patient, they’ve got a platelet count of 40,000. What do you think that transition would look like? Do you think you would stop ruxolitinib on Friday, and they start pacritinib on Saturday? Would you overlap it? We’re going to learn as we go, because we don’t have a lot of experience with that. But what do you think we should do?
Jamile Shammo, MD, FACP, FASCP: That’s a very good question. I’ve thought about this because obviously, I’ve had to deal with this for many patients. And if I’m believing that somebody is actually failing the drug, then I’m tapering them off of the medicine at some point, and they will get to a point where they’re on nothing.
Then again, and I don’t know how many times you’ve seen this, people do develop splenomegaly when you’re tapering their drug, which leads you to believe that there must have been some improvement that you are deriving from this. But let’s argue that this patient totally grew on their current JAK inhibition, then I taper them off, and then I start a new medicine. I don’t like to overlap because you don’t know the toxicity, and the cytopenias tend to be a little bit harder. That’s my approach.
Ruben Mesa, MD: That’s very helpful. I can share with the fedratinib studies, we learned, one, the dose that they were on of the ruxolitinib was important. If people were on 20 mg twice a day, to stop them abruptly and start fedratinib without an overlap didn’t work well. It was probably better to have tapered them down to 10 mg BID [twice a day] or less, and then switch. I suspect with pacritinib it likely will sort itself out because you’re right. I don’t see a lot of people being markedly thrombocytopenic, and being on a ruxolitinib dose of 20 [mg] BID, and likely we’ll think that transition may be a little easier for folks.
Stephen, any thoughts? We have these things, switching between them, biologically they all may kick in at slightly different rates. I’d say our experience with fedratinib has been favorable in the second line, but it does not kick in instantly. So again, I’ve been mindful of this, having maybe a little bit of overlap and having it a little lower down. What do you think?
Stephen Oh, MD, PhD: I think like you said, and from a practical standpoint with regard to patients who might be transitioning to pacritinib, they’re not likely to have been on 20 mg BID of ruxolitinib. I don’t see it as a big issue, and these are often going to be patients who if they were on ruxolitinib, they have already been taken off of it because of the thrombocytopenia, or lack of effectiveness of the low dose that they were on. I don’t really see that as a big concern in a practical setting.
It is clear that with ruxolitinib you do have this kind of rebound phenomenon that can occur, particularly if they were on a higher dose. So that is something to be cognizant of. With fedratinib, my understanding with it being a bit of a longer-acting drug, it’s generally less of an issue for coming off of it, at least in terms of withdrawal-type symptoms. So, I don’t see that as much of a problem.
This transcript has been edited for clarity.