The Use of Ruxolitinib in Myelofibrosis

Transcript:

John Mascarenhas, MD: There was a study to try to evaluate, a study called WETHINK, that unfortunately didn’t go anywhere. But it was a study providing RUX [ruxolitinib] to patients with low-risk disease who had a high molecular risk genotype. Unfortunately, accrual was poor and the study was stopped. That would have maybe given some credence to the idea that maybe starting the drug earlier would have improved the outcomes.

Moshe Talpaz, MD: I was interested in the same point of going to very early disease of a low-risk to an intermediate one, and I think it was pursued to some extent in Europe. We didn’t do it in the United States. I did it in some patients, and if I have seen a change in fibrosis, it was in these patients. Again, this is anecdotal, and I don’t argue that this is a definitive study.

I want to bring up a word of caution. I ran into a significant number of patients with infections with high-dose ruxolitinib. Once I used the dosage of 25 mg daily or even 20 mg twice a day, we may run into some problems with opportunistic infections. I’ve seen the whole gamut of infections, anywhere from fungal infections to unusual viral infections to perhaps increased risk of squamous cell carcinoma, with additional cases.

I just want to create awareness that it’s not a total innocuous drug. It’s an inhibitor of JAK1 and JAK2. The argument is that inhibition of JAK1 can interfere with the immune signaling of both alpha interferon, gamma interferon, and other cytokines. Whether that is correct or not, it needs to be addressed cautiously.

Robyn Scherber, MD: I agree with that. At least in my practice, when I’m seeing a patient that I’m thinking about starting on ruxolitinib initially, I am thinking about whether they’re at risk for hepatitis, hep B, hep C. I might consider starting an antiviral prophylaxis if they are positive. The other thing is that in all my patients who are starting ruxolitinib, I’m recommending that they get the new shingles, the Shingrix vaccine.

Moshe Talpaz, MD: So do I.

Robyn Scherber, MD: If they do get shingles while on the drug, I’m usually continuing on basically prophylaxis with acyclovir as long as they’re on it.

John Mascarenhas, MD: On that same vein, are you guys also checking to see if there’s any sense of clonal B-cell populations in these patients?

Moshe Talpaz, MD: That’s another important issue. Yes, it does happen more than we have appreciated it.

Harry Erba, MD, PhD: I think that’s true.

Moshe Talpaz, MD: Not necessarily as a result of the treatment.

Harry Erba, MD, PhD: Exactly.

Moshe Talpaz, MD: Not as a result of the treatment. But we do see the 2 together, not to mention I published and others have published on the coexistence of CML [chronic myeloid leukemia] and myelofibrosis.

Harry Erba, MD, PhD: That’s really the issue. There is an overlap, and you do a marrow and you find a small B-cell clone many times in these patients with MPNs [myeloproliferative neoplasms].

Moshe Talpaz, MD: The bigger problem is that we cannot put them on studies, because the minute the company hears that they have B-cell clones, they say no.

Harry Erba, MD, PhD: Mary Frances, I want to come to your insights on dosing of ruxolitinib. There’s quite a bit of controversy there. Do you start with the label dose, or do you start low and go high? I inform my decision partly from Moshe’s study of low platelets, where if the platelets grew between 50 and 100,000, I start at 5 twice a day. Most patients were able to go up. Then the other observation in COMFORT-I is that 80% of the patients you started on 50 mg twice a day for a platelet count of 100 to 200 mm³, required a dose reduction. To me it says start low, don’t scare the patient off, but remember to escalate the dose. I’ve gotten pushback on that. Why don’t you walk us through that.

Mary Frances McMullin, MD: I agree with you, but the important bit is to remember to escalate the dose, because as we get these drugs, particularly outside the people doing the trials, they get timid in a way, and they’d start low. We quite often see patients who haven’t had the dose pushed up, and so I would tend to start at 10 or 15 mg bid [two times a day]. We’re trying to remember to push it up if their platelet counts are OK. The other group to remember is those with the very low platelet counts and occasionally are recommended not to give it if the platelet count is less than 50 mm³. But we’ve all seen patients who start on it, and as soon as they get ruxolitinib, their platelet count goes up. And presumably since in some way the spleen is being squeezed or the platelets are repairing.

Moshe Talpaz, MD: We described it, yes.

Harry Erba, MD, PhD: I think that was the observation in the RESPONSE trial. Very quickly, within 2 weeks, the platelet counts went up, probably because of the rapid reduction in spleen size. I want to come back to management of thrombocytopenia later on when we talk about pacritinib. Robyn, how do you then judge when a patient has not responded to ruxolitinib, has had enough of ruxolitinib, is intolerant? How do you judge when you need to go to whatever is next?

Robyn Scherber, MD: That’s a great question and 1 that we don’t necessarily have great guidelines in exactly, or at least consensus guidelines, in terms of what is ruxolitinib refractory intolerant. What I can say is there are a number of different factors that people have used. So everything from worsening anemia to worsening thrombocytopenia, to increase in spleen size and worsening symptoms. Although that’s not very routinely included in the clinical trials, I do think it’s a very significant clinical marker, bleeding events or increasing blast count, or at least myeloid precursors in the peripheral blood.

From my perspective, so in the COMFORT studies, what we were able to see is that at 3 years, around 50% of patients went off ruxolitinib, most often because of loss of response. Specifically for them it was loss of either symptom or spleen response. Now more than ever, we have quite a few different drugs that have been studied, usually in phase II studies that have been combined with ruxolitinib to potentially optimize the ruxolitinib dosing. That’s something that, in my practice, if I don’t have a good clinical trial for someone, I am trying to optimize that ruxolitinib dosing by either if it’s anemia that’s a problem but adding potentially erythropoietin analogue or maybe Danazol and really trying to get that patient back up to an optimal dose of ruxolitinib.

There have been a few studies out that have shown that there is dose response in terms of symptoms and spleen size, and that ideally the best response can be seen between 20 mg bid [twice a day] and 25 mg bid [twice a day]. So if I have a patient on 10 bid [twice a day] who maybe is dose limited because of anemia, I’m going to try to push that dose a little, if they’re losing symptom or spleen response, to get them up to optimal dosing.

Harry Erba, MD, PhD: John, how about the patient who comes to you with diagnosed MF [myelofibrosis], doesn’t really have much in the way of constitutional symptoms. I’m going to make real light. They have a drenching night sweat once a month, we’ll say. Everything else is OK. You can palpate their spleen. It’s 5 cm below the costal margin, and they would have gotten on the COMFORT-I study but that’s it, no symptoms. Is that a patient you start RUX [ruxolitinib] on?

John Mascarenhas, MD: This is a scenario that happens not infrequently, in which you have a patient where you’re really asking yourself, what’s the immediate benefit of putting them on ruxolitinib and perhaps what’s the long-term benefit? I think we don’t really know the problem. It’s obvious and it’s easy when someone comes in highly symptomatic. You make them feel better, and you feel better as a physician. When you put someone on ruxolitinib who doesn’t really have symptomatology and maybe has a spleen that’s not bothering them, sometimes the payoff is not quite as clear.

I don’t necessarily belong to the camp that probably everyone else here does in which more is better. If I believe that potently inhibiting JAK/STAT signaling would put patients in remission, I would buy that. But it doesn’t, so I don’t buy that. I think what you get is more anemia and more cytopenias. Although that may not have the same significance as disease related, I’m not sure I really think that the outcome for that patient really changes substantially. I’m a believer that we need to combine, in a rational way, alternative agents that have other modes of action with ruxolitinib to improve those responses. I struggle with patients who are without symptoms or splenomegaly, but I will acknowledge that I often end up putting them on ruxolitinib. It’s a discussion.

Harry Erba, MD, PhD: We’re going to come back to those discussions about combinations because I think that’s important—something I’m seeing in my referral pattern, questions I’m getting asked all the time.

Transcript Edited for Clarity