Dosing of Ruxolitinib in PV and MF

Transcript:Harry P. Erba, MD, PhD: Jamile, I’m going to break this up a little bit. I’m going to come to you. Here’s a drug where, in the 2 indications, you can find doses in the package insert for 20 mg twice a day, 15 mg twice a day, 10 mg twice a day—I know that’s PV [polycythemia vera]—and then 5 mg twice a day. What is a doctor supposed to do? How do you pick the starting dose?

Jamile M. Shammo, MD, FASCP, FACP: It’s safe to say the least effective dosage is 10 mg twice a day, but I think it’s reasonable to also go by the platelet count. That was done in the study, and I think every patient has to be evaluated individually. We may have someone who may have a touch of kidney dysfunction. Well, I probably won’t be starting with 20 mg twice a day, even though their platelet count may be above 200 mm3. Each person has to be assessed separately.

Harry P. Erba, MD, PhD: Mary Frances, how do you make dose adjustments? I’m going to come to you with this question, and then you can talk about dose adjustments. One of the concerns I’ve heard about using RUX [ruxolitinib] is, “I know the patient is symptomatic, but they’re not red cell transfusion dependent. I’m afraid I’m going to make them that way.” Or alternatively, “Oh, my lord, they have this red cell transfusion requirement. It’s only going to get worse.” It seems like a catch-22 to never use the drug.

Mary Frances McMullin, MD, FRCP, FRCPath: I think that’s the most difficult 1, particularly in this sort of patient, because it certainly makes people anemic, particularly if you change somebody from not being transfusion dependent to being transfusion dependent. It does plateau, so it may come up a bit, and you can add in erythropoietin-stimulating agents to see if you can push their hemoglobin up. For a drug that is so effective, how long do you hold off using it just on that? That’s probably not an argument, if they have myelofibrosis to the extent that they’re anemic.

What dosage do you start with? It’s very much the platelet count. You want to try and get as much as you can, so you want to get to the 20 mg twice a day, if possible. The instructions are quite clear that if the platelets are over 200 mm3, you can do that. If the count is 100 to 200 mm3, you have to start at 15 mg twice a day, and if it’s 50 to 100 mm3, lower. Of course, if the platelets are under 50 mm3, you’re not supposed give it, though I think many people will start ruxolitinib and hope that the platelet count will come up with time, with a lower platelet count. Again, once you’ve started, if the counts improve, you can get the dose up.

Harry P. Erba, MD, PhD: Yes, it was interesting. In PV, in the first 2 weeks, the platelet counts did go up in the RESPONSE trial, right?

Mary Frances McMullin, MD, FRCP, FRCPath: Yes.

Harry P. Erba, MD, PhD: I think that’s more because you get rapid reductions in splenomegaly, and it’s still a proliferative disease, but we don’t see that.

Mary Frances McMullin, MD, FRCP, FRCPath: Of course, the 1 thing you do see when you start people on ruxolitinib is that the white cell count goes way up, and that can be quite alarming. You have to hold your nerves and keep going, because they can get very high white cell counts temporarily.

Harry P. Erba, MD, PhD: You don’t adjust the doses based on whether the patients required a red cell transfusion. It’s platelets?

Mary Frances McMullin, MD, FRCP, FRCPath: Yes, the platelets.

Harry P. Erba, MD, PhD: Anything else where you’ve had to adjust it?

Mary Frances McMullin, MD, FRCP, FRCPath: That’s the main 1.

Harry P. Erba, MD, PhD: OK.

Rami Komrokji, MD: The key is really close observation at the beginning, in the first couple of months. Neither of the counts is typical around weeks 8 to 10. That’s where you really need to titrate the dose. If the patient is titrating well, I think titrating the dose early on has benefits. Those patients get better, but also we don’t want to render those patients transfusion dependent if the dose is very high. I clearly see a dose-dependent spleen response, so the higher the dose, the better the spleen response.

For symptom improvement, patients do relatively well on a lower dose. They get benefits from the lower dose, in terms of symptom improvement, but it’s definitely a dose-dependent response that needs 15 mg or higher to see a good spleen response. That also brings me to a point when I think, “What is a meaningful spleen reduction for the patient?” We’ve got all those studies where our primary endpoint is 35% reduction by MRI [magnetic resonance imaging] in the volume of the spleen, which correlates with 50%.

Harry P. Erba, MD, PhD: A 50% reduction by physical exam.

Rami Komrokji, MD: A 50% reduction by physical exam. In reality, more than 90% of the patients on those treatments will have some spleen reduction. That’s what is meaningful for the patient. What correlates with better outcome is not clear to me, but in my experience, most of the patients will have some spleen reduction with those treatments.

Harry P. Erba, MD, PhD: We know there’s about a 5% incidence of herpes zoster. Do you prophylax these patients? Have you seen it?

Jamile M. Shammo, MD, FASCP, FACP: No. If I’m starting a new patient, now that we have the nonlive vaccine, I’m advising all my patients to receive that prior to therapy.

Harry P. Erba, MD, PhD: Do you give it a little bit of time to work before you give an immunosuppressant? What do you actually do? Do you just give at start the next day?

Jamile M. Shammo, MD, FASCP, FACP: Well, it’s 2 doses that they have to take, and then you could start perhaps a month later.

Harry P. Erba, MD, PhD: OK, you do give some.

Jamile M. Shammo, MD, FASCP, FACP: Yes, I wait a little bit, and I’m advising everybody to receive that.

Harry P. Erba, MD, PhD: OK, I think that’s helpful, because that’s a change from what we’ve been doing, it sounds like. Are you doing that?

Mary Frances McMullin, MD, FRCP, FRCPath: We haven’t gotten that vaccine yet.

Harry P. Erba, MD, PhD: You don’t have the vaccine. Let’s pull this together with any closing thoughts on what your experience has been with ruxolitinib. It sounds like it’s been generally positive, but is there anything that the viewers should be particularly on the watch for?

Ruben A. Mesa, MD, FACP: I would say that in myelofibrosis, folks have learned how to use it, overall. There are some times that underdosing occurs. I think the prevalence of use is good. I would say, in P vera [polycythemia vera], it is underutilized. There are a lot of patients who are having an inadequate response to frontline cytoreductive therapy, who would benefit from ruxolitinib and are delayed in receiving it. That’s probably the biggest gap in that spectrum, in my eyes.

Harry P. Erba, MD, PhD: One of the things I often say about the incorporation of ruxolitinib into our armamentarium for PV is that it really has focused attention on the optimal management of the PV patient before we decide that they need RUX.

Ruben A. Mesa, MD, FACP: Sure.

Harry P. Erba, MD, PhD: Titrating the dose, hydroxyurea, aspirin, and phlebotomy. Any other comments?

Jamile M. Shammo, MD, FASCP, FACP: The challenge now is coming in the era of ruxolitinib failure. What would you do after the treatment stops working? We do have patients who have durable responses, but eventually treatments stop in most of those patients. The outcome for those patients is not the best, and the options are limited. That’s an area of unmet need for second generation—JAK2 inhibitors, new treatment. We are starting to face some of those referrals. It used to be, you’d decide up front on ruxolitinib or not.

As Ruben mentioned, now, people are comfortable using those medications up front. We are starting to see those patients when those treatments stop working.

Mary Frances McMullin, MD, FRCP, FRCPath: That’s fairly true. That’s a huge change. You’ve gone from patients who we have nothing you could do for. Now they all come and get their ruxolitinib. That’s great. We’re now getting them sent back. What are you going to do now? They’re not responding to it anymore.

Transcript Edited for Clarity

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