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Ruxolitinib's Role in Treating Myelofibrosis

Panelists: Harry P. Erba, MD, PhD, Duke University; Rami Komrokji, MD, Moffitt Cancer Center; Ruben A. Mesa, MD, FACP, The Mays Cancer Center, the newly named center of UT Health San Antonio MD Anderson Cancer Center; Jamile M. Shammo, MD, FASCP, FACP, Rush University Medical Center; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center; Srdan Verstovsek, MD, PhD, MD Anderson Cancer Center
Published: Wednesday, Aug 15, 2018



Transcript: 

Harry P. Erba, MD, PhD: Ruben, what are the goals of therapy?

Ruben A. Mesa, MD, FACP: The goals of therapy in myelofibrosis fundamentally fall on: Are you on a curative path, or are you on a path trying to modify the disease in the most favorable way? I share with patients that our therapy fundamentally falls into observation, medical therapies, or transplant.

I think our medical therapies can be quite impactful, but as Srdan had mentioned, we really have that dichotomy in terms of a curative path with transplant that has a lot of complexities and a lot of careful patient selection. When I visit a patient with myelofibrosis, that’s really the first decision point. Based on age, based on risk for the disease, and based on a variety of factors, which of those 2 paths are we going to try?

We’re trying to diminish the suffering the patient experiences to the greatest degree that we can. I think that in and of itself is disease modification. Even with people on medical therapies, I think their goals of therapy in terms of things we can measure include objective improvement in symptoms; reduction in splenomegaly, which I do think is easily meaningful in clinical benefit; and improvement in cytopenias. It would be decreasing that morbidity. I do think in myelofibrosis, decreasing morbidity is in and of itself disease modification. Many patients die from progressive morbidity, progressive debilitation.

Harry P. Erba, MD, PhD: Srdan, why don’t you summarize for us the results of the COMFORT studies that support the use of ruxolitinib in myelofibrosis.

Srdan Verstovsek, MD, PhD: The 2 studies, COMFORT-I and COMFORT-II, compared ruxolitinib to a placebo in a blinded way or to the best valuable therapy. It has been quite a few years since then, so we have long-term follow-up. We know very well by now that with ruxolitinib, they did very good on controlling the symptoms and the spleen in these patients. These are patients with advanced features who had a large spleen and bad symptoms. These are, as Ruben had described, valuable measures set to improve quality of life in these patients, to decrease the morbidity and make them live at least decently if not much longer.

But to that point, there was a longer term follow-up. Now we have a past 5 years’ of follow-up of these studies. We now know—and this was not the goal of the study—that people with good control of signs and symptoms actually lived longer, on average about 3 years, in both of the studies. And when we look back at the phase I/II study, which was done in quite the distant past, the same happened comparing historical control to good control of signs and symptoms, spleen and weight, cholesterol, albumin, and performance status. We can actually make people live longer with the disease under control, which was not envisioned in the past. We are not eliminating disease, we are just controlling it: controlling proliferation, controlling inflammation. People live longer with that. The starting dose of ruxolitinib is usually made based on the platelet level.

We have guidelines in place. They should be, in my view, followed because what I see quite often—and this is probably the topic to raise—is prophylactic underdosing of ruxolitinib because many patients may have anemia, as was already pointed out. Ruxolitinib may aggravate not just thrombocytopenia or cause thrombocytopenia, but aggravate anemia. Dose adjustments are necessary, but that does not resonate well with underdosing patients regarding the benefits in the spleen and symptoms and prolongation of life.

My goal is usually to start with the suggested dose as per the guidelines, and modify if necessary for a myelosuppression that may or may not happen. For about 70% of patients, we’ll make dose adjustments. But that will also lead to potentially the most benefit received from a higher dose of ruxolitinib at the beginning in terms of the spleen reduction. The degree of spleen reduction is directly correlated to survival. So, my goal is to optimize to the maximum safe dose of ruxolitinib at the beginning of therapy.

Harry P. Erba, MD, PhD: If the patient’s already red cell transfusion-dependent, do you consider ruxolitinib?

Srdan Verstovsek, MD, PhD: I do. Presence of anemia or developing anemia does not deter me from using ruxolitinib. I do follow the guidelines based on platelet number. I would transfuse as necessary, and perhaps add in my own practice antianemia medication, danazol for example. There are clinical studies with anti-anemia medications that are being combined with ruxolitinib for these type of patients, where they measure erythropoietin levels to see whether it’s possibly low erythropoietin. But for the benefit of a survival, which is coupled with a good spleen response, I would for first 3 or 4 months strictly follow guidelines based on the platelet number, and only adjust the dose if anemia is so bad.            

Rami Komrokji, MD: To remind everyone, the indication is not in treating anemia, because I see patients who come with no splenomegaly and no constitutional symptoms and are started on JAK2 inhibitors because of anemia. That’s not going to help that small subset of patients.

Harry P. Erba, MD, PhD: If I could just maybe give an alternative—and I do not have your experience with this drug—I often start a little bit lower, I’ll be honest with you, based on the platelet count and based on hepatic and renal function in my older patients. But based on the low platelet study, if a patient has any degree of thrombocytopenia or low normal, I start at 5 mg twice a day. Within a month, if they’re tolerating it, I go up with it. In the low platelet study, they were able to go up with it. I want to be clear that just like what I said with hydroxyurea and with ruxolitinib for PV, you have to push the dose to its maximal effect.

Srdan Verstovsek, MD, PhD: The key here is the monthly increment of the dose. We actually, as a part of phase I/II study, had a starting dose of 10 mg twice a day with an allowance before increasing it of up to 3 months, and this did not work well. This was published as part of a New England Journal of Medicine paper, and it did not achieve very good results with the spleen. So, if you do start low—and I see quite often my referrals starting with 10 mg twice a day because of anemia—that’s OK, as long as you go to 15 mg next month and then 20 mg the next month, and not wait 3 months.

Harry P. Erba, MD, PhD: Yes, I agree.

Ruben A. Mesa, MD, FACP: I’ll just chime in to reemphasize that point because that’s probably a large percentage of the second opinions that I see, individuals who were started on ruxolitinib and were too conservatively dosed. They never really responded, but never really had that chance to begin with. I think the issues regarding the dose and the counts as Srdan, others, and I were involved with those early studies existed before we really had a mature experience. I think over time, we’ve learned the safety of dosing in patients with thrombocytopenia and whether the likelihood of causing hemorrhage on the basis of using it in people with thrombocytopenia, which is what we’re really concerned about, actually ends up not being a big factor.

Harry P. Erba, MD, PhD: Let me turn it to the panel then. We’ve now had 5 years since the COMFORT study. 2011 was when the drug was approved. What has been your experience using ruxolitinib in myelofibrosis? Do you see responses? What kind of responses? Are they durable responses, Rami?

Rami Komrokji, MD: I would say we recently published our experience looking at the real-life use of it, and I think the clinical benefit is there. Actually, it’s probably more than what was reported on the study because the study did not consider any patients who had less than 35% reduction in splenomegaly, but more so the patients actually do have spleen reduction and improved symptoms. I think in real life the benefit is there even more than in the clinical studies. The challenge is obviously, as mentioned, that those patients are mostly always referred, so many times the dose adjustments are not appropriate and patients don’t get the maximum benefit because of that role. I see the clinical benefit probably more than in clinical trials.

We are starting to see a challenge in what we call the ruxolitinib failures and what happens to those patients. That’s the unmet need now. I think Srdan recently published on experience from patients who were on a trial at The University of Texas MD Anderson Cancer Center, and the survival for those patients was in the range of around 17 months. We looked at the real-life experience after ruxolitinib failure, and it’s the same thing, 14 to 17 months. So now, I think we are starting to deal with that challenge: what to do after ruxolitinib failure. But the clinical benefit is there, and my experience has been better than the clinical trials. Dosing and familiarity with the treatment is a key for its success.

Transcript Edited for Clarity

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Transcript: 

Harry P. Erba, MD, PhD: Ruben, what are the goals of therapy?

Ruben A. Mesa, MD, FACP: The goals of therapy in myelofibrosis fundamentally fall on: Are you on a curative path, or are you on a path trying to modify the disease in the most favorable way? I share with patients that our therapy fundamentally falls into observation, medical therapies, or transplant.

I think our medical therapies can be quite impactful, but as Srdan had mentioned, we really have that dichotomy in terms of a curative path with transplant that has a lot of complexities and a lot of careful patient selection. When I visit a patient with myelofibrosis, that’s really the first decision point. Based on age, based on risk for the disease, and based on a variety of factors, which of those 2 paths are we going to try?

We’re trying to diminish the suffering the patient experiences to the greatest degree that we can. I think that in and of itself is disease modification. Even with people on medical therapies, I think their goals of therapy in terms of things we can measure include objective improvement in symptoms; reduction in splenomegaly, which I do think is easily meaningful in clinical benefit; and improvement in cytopenias. It would be decreasing that morbidity. I do think in myelofibrosis, decreasing morbidity is in and of itself disease modification. Many patients die from progressive morbidity, progressive debilitation.

Harry P. Erba, MD, PhD: Srdan, why don’t you summarize for us the results of the COMFORT studies that support the use of ruxolitinib in myelofibrosis.

Srdan Verstovsek, MD, PhD: The 2 studies, COMFORT-I and COMFORT-II, compared ruxolitinib to a placebo in a blinded way or to the best valuable therapy. It has been quite a few years since then, so we have long-term follow-up. We know very well by now that with ruxolitinib, they did very good on controlling the symptoms and the spleen in these patients. These are patients with advanced features who had a large spleen and bad symptoms. These are, as Ruben had described, valuable measures set to improve quality of life in these patients, to decrease the morbidity and make them live at least decently if not much longer.

But to that point, there was a longer term follow-up. Now we have a past 5 years’ of follow-up of these studies. We now know—and this was not the goal of the study—that people with good control of signs and symptoms actually lived longer, on average about 3 years, in both of the studies. And when we look back at the phase I/II study, which was done in quite the distant past, the same happened comparing historical control to good control of signs and symptoms, spleen and weight, cholesterol, albumin, and performance status. We can actually make people live longer with the disease under control, which was not envisioned in the past. We are not eliminating disease, we are just controlling it: controlling proliferation, controlling inflammation. People live longer with that. The starting dose of ruxolitinib is usually made based on the platelet level.

We have guidelines in place. They should be, in my view, followed because what I see quite often—and this is probably the topic to raise—is prophylactic underdosing of ruxolitinib because many patients may have anemia, as was already pointed out. Ruxolitinib may aggravate not just thrombocytopenia or cause thrombocytopenia, but aggravate anemia. Dose adjustments are necessary, but that does not resonate well with underdosing patients regarding the benefits in the spleen and symptoms and prolongation of life.

My goal is usually to start with the suggested dose as per the guidelines, and modify if necessary for a myelosuppression that may or may not happen. For about 70% of patients, we’ll make dose adjustments. But that will also lead to potentially the most benefit received from a higher dose of ruxolitinib at the beginning in terms of the spleen reduction. The degree of spleen reduction is directly correlated to survival. So, my goal is to optimize to the maximum safe dose of ruxolitinib at the beginning of therapy.

Harry P. Erba, MD, PhD: If the patient’s already red cell transfusion-dependent, do you consider ruxolitinib?

Srdan Verstovsek, MD, PhD: I do. Presence of anemia or developing anemia does not deter me from using ruxolitinib. I do follow the guidelines based on platelet number. I would transfuse as necessary, and perhaps add in my own practice antianemia medication, danazol for example. There are clinical studies with anti-anemia medications that are being combined with ruxolitinib for these type of patients, where they measure erythropoietin levels to see whether it’s possibly low erythropoietin. But for the benefit of a survival, which is coupled with a good spleen response, I would for first 3 or 4 months strictly follow guidelines based on the platelet number, and only adjust the dose if anemia is so bad.            

Rami Komrokji, MD: To remind everyone, the indication is not in treating anemia, because I see patients who come with no splenomegaly and no constitutional symptoms and are started on JAK2 inhibitors because of anemia. That’s not going to help that small subset of patients.

Harry P. Erba, MD, PhD: If I could just maybe give an alternative—and I do not have your experience with this drug—I often start a little bit lower, I’ll be honest with you, based on the platelet count and based on hepatic and renal function in my older patients. But based on the low platelet study, if a patient has any degree of thrombocytopenia or low normal, I start at 5 mg twice a day. Within a month, if they’re tolerating it, I go up with it. In the low platelet study, they were able to go up with it. I want to be clear that just like what I said with hydroxyurea and with ruxolitinib for PV, you have to push the dose to its maximal effect.

Srdan Verstovsek, MD, PhD: The key here is the monthly increment of the dose. We actually, as a part of phase I/II study, had a starting dose of 10 mg twice a day with an allowance before increasing it of up to 3 months, and this did not work well. This was published as part of a New England Journal of Medicine paper, and it did not achieve very good results with the spleen. So, if you do start low—and I see quite often my referrals starting with 10 mg twice a day because of anemia—that’s OK, as long as you go to 15 mg next month and then 20 mg the next month, and not wait 3 months.

Harry P. Erba, MD, PhD: Yes, I agree.

Ruben A. Mesa, MD, FACP: I’ll just chime in to reemphasize that point because that’s probably a large percentage of the second opinions that I see, individuals who were started on ruxolitinib and were too conservatively dosed. They never really responded, but never really had that chance to begin with. I think the issues regarding the dose and the counts as Srdan, others, and I were involved with those early studies existed before we really had a mature experience. I think over time, we’ve learned the safety of dosing in patients with thrombocytopenia and whether the likelihood of causing hemorrhage on the basis of using it in people with thrombocytopenia, which is what we’re really concerned about, actually ends up not being a big factor.

Harry P. Erba, MD, PhD: Let me turn it to the panel then. We’ve now had 5 years since the COMFORT study. 2011 was when the drug was approved. What has been your experience using ruxolitinib in myelofibrosis? Do you see responses? What kind of responses? Are they durable responses, Rami?

Rami Komrokji, MD: I would say we recently published our experience looking at the real-life use of it, and I think the clinical benefit is there. Actually, it’s probably more than what was reported on the study because the study did not consider any patients who had less than 35% reduction in splenomegaly, but more so the patients actually do have spleen reduction and improved symptoms. I think in real life the benefit is there even more than in the clinical studies. The challenge is obviously, as mentioned, that those patients are mostly always referred, so many times the dose adjustments are not appropriate and patients don’t get the maximum benefit because of that role. I see the clinical benefit probably more than in clinical trials.

We are starting to see a challenge in what we call the ruxolitinib failures and what happens to those patients. That’s the unmet need now. I think Srdan recently published on experience from patients who were on a trial at The University of Texas MD Anderson Cancer Center, and the survival for those patients was in the range of around 17 months. We looked at the real-life experience after ruxolitinib failure, and it’s the same thing, 14 to 17 months. So now, I think we are starting to deal with that challenge: what to do after ruxolitinib failure. But the clinical benefit is there, and my experience has been better than the clinical trials. Dosing and familiarity with the treatment is a key for its success.

Transcript Edited for Clarity
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