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Optimal Timing of JAK Inhibition in Myelofibrosis

Insights From: Srdan Verstovsek, MD, PhD, University of Texas MD Anderson Cancer Center; Daniel J. DeAngelo, MD, PhD, Dana-Farber Cancer Institute; Kim-Hien T. Dao, DO, PhD, Oregon Health & Science University
Published: Wednesday, Nov 30, 2016


Transcript:

Srdan Verstovsek, MD, PhD:
Within the myelofibrosis patients, we usually have 4 types of patients based on the prognostications of their longevity. The low-risk patients have an average survival of 11 years, the intermediate group of patients have about 4 to 8 years, and then the high-risk patients have 2 years. Ruxolitinib is indicated in the United States for patients who have an intermediate- or high-risk of dying. This is very good to identify if we can, if you know how to using the IPSS, and also to really look whether the patient suffers from what ruxolitinib is good for—progressive splenomegaly. That is, systemic symptoms that bother patients and decrease the quality of life. Within these groups of patients, intermediate- and high-risk ruxolitinib is certainly a very good choice. It will, in a great majority of the patients, control the signs and symptoms, and eventually make people live longer.

Daniel J. DeAngelo, MD, PhD: The optimal timing to initiate a JAK inhibitor or ruxolitinib, which is the only approved agent at this point, is unclear. The COMFORT-I and COMFORT-II studies looked at patients with more advanced disease. These were randomized studies either to placebo or to the best available therapy, both showing an improvement, not only in terms of response, but in terms of quality of life as well as survival to those patients who were randomized to the ruxolitinib arm.

Now, the timing of therapy is in question. Should this therapy be used earlier? Should this therapy be used in patients with lower risk disease? That’s just unclear. What I can tell you is in my clinical practice, I look at the prognostic scoring system. I evaluate a patient based on the IWG [scoring system] at the time of diagnosis, and I follow the dynamic score throughout to try and help me assess the time to intervene. But, I use my clinical acumen, such as, is this patient’s spleen size rapidly growing? Why is that important? Because patients, at least in the COMFORT-I and COMFORT-II studies, typically saw roughly a 50% reduction in the size of their spleen. If you wait too long when the spleen is extremely large, you’re just not going to see as huge of a benefit. So, earlier intervention in that particular case may be important. When a patient has constitutional symptoms, that is a second clinical sign of progression. Patients who are having trouble sleeping at night, for example, because of fevers, night sweats or troubled by pruritus, these are times when intervention may really improve the quality of life. Fatigue is another one. Patients can have really dramatic fatigue, leading to inability to get through the day, inability to complete work. And I found that intervention in these patients can be really a quality of life improvement or disease-modifying improvement in their outcome, and really has dramatically impacted the improvement in their well-being.

Srdan Verstovsek, MD, PhD: The evidence that we have about ruxolitinib use in myelofibrosis comes from clinical studies. And recently, we had a long-term summary of the COMFORT I study where it was presented that patients that start earlier with ruxolitinib, versus those that do not, fair better. The same was seen a few months ago in another controlled prospective randomized study where ruxolitinib was compared to the best available therapy. In both studies, survival benefit is evident if you start ruxolitinib earlier. That means that we should not be waiting in everyday practice for patients to really be in bad shape. If the patient has intermediate- or high-risk disease, one should be looking at the spleen or symptoms. If those are present, there is no reason to wait with the therapy. If the patient is suffering from symptomatic splenomegaly or general symptoms, that is, for me, a very good indication to start out with ruxolitinib. Because, evidence suggests that with earlier intervention in patients that suffer from the disease signs and symptoms, we not only control those symptoms but make them live longer. The question is whether the early intervention with ruxolitinib in patients that do not even have an enlarged spleen or symptoms would make sense to prolong their life. This is a real question. It is being studied in a prospective randomized study in Europe, as we speak. Patients who have low-risk disease without any problems at all are being randomized in a blinded way between low-dose ruxolitinib and a watch-and-wait approach, which is still standard practice here in the United States to see whether early intervention will make a difference. So, prevention of the symptoms and prevention of the spleen enlargement will make an impact on the survival of the patients.

Transcript Edited for Clarity
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Transcript:

Srdan Verstovsek, MD, PhD:
Within the myelofibrosis patients, we usually have 4 types of patients based on the prognostications of their longevity. The low-risk patients have an average survival of 11 years, the intermediate group of patients have about 4 to 8 years, and then the high-risk patients have 2 years. Ruxolitinib is indicated in the United States for patients who have an intermediate- or high-risk of dying. This is very good to identify if we can, if you know how to using the IPSS, and also to really look whether the patient suffers from what ruxolitinib is good for—progressive splenomegaly. That is, systemic symptoms that bother patients and decrease the quality of life. Within these groups of patients, intermediate- and high-risk ruxolitinib is certainly a very good choice. It will, in a great majority of the patients, control the signs and symptoms, and eventually make people live longer.

Daniel J. DeAngelo, MD, PhD: The optimal timing to initiate a JAK inhibitor or ruxolitinib, which is the only approved agent at this point, is unclear. The COMFORT-I and COMFORT-II studies looked at patients with more advanced disease. These were randomized studies either to placebo or to the best available therapy, both showing an improvement, not only in terms of response, but in terms of quality of life as well as survival to those patients who were randomized to the ruxolitinib arm.

Now, the timing of therapy is in question. Should this therapy be used earlier? Should this therapy be used in patients with lower risk disease? That’s just unclear. What I can tell you is in my clinical practice, I look at the prognostic scoring system. I evaluate a patient based on the IWG [scoring system] at the time of diagnosis, and I follow the dynamic score throughout to try and help me assess the time to intervene. But, I use my clinical acumen, such as, is this patient’s spleen size rapidly growing? Why is that important? Because patients, at least in the COMFORT-I and COMFORT-II studies, typically saw roughly a 50% reduction in the size of their spleen. If you wait too long when the spleen is extremely large, you’re just not going to see as huge of a benefit. So, earlier intervention in that particular case may be important. When a patient has constitutional symptoms, that is a second clinical sign of progression. Patients who are having trouble sleeping at night, for example, because of fevers, night sweats or troubled by pruritus, these are times when intervention may really improve the quality of life. Fatigue is another one. Patients can have really dramatic fatigue, leading to inability to get through the day, inability to complete work. And I found that intervention in these patients can be really a quality of life improvement or disease-modifying improvement in their outcome, and really has dramatically impacted the improvement in their well-being.

Srdan Verstovsek, MD, PhD: The evidence that we have about ruxolitinib use in myelofibrosis comes from clinical studies. And recently, we had a long-term summary of the COMFORT I study where it was presented that patients that start earlier with ruxolitinib, versus those that do not, fair better. The same was seen a few months ago in another controlled prospective randomized study where ruxolitinib was compared to the best available therapy. In both studies, survival benefit is evident if you start ruxolitinib earlier. That means that we should not be waiting in everyday practice for patients to really be in bad shape. If the patient has intermediate- or high-risk disease, one should be looking at the spleen or symptoms. If those are present, there is no reason to wait with the therapy. If the patient is suffering from symptomatic splenomegaly or general symptoms, that is, for me, a very good indication to start out with ruxolitinib. Because, evidence suggests that with earlier intervention in patients that suffer from the disease signs and symptoms, we not only control those symptoms but make them live longer. The question is whether the early intervention with ruxolitinib in patients that do not even have an enlarged spleen or symptoms would make sense to prolong their life. This is a real question. It is being studied in a prospective randomized study in Europe, as we speak. Patients who have low-risk disease without any problems at all are being randomized in a blinded way between low-dose ruxolitinib and a watch-and-wait approach, which is still standard practice here in the United States to see whether early intervention will make a difference. So, prevention of the symptoms and prevention of the spleen enlargement will make an impact on the survival of the patients.

Transcript Edited for Clarity
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