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When to Initiate Therapy 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: Tuesday, Nov 15, 2016


Transcript:

Daniel J. DeAngelo, MD, PhD:
There are a limited number of treatment options for patients with myelofibrosis. Fortunately, many patients have indolent disease. That means they’re asymptomatic. They’re not having any constitutional symptoms, their weight’s stable, their spleen is minimally or modestly enlarged but not causing any problems, and most of these patients can be watched. If you go to the prognostic scoring systems, these would be patients who would fall into the low-risk or the low intermediate-risk group. And some of their disease may be stable for years to a decade or so.

There are those patients, however, who have more proliferative nature of their disease. That means their spleen is rapidly growing, they have higher circulating blasts, and they’re more anemic. They’re having symptoms from their disease, and these patients really should initiate some form of therapy. Historically, at least in the United States, therapy was very limited. Therapy included transfusions, growth factors, lenalidomide for some patients with 5q abnormalities—which is rare—and hydroxyurea to suppress or decrease the spleen size. Now with JAK2 inhibitors, specifically ruxolitinib, initiation of therapy [can happen] not just in high-risk patients, but also in patients with symptomatic splenomegaly or patients with troubling constitutional symptoms. Those are the two key issues for which I initiate therapy in my patients.

And, in the context of evaluating the patient, is the patient a transplant candidate or not? Transplantation is probably the only curative modality. Although this is a disease of older folks, in a young patient with advanced myelofibrosis, an appropriate referral for a transplant consultation should be done early to really assess the timing. That does not mean that the patient shouldn’t be started on a therapeutic option, such as ruxolitinib, in between, but just so that the transplant team can assess the patient’s validity for transplant and whether or not a donor can be identified.

Kim-Hien T. Dao, DO, PhD: For low-risk patients, the current standard of care is to monitor their blood counts on a regular basis, monitor their symptoms, and also try to improve their quality of life. And right now, we don’t have effective therapies to do that, but it’s also individualized. So, for example, if a patient is in a low-risk category but has increasing splenomegaly, that patient might benefit from using hydroxyurea or ruxolitinib to improve their symptoms from the splenomegaly.

In low-risk myelofibrosis patients, sometimes this group has to be individualized in terms of management and treatment because they don’t have all the high-risk characteristics of myelofibrosis. But some of them will have severe symptoms that are quality-of-life affecting. And so, I think a provider needs to consider their symptoms, use some of the tools that evaluate their symptom burden, and also consider the impact on their quality of life. Because a patient may not have high-risk features or features that warrant treatment, but their symptoms may be affecting their ability to function and work. So, these are considerations that we should evaluate in order to properly manage and treat these patients.

Srdan Verstovsek, MD, PhD: A reason to implement therapies in myelofibrosis needs to be there. And traditionally, there are three reasons why to treat patients: progressive symptomatic splenomegaly, progressive systemic symptoms, or significant anemia. As you see, that does not include assessment of a risk of dying because we did not have a therapy so far that would be prolonging life of the patients. Therefore, the primary reason for prognostication is usually to assess when to refer patients for the transplant. Going back to the standard look at the patients, whether there are progressive splenomegaly symptoms and the anemia, if this progressive splenomegaly is evident or systemic symptoms develop, that would be a commonsense reason to implement therapy to counteract that, and that would be a JAK inhibitor, ruxolitinib.

Progressive anemia or pancytopenia—lowering of the blood cell count—usually do not respond to therapy with ruxolitinib. In fact, ruxolitinib, by its mechanism of action—which is inhibition of the JAK/STAT pathway, known for normal blood cell production—therapy with ruxolitinib may lead to a suppression of the blood cell count and cause anemia. So, even if you assess the risk of dying of the patients with the International Prognostic Scoring System, and say this patient has intermediate- and high-risk disease, if the only problem is the anemia, that should be treated with alternative therapies rather than ruxolitinib. On the other hand, regardless of the risk of assessment of dying, if there is a progressive spleen that is causing symptoms or progressive systemic symptoms that cause problems, that is a good reason to start therapy with ruxolitinib.

Transcript Edited for Clarity
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Transcript:

Daniel J. DeAngelo, MD, PhD:
There are a limited number of treatment options for patients with myelofibrosis. Fortunately, many patients have indolent disease. That means they’re asymptomatic. They’re not having any constitutional symptoms, their weight’s stable, their spleen is minimally or modestly enlarged but not causing any problems, and most of these patients can be watched. If you go to the prognostic scoring systems, these would be patients who would fall into the low-risk or the low intermediate-risk group. And some of their disease may be stable for years to a decade or so.

There are those patients, however, who have more proliferative nature of their disease. That means their spleen is rapidly growing, they have higher circulating blasts, and they’re more anemic. They’re having symptoms from their disease, and these patients really should initiate some form of therapy. Historically, at least in the United States, therapy was very limited. Therapy included transfusions, growth factors, lenalidomide for some patients with 5q abnormalities—which is rare—and hydroxyurea to suppress or decrease the spleen size. Now with JAK2 inhibitors, specifically ruxolitinib, initiation of therapy [can happen] not just in high-risk patients, but also in patients with symptomatic splenomegaly or patients with troubling constitutional symptoms. Those are the two key issues for which I initiate therapy in my patients.

And, in the context of evaluating the patient, is the patient a transplant candidate or not? Transplantation is probably the only curative modality. Although this is a disease of older folks, in a young patient with advanced myelofibrosis, an appropriate referral for a transplant consultation should be done early to really assess the timing. That does not mean that the patient shouldn’t be started on a therapeutic option, such as ruxolitinib, in between, but just so that the transplant team can assess the patient’s validity for transplant and whether or not a donor can be identified.

Kim-Hien T. Dao, DO, PhD: For low-risk patients, the current standard of care is to monitor their blood counts on a regular basis, monitor their symptoms, and also try to improve their quality of life. And right now, we don’t have effective therapies to do that, but it’s also individualized. So, for example, if a patient is in a low-risk category but has increasing splenomegaly, that patient might benefit from using hydroxyurea or ruxolitinib to improve their symptoms from the splenomegaly.

In low-risk myelofibrosis patients, sometimes this group has to be individualized in terms of management and treatment because they don’t have all the high-risk characteristics of myelofibrosis. But some of them will have severe symptoms that are quality-of-life affecting. And so, I think a provider needs to consider their symptoms, use some of the tools that evaluate their symptom burden, and also consider the impact on their quality of life. Because a patient may not have high-risk features or features that warrant treatment, but their symptoms may be affecting their ability to function and work. So, these are considerations that we should evaluate in order to properly manage and treat these patients.

Srdan Verstovsek, MD, PhD: A reason to implement therapies in myelofibrosis needs to be there. And traditionally, there are three reasons why to treat patients: progressive symptomatic splenomegaly, progressive systemic symptoms, or significant anemia. As you see, that does not include assessment of a risk of dying because we did not have a therapy so far that would be prolonging life of the patients. Therefore, the primary reason for prognostication is usually to assess when to refer patients for the transplant. Going back to the standard look at the patients, whether there are progressive splenomegaly symptoms and the anemia, if this progressive splenomegaly is evident or systemic symptoms develop, that would be a commonsense reason to implement therapy to counteract that, and that would be a JAK inhibitor, ruxolitinib.

Progressive anemia or pancytopenia—lowering of the blood cell count—usually do not respond to therapy with ruxolitinib. In fact, ruxolitinib, by its mechanism of action—which is inhibition of the JAK/STAT pathway, known for normal blood cell production—therapy with ruxolitinib may lead to a suppression of the blood cell count and cause anemia. So, even if you assess the risk of dying of the patients with the International Prognostic Scoring System, and say this patient has intermediate- and high-risk disease, if the only problem is the anemia, that should be treated with alternative therapies rather than ruxolitinib. On the other hand, regardless of the risk of assessment of dying, if there is a progressive spleen that is causing symptoms or progressive systemic symptoms that cause problems, that is a good reason to start therapy with ruxolitinib.

Transcript Edited for Clarity
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