Emerging Agents for Myelofibrosis - Episode 5
Moshe Talpaz, MD: The NCCN guidelines are similar to the FDA approval line, which is that patients with intermediate risk 2—and I assume that we will discuss a little bit later what the prognostic models are in myelofibrosis—should be treated with the approved JAK2 inhibitor, with ruxolitinib. In some patients with anemia, there is good reason to try erythropoietin-based hormones, and in some male patients, a hormone such as danazol should be tried as well. The role of Revlimid can be of some help in some patients, and the role of steroids in symptom control is offered in some patients. In other words, there is 1 definitive treatment, which is ruxolitinib, but there are some options for symptom control, anemia control, that can help a small fraction of the patients.
The issue of bone marrow transplant in myelofibrosis is an important issue and to some extent still a research-based issue. Let me elaborate. There have been very few published studies on bone marrow transplant in myelofibrosis. And retrospective analysis has shown that the advantage of bone marrow transplant is present only for patients with high-risk myelofibrosis. However, recent work, some of it presented in this meeting, suggests that transplant provides survival advantage also to patients with earlier-stage disease. Because this issue of bone marrow transplant in myelofibrosis is still an uncertain issue, I will describe a little bit of my experience.
I send to transplant every patient who is under 50, and regretfully some young patients may have myelofibrosis. I always first try a JAK2 inhibitor because some patients can have a very long remission without taking any particular risk with a JAK2 inhibitor. We proceed with transplant in patients who failed JAK2 inhibitors and consider transplant for patients up to their early 70s. So we do consider transplant as one of the treatment options. Regretfully, we have to be aware that the outcome of bone marrow transplantation or stem cell transplantation in patients with myelofibrosis still has a lot of issues to address, issues of high incidence of relapse, graft failure, and overall mortality, which indicates that the treatment is still not optimal and there is a lot to be done to optimize this treatment.
Ruben Mesa, MD, FACP: Anemia is a common problem in myelofibrosis and one that we have struggled with. We have 1 FDA-approved therapy in myelofibrosis, which is ruxolitinib. It’s been a very beneficial therapy. It has improved survivals, splenomegaly, and symptoms. But it has not had a significant impact on improving anemia. There is a range of things we can use off label that have some benefit. My group has been involved with many trials over the years with the immunomodulatory drugs, all of which have some activity—thalidomide, lenalidomide, pomalidomide—all have demonstrated activity. Low-dose thalidomide and prednisone is probably the most broadly used combination globally for difficult anemia, especially when transfusion is required in individuals with myelofibrosis.
Erythropoietin-stimulating agents sometimes can be beneficial, either alone or sometimes added to ruxolitinib if patients have that as a baseline. I found that’s particularly helpful if individuals have chronic renal insufficiency or have a suboptimal baseline serum erythropoietin level. Because you’re really giving a supplemental hormone, the baseline level of that hormone in the blood is important. If they already have a very robust erythropoietin response, giving them additional erythropoietin is less likely to be beneficial.
Finally, androgens. Androgens for many years, many decades, have been reported to have activity in patients with myelofibrosis with anemia. That continues to be the case. Our group performed a trial of danazol along with ruxolitinib and demonstrated that it is active. Not dramatically active, but it can help. It can help to alleviate some of the drug-emergent anemia with ruxolitinib as well as help with some baseline amount of anemia at 600 mg of danazol a day.
Cytoreductive therapies of hydroxyurea and interferon both potentially have a role in myelofibrosis. First, there are the individuals who truly need a cytoreduction, either because of thrombocytosis or extreme leukocytosis, those who have a white count of 75,000, 100,000, etc. There are times that if they’re on JAK inhibition, the JAK inhibition is insufficient to really control those extremes of elevated counts. I think that remains the primary role of hydroxyurea, of supplemental cytoreduction. Now, whether interferon plays an additional role—it may. There certainly are early cases with myelofibrosis, before they have very advanced disease, that there may be some benefit. And I have been involved with clinical trials looking at those agents. There is some benefit to using that in early disease to try to avoid progression. In addition, at this year’s American Society of Hematology meeting, there was an updated presentation from our colleagues in France looking at the combination of ruxolitinib and pegylated interferon in patients with myelofibrosis that showed both safety and tolerability as well as some evidence of efficacy by the combination. I think it is premature to call it a regimen that we fully know what the indication is for that combination, but further studies are warranted.