Advances in the Treatment of Myelofibrosis - Episode 6
Circumstances for which hydroxyurea, ruxolitinib, or other therapy may be selected to treat newly diagnosed myelofibrosis.
John Mascarenhas, MD: Maybe we’ll go backward for a second and talk about a drug that used to be used much more frequently than it’s used today, but still maybe has a role. I’ll start with Srdan. Hydroxyurea, we use it in ET [essential thrombocythemia] and PV [polycythemia vera] pretty frequently. I think less frequently in myelofibrosis. Are there any circumstances today, in 2021, where you would use hydroxyurea in an MF [myelofibrosis] patient?
Srdan Verstovsek, MD, PhD: There are still some clinical scenarios where it’s very useful. In earlier stage patients that present with high platelets or high white cell count where you need cytoreduction; hydroxyurea is a very good cytoreductive therapy. It is not going to provide that symptomatic relief as JAK [Janus kinase] inhibitors can do, so if the symptoms are not troublesome, but you need to reduce thrombotic risk of too many cells in the circulation, like early stage myelofibrosis or prefibrotic myelofibrosis, I will be using hydroxyurea. Otherwise, you can say perhaps there is also a role in the patients that are not optimally responding to a JAK inhibitor. If there are still too many white cells or too many platelets, while you are using JAK inhibitors, you can add hydroxyurea to them and do a combination of the 2 drugs together. That’s not very common, but it’s 1 of many clinical scenarios.
John Mascarenhas, MD: You’ve built a career on evaluating novel drugs and clinical trials and now, of course, we have 2 approved JAK inhibitors, ruxolitinib [Jakafi] and fedratinib [Inrebic]. As you pointed out, there are still these niches for hydroxyurea and, of course, transplantation for those patients in which there’s a curative intent. But where does clinical trial fit in, in terms of assessing patients for novel therapies?
Srdan Verstovsek, MD, PhD: If you look at the spectrum of the patients in a frontline setting, we have a very big hole here in patients who have low platelets. If it’s just the frontline setting, if the platelets are above 50, you have 2 drugs as you said. We can argue about which 1 to use. Is it ruxolitinib or fedratinib? Which drug to use based on platelet numbers, is it between 50 and 100, 100 to 200? What’s the dose? But neither of these 2 are supposed to be given to patients with platelets below 50, so the frontline setting has a big hole. That’s about 10% to 15% of the patients you can’t help much. They typically have a low red blood cell count, they are not feeling well, maybe the spleen is not as big, but this is a cytopenic patient frontline setting that needs something new. Now, you also have a hole here in respect to the problems that you cover. JAK inhibitors cover the spleen and symptoms, but they may worsen the anemia. So in the frontline setting, what do we do about anemia? Anemia compromises the delivery of JAK inhibitors, so you need a drug for anemia. There are drugs that have been developed to be combined like luspatercept, for example, to be combined with JAK inhibitors in the frontline setting. Ideally, you want to have a combination that would enhance what the JAK inhibitors do, so more of the spleen and symptom control perhaps with some biological effect on the disease so that the durability of the response is much longer, progression-free survival, and overall survival extension is another goal. It’s an elusive goal so far, but that’s where we are heading. And, of course, then you have a second-line therapy of the JAK inhibitors.
John Mascarenhas, MD: Raajit, I’m going to ask you this specifically because you’ve done a lot of the work particularly more recently on the use of IMiDs [immunomodulatory drugs] in myelofibrosis. If you go backward, thalidomide [Thalomid] was initially evaluated in MF with some anemia responses and spleen responses, may have some issues with tolerability, and probably would be best used in combination with steroids. What about lenalidomide [Revlimid], a drug that is often used in myeloma?
Raajit K. Rampal, MD, PhD: Lenalidomide certainly has some utility. I think really in specific niches as a single agent. In patients, for example, who have thrombocytosis but also have anemia, it’s oftentimes a really good fit for those patients. Although the reality with almost all of these types of drugs, not exclusive of IMiDs is that their anemia response hovers around the magic 30%. In some cases, the lenalidomide does have the favorable side effect of lowering platelets, but that of course is a limitation in using it routinely in clinical practice to treat anemia. There are, I think, only select patients where it really has clear utility as a single agent. It certainly has been combined and studied with ruxolitinib, Srdan’s group has done that work. It certainly can be utilized in that setting but again, it’s very much dependent on the patient’s hematologic profile as to whether or not it’s going to be tolerable.
John Mascarenhas, MD: What about combination thalidomide and ruxolitinib?
Raajit K. Rampal, MD, PhD: That’s something that Srdan and I have studied in recent times. I think that what we have seen and what is of interest to us is that there is an increase in the platelet count in many patients who are thrombocytopenic. The increases in platelet counts were observed many years ago when this drug was used as a single agent or in combination with prednisone. But that potentially can give one some utility petition, particularly with patients with somewhat lower platelet counts, because it will allow you to both increase the platelet count and thereby also increase the dosing of ruxolitinib for example, which of course is platelet-based dosing. There is certainly utility there in the setting of thrombocytopenia and to some degree anemia.
Transcript edited for clarity.