Practical Use of Targeted Therapy in Patients With Myelofibrosis
Focusing on real-world management of myelofibrosis, experts share insight on how they would select and sequence therapies within the current paradigm.
Transcript:
Pankit Vachhani, MD: Dr Komrokji, these 3 JAK inhibitors which are available right now for use, my question to you is, how do you use and sequence these drugs in particular in frontline space? How do you use them and do some symptoms play a role or what features guide your decision making?
Rami S. Komrokji, MD:Absolutely. Obviously, it's a good thing to have more than one option. I try to keep things simple in my mind. As we mentioned, the first step I risk assess the patients. If they're on the higher risk, potentially eligible for transplant, I bring that discussion and may refer them to my colleagues in the transplant to have that discussion and then decide, do they need a treatment or not. And obviously that's based mostly on symptoms, and the symptoms as we said could be either constitutional, cytopenia or a combination. If patients are just cytopenic, anemic from both cytopenic with no splenomegaly and constitutional symptoms so far we don't have much role for the JAK2 inhibitors. Maybe as you did with the pacritinib and momelotinib, down the road they may have some role there but currently active patients' cytopenia’s would worsen with those treatments and we unfortunately that's an area of unmet need. We use you ASA, [acetaminophen] danazol medications with some limited success. That could be an area of different topic. But most of the patients do have constitutional symptoms and splenomegaly. Plus, minus cytopenia that may dictate your choice. If patients are symptomatic, those are the patient’s candidates for JAK2 inhibitors and the NCCN [National Comprehensive Cancer Network] guidelines are very reasonable. For patients that we call proliferative, and they don't have profound cytopenia, I think ruxolitinib is still going to be our backbone treatment up front for many of those patients. It has in almost a decade data, people have used it, they might know how to manage the toxicity and its pretty effective treatment. Obviously, you expect some anemia and cytopenia with it, those are just for that. But it has been our main treatment and it's effective and its role is going to continue in patients with proliferative disease. Fedratinib is listed in that setting as an option. Obviously, you know, with probably less data and people being used to ruxolitinib, rarely fedratinib as a first line would offer advantage over ruxolitinib because it's probably for the same proliferative group. Now the NCCN guidelines currently incorporated, you know, what you discussed with the data with pucritinib in their guidelines saying that if patients have thrombocytopenia platelets less than 50 by the package insert- as you mentioned, the study was even below less than 100, that pacritinib is going to be the first choice up front. And the reason for that, although ruxolitinib has been used in settings of platelets 50 and above, many times it's hard to get to a meaningful dose that will lead to reduction in discipline in that setting because of the cytopenia’s. Pacritinib is now an upfront choice for patients with thrombocytopenia. Ruxolitinib fedratinib for the proliferative. Maybe ruxolitinib still is going to be the main pacritinib for patients with thrombocytopenia. In the second line, I think all of those could be an option and as you mentioned, we have some data on activity sequencing those JAK2 inhibitors. Fedratinib could be a second line after ruxolitinib failure in patients that are proliferative. Pacritinib in the NCCN guidelines is listed as second line regardless of the platelet counts as we mentioned. So that's how I think of it, but obviously all those agents have their unique safety profile and need monitoring and maybe you can highlight how do you do that in your practice. How do you monitor those patients? What are the adverse events you look at and do you add other agents and probably like when do you make the shift? That's probably an area of debate now. Maybe you can tell us a little bit more how you do it.
Pankit Vachhani, MD: On anyone who goes on a JAK inhibitor therapy, any of the 3 that we talked about before, I like to get labs and by that I mean CPC even a CMP ideally on a 2 to 4 week basis at least initially when I'm beginning the JAK inhibitor therapy. Subsequently that it could be every maybe every month to maybe even every 3 or 4 month basis to monitor mostly for cytopenia’s but even otherwise. I do like to make sure that I have a good assessment of the spleen and baseline and subsequently. If I can do that with my physical examination skills then and that's great. But if I'm not comfortable or I'm not sure, then I do make sure to get an ultrasound or a CT scan at least and baseline then subsequently it would depend on the scenario. And the third piece over here is symptom burden assessment, which I do at baseline using one of the forms. For example, we can access that from the NCCN guidelines and subsequent to that I use it on an as required basis when I feel that maybe that the disease course is changing. You brought it up, Dr Komrokji about what counts as a first line JAK inhibitor failure or ruxolitinib failure. This has been an area where we have had a few different struggles in terms of understanding what exactly constitutes that. Many of us would agree that if we just don't see a response with the JAK inhibitor after we begin, that would be counted as a failure. But an additional area might be a scenario where for example, a patient achieved a nice spleen response and subsequently lost that response or progress to an accelerated phase or a blast phase, meaning more than 10 to 20% plus. That would be an area where the first line treatment has failed. Yet another area would be ruxolitinib treatment or the JAK inhibitor treatment leading to adverse events or toxicities which are just unacceptable to the patient at least after 4 weeks of treatment. Primarily, this comes up in the form of cytopenia’s like anemia or thrombocytopenia. The presence of symptoms to some extent even on JAK inhibitor therapy is to be expected, but if some symptoms go away and the new emergence of let's say very specific MF related symptoms like night sweats may also be reflective of a failure scenario. Now, the way I think about adding, changing, or sequencing therapy all in addition to everything that Dr Komrokji mentioned is that if I have a patient on let's say ruxolitinib my frontline JAK inhibitor therapy of choice in the vast majority of our patients and if the primary issue is anemia only, then I try to incorporate an anemia directed therapy there that could be an edit reporting stimulating agent. Maybe in those with a high equal level that might be danazol or sometimes one of these medications or very occasionally steroids. These agencies, additive agents don't have a substantial improvement IM in terms of the hemoglobin improvement, but they do have 1 to 2 grams, occasionally more of hemoglobin improvement or at least stabilization in many patients. If the primary concern is thrombocytopenia and this is much in agreement with what Dr Komrokji said that if we cannot even sustain our patients on a stable dose of let's say ruxolitinib 10 mg twice a day, then there my choice too would be pacritinib. But we want to make sure that if we are using drugs, we should at least use ruxolitinib 10 mg twice daily. That would be the idea. As Dr Komrokji mentioned pacritinib can be used even in those who have platelets more than 50,000 and this would be a point especially true in second line scenario. Fedratinib is an agent which too can be used in second line setting and I would tend to use it only in those who were very proliferative features after ruxolitinib. Let's not forget clinical trials. These are the backbones at many places, and if possible, clinical trial enrollment would be great. We talked about cytopenia’s as being one of the major adverse events that we should keep in mind and that is true. Platelet counts initially increase but subsequently decrease in the 4 to 12 week time period after starting a JAK inhibitor therapy and this is especially true for ruxolitinib. Knowing that is of help. Hemoglobin levels may decrease by 1.5 grams to 2 grams per deciliter, but subsequently they stabilize and improve at a baseline that's just below where the patients had started in the first few weeks after you begin. Knowing these and supporting the cytopenia’s is very important with some of the addictive drugs like you mentioned or maybe even with appropriate dose reductions as and when required. The second set of adverse events that comes up frequently is nausea, vomiting or diarrhea. The GI adverse events and these are primarily seen with fedratinib or pacritinib which happen to be FLT3 inhibitors as well. An important point is to use prophylactic drugs, antiemetics or antidiarrheal agents like Imodium. I tend to send my patients home on these medications so that they have it ready whenever it this happens. And usually, these adverse events happen early on in the course. And then there are the rarer adverse events, but certainly the ones which are being seen for example like viral reactivation, shingles and so on and so forth. I try to make sure that my patients have had vaccination to that. Don't usually use acyclovir as a prophylactic drug, but should that episode of shingles for example happen, I try to keep my patients on a suppressive antiviral therapy subsequent to that.
Transcript edited for clarity.
