Monitoring Disease Response or Progression in MF

Ruben Mesa, MD, FACP: Jamile, what’s the best approach for monitoring these patients’ response or progression?

Jamile Shammo, MD, FASCP, FACP: It’s interesting that when you think about response, it has to do with the goals of starting someone on JAK inhibition. Most of the time, you’re trying to control symptoms; you’re trying to reduce spleen size. For me, it ties into the time frame: How long do I want to, and when do I want to, evaluate response? Often, I see people giving up on a particular treatment a little too soon. It’s very important to assess response at certain points in time. To me, the initial assessment, aside from managing for toxicity, is done at 3 months. For the first time, 3 months would be very reasonable. While you’re examining the patient, every time you see them in the clinic—it would be very reasonable to assess the spleen at that time.

Equally important is to assess the symptoms while you’re going through this, to see how they’re feeling. That’s when the MPN10 [Myeloproliferative Neoplasm Symptom Assessment Form] becomes handy. At baseline, you do this; when evaluating the spleen size, another MPN10 becomes important. In the COMFORT I and II trials—which I know we’re going to be talking about—at 6 months, this is 1 of the primary end points that was evaluated. That would be a very reasonable end point to look at. It’s very important to explore a reasonable time frame to assess the efficacy of a particular agent. In my clinic [Rush University Medical Center], that’s what I typically do. If you’re looking at a clinical trial, obviously it’s a different point altogether because you’re looking at bone marrow, degree of fibrosis, blasts, etc. In clinical practice, that’s an entirely different piece. It’s 2 items: tolerability of the drug symptoms and spleen size.

Ruben Mesa, MD, FACP: That’s very helpful. Things continue to evolve. All those are important end points and things for us to monitor. It’s interesting. We just did an analysis—Srdan and I were involved—with momelotinib, looking at the issue of anemia and whether improving anemia matters. We think it certainly can matter in terms of symptomatic improvement and oxygen-carrying capacity. There’s a presentation at this year’s ASCO [American Society of Clinical Oncology Annual Meeting], an analysis that the achievement of transfusion independence was associated with improved overall survival in patients treated with momelotinib. In particular, it’s about the SIMPLIFY-1 study, which was the up-front study. We’re excited about that. What does that mean? Is it because the anemia is better? Is it that the mechanism of improving anemia—we believe—is inhibition of ACVR1? Perhaps there’s a decrease in hepcidin, a decrease in inflammation to drive prolong survival. We don’t know.

Increasingly, we’re seeing that there’s a strong story about survival involving with myelofibrosis. There are data with ruxolitinib, data with fedratinib potentially being presented at this year’s meetings. There are data with momelotinib. There have been data suggesting a middle stat. They have an impact. It’s all interesting. Srdan, 1 area people have asked me about is if we could monitor for response or progression, repeating the next-generation sequencing [NGS] panel. Do you view that as a change in a favorable or a negative direction as it relates to the NGS panel? Do you factor that into your decision-making yet?

Srdan Verstovsek, MD, PhD: This is the extension of the discussion with the anemia, because the anemia is the major leading cause for stopping ruxolitinib. It appears in the analysis; you’ll have difficulties in management of patients with anemia. That shortcut is what you can do. That will act as a shortcut and better your ability to control signs and symptoms if you must stop the JAK inhibition therapy. That will lead to shorter survival. I’m very happy to see an NCCN [National Comprehensive Cancer Network] Guideline, an addition, a possibility of giving luspatercept to counteract the anemia. There’s also the 2 drugs together: whatever JAK inhibitors you combine with the anemia drug that would prolong the durability of overall benefit and make people live longer even more than with the JAK inhibitor alone. That’s a good 1, but biologically, what also contributes to stopping ruxolitinib is the genetic complexity of the patients you treat. The genetic complexity leads you to worry about progression to leukemia or progression of the myelofibrosis signs and symptoms. Also, in terms of losing that response—reports show that patients that have a genetic complexity—meaning more mutations on top of drug mutations…not to go to their names, but just to give you a sense of what I’m saying, these patients do have a chance to respond, but it’s not going to last that long.

The implication is that you should encourage patients to explore the transplant sooner rather than later and not to depend on the JAK inhibition—prolonging their life if they have genetic complexity. Therefore, there’s practical utility of testing for NGS at the beginning of a JAK2 inhibition. You would even, during the therapy, see if there’s clonal evolution in the patients because the acquisition of mutations can happen throughout the lives of the patients. That usually also contributes to the loss of response. We’re not there yet. Perhaps I would have that information—NGS—at the beginning of JAK2 inhibition therapy, but not periodically. It’s costly, and it’s really less applicable to everyday practice, but certainly we’re getting there. The genetic complexity must be accounted for in your discussion with the patients of their expectations, of what we can achieve with the JAK inhibitor.

Ruben Mesa, MD, FACP: That’s very helpful. We’re monitoring patients. We’re checking spleen symptoms, potentially anemia, and other things under investigation, such as NGS. Jamile, in your practice, what are the main triggers for you to either change medical therapies or send them to your transplants?

Jamile Shammo, MD, FASCP, FACP: If I feel like I’ve given the drug a fair chance and there’s no meaningful response to the patient or if the patient is having side effects, I will change treatments. Srdan already mentioned anemia; you must dose reduce the drug, unfortunately. That results in loss of spleen response. You’re stuck because if you increase the dose, you have cytopenias. If you don’t do this, then the spleen will get larger. It’s a dilemma. I suppose that would be 1 situation where you’d say, “I might consider switching to an alternative medication.” Meanwhile, you may want to evaluate or consider sending the patient to transplant. Having said that, my patients who had intermediate-2 disease get evaluated for transplant early on, while I’m sending authorization for ruxolitinib or JAK inhibitors. They’ll see if they can get a transplant at the same time. Loss of efficacy, lack of tolerability, intolerable adverse effects—that would be what would drive me to either switch or stop, but I can’t overemphasize that you need to give it sufficient time. You need to ask yourself, “Have I given it enough time? Have I given a sufficiently effective dose?” A lot of times, people may be underdosing patients and and then giving up too early.

Transcript Edited for Clarity