Pankit, you’re a member of the panel that’s on the NCCN [National Comprehensive Cancer Network]. They recently had some updates to the guidelines in treating myelofibrosis. Why don’t you share what a hematologist needs to know about some of the changes, or the adjustments that you made to the guidelines?

Absolutely. I will mention 2 of those. One is related to the point about ruxolitinib and fedratinib, which is that the NCCN Guidelines have made it more clear in terms of its language. If you had an inadequate response or you lost response to 1, then you could use the other, in cases of high-risk myelofibrosis. The biggest change that there has been compared with the NCCN Guidelines from 2020 is the addition of the luspatercept to the guidelines. Luspatercept, as you may know, was approved a couple of years ago for the treatment of anemia of patients with beta-thalassemia, as well as those with myelodysplastic syndromes, ringed sideroblasts, myelodysplastic syndromes, myeloproliferative neoplasms, and thrombocytosis.

Luspatercept is given as a skin injection once every 3 weeks. It was studied in a phase 2 trial that was previously reported, a trial that examined patients who were on ruxolitinib or who were not on ruxolitinib, who were transfusion dependent or not. Efficacy was seen in these different cohorts; it was somewhere in the range of 15% to 30%. It’s now added as a suggestion to use in those patients with myelofibrosis [MF] related–anemia and for patients with an underlying erythropoietin level of more than 500 IU/L. That’s an area where erythropoietin-stimulating agents are less likely to work. Of note is the phase 3 clinical trial looking at luspatercept vs placebo in patients with MF-related anemia while on JAK inhibitors and transfusion dependent; the phase 3 independent study is ongoing. That’s a big addition to the guidelines.

In the guidelines, it has been gratifying to see. The guidelines provide some framework for a practice that had been quite heterogeneous, particularly in the United States, where some utilized the last review article they read or the last board review they heard or an outdated chapter of the Ronald Hoffman textbook [

Hematology: Basic Principles and Practice

] to guide how they were treating folks. It has helped to bring it into greater alignment. With more therapies in development, its needs have been so important. According to those guidelines, you start people on the therapy. Then you monitor the patients for response and assess signs and symptoms of disease progression.

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Pankit Vachhani, MD, reviews recent changes to the NCCN Guidelines, highlighting the addition of luspatercept for the treatment of primary myelofibrosis. 

Recent Updates to NCCN Guidelines on MF Treatment

Srdan, as we’ve heard about the risk of premature death from myelofibrosis—it’s clearly a major concern, it’s clearly a burden these patients can face—how do you factor in these goals and the burden of disease as you try to come up with a treatment plan?

 We all agree on the aspect of prognostication as valuable, particularly for patients who are justified to go with the transplant as an option. Pankit already outlined the value of prognostication; we do NGS [next-generation sequencing], for example, to refine it better for patients who are intermediate-1, for whom we’re not sure whether they should go with the transplant. The main reason to prognosticate is to get the patients to do the transplant. If they have a life expectancy of less than 5 years, you should suggest the transplant. Otherwise, to extend that train of thought to practical points—do I need to prognosticate every patient I see? If the patient is 85 years old, what’s the value of all this testing? You’re going to go by the symptoms.

That’s what you’re asking me, Ruben: What’s the next fork? The first fork is the prognostication for those for whom the transplant is an option. It’s not really for everybody. If the patient is also high risk by the standard IPSS without the molecular findings, do you really need to do the molecular findings to recommend transplant? That’s another topic. The first fork is for transplant-eligible patients. The second is, what’s the problem with the patient? The symptoms come as No. 1. I really applaud your efforts and your team’s efforts to develop the MPN10 [Myeloproliferative Neoplasm Symptom Assessment Form], the questionnaire that’s now incorporated in NCCN [National Comprehensive Cancer Network] Guidelines. It should be used in every practice to objectify those symptoms. If the symptoms are judged to be—and you have this semiobjective way of looking at those answers—bothersome for the quality of life of the patients, go ahead and treat the patients for the symptoms, whether they’re lower risk or higher risk. If they’re symptomatic, that’s the next fork. Then you go with JAK inhibitors to counteract the quality-of-life issues, to improve those and decrease the symptomatic splenomegaly. We have 2 aspects of those symptoms, I’d say. One is related to general myelofibrosis systemic symptoms. The other is symptomatic splenomegaly.

In the treatment guidelines, there’s the JAK inhibition as a positional frontline therapy, but there are also a couple of caveats of being able to selectively utilize hydroxyurea or interferon or some other therapies. I know that there’s probably more heterogeneity, particularly in countries where JAK inhibitors are very difficult for a patient to afford, particularly if it’s a self-paid system. Where do you see those other therapies coming in for managing myelofibrosis?

The point about being able to afford or have access to JAK inhibition is important. I’ll tie that to a question about the assessment of symptoms, which is so important. Often, I get patients referred who have myelofibrosis, but they’re labeled as asymptomatic. How much time has anyone spent looking at the symptoms to truly understand how many symptoms they have? If someone has evidence of a myeloproliferative disease—perhaps early myelofibrosis—the goal is to control, to some extent, the counts and perhaps the splenomegaly that these patients are feeling on the exam. Maybe you’re not dealing with a lot of cytopenias. I’d see utilizing hydroxyurea to control myeloproliferative disease and splenomegaly in hematology for someone who may not have access to JAK inhibitors. The interferons have been utilized. Myelofibrosis is not the only MPN [myeloproliferative neoplasm] that has been treated as such. I’m an old-timer who—all of us are, except Pankit, perhaps—has used interferon in CML [chronic myelogenous leukemia], and it works. It takes a long time and involves a lot of pain, but with early stage myelofibrosis, it may actually be a reasonable choice for someone who doesn’t have access to this. I may even start to talk about anemia, but ultimately, this is a disease that’s characterized by progression. At some point, those patients will be experiencing symptoms and signs, and they will be requiring JAK inhibition. That’s my experience.

That’svery helpful. Srdan, we have fedratinib, which has been available to folks since September 2019. Many watching this perhaps haven’t had a chance to use fedratinib. What would you recommend to them in terms of which patient they should be considering for fedratinib? Should it be used in the front line or the second line? What situations should they look out for, in particular, when they don’t have a clinical trial as an alternative?

 First, it’s very gratifying to see that we finally have more than 1 proved medication for patients with myelofibrosis. Although it’s a JAK inhibitor, it’s not identical to ruxolitinib. When we look at the face value of the benefits, they appear to be similar, in terms of controlling the systemic symptoms and that symptomatic splenomegaly. It’s a valid option in the frontline setting, particularly for patients with the lower platelets. You remember that the dosing of ruxolitinib for patients with platelets below 100 per mm3 is very low. It’s 5 mg twice a day. You are supposed to go up on a dose—maybe you can—to 10 mg twice a day, but hardly anybody can go higher. Therefore, you don’t get that good spleen control, and durability is very short. Perhaps, in that case, there’s a role for fedratinib, with no dose adjustment based on the platelet numbers. The majority of my patients—and those coming as referrals—are exposed to fedratinib as a second-line choice. If I’m aware and correct, that’s also included in NCCN Guidelines as a possibility because there’s good evidence that fedratinib, for patients previously treated with ruxolitinib, can control the spleen symptoms, and there’s no resistance to it. It’s not a class resistance. If you fail 1, you won’t do well on the other line—that’s not true. There’s no acquisition of mutations or anything like that that would lead to the lack of a possibility of treating patients with another JAK inhibitor after the first month. Most of the time, we use fedratinib in the second-line setting, with good control of the spleen symptoms.

That’s a very important point. Because of the pandemic, although I’ve had many trials open for patients with myelofibrosis, traveling has been difficult for many. For second-line therapy, though I might normally consider a clinical trial, I’ve been able to treat patients. Some did telemedicine with fedratinib, and there was success. Overall, it’s well tolerated. We use GI [gastrointestinal] medicines and prophylaxis: some Imodium [loperamide], some Zofran [ondansetron]. Most people really don’t need them or don’t need them for very long. I prescribe them thiamine—over-the-counter thiamine, according to the black-box warning, in terms of trying to avoid a very small risk of Wernicke encephalopathy. But it’s fairly easy to use. I’ve seen some really nice responses in individuals who had lost their benefit for ruxolitinib, and we’ve regained control of splenomegaly symptoms. It has been helpful.

Key opinion leaders in the management of myeloproliferative neoplasms review factors to consider when selecting treatments for patients and highlight the role of fedratinib in the first- or second-line settings.

Therapeutic Decision-Making for Primary Myelofibrosis

® program on the updates and the management of myeloproliferative neoplasms. I’m Ruben Mesa. I am the executive director of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center. I’m joined by 3 wonderful MPN [myeloproliferative neoplasm] experts and good friends for this discussion today. First, I’m going to introduce Professor Jamile Shammo from Rush University in Chicago, Illinois. Welcome.

Next, we have Pankit Vachhani from the University of Alabama at Birmingham (UAB).

We also have my good friend and fellow Texan Dr Srdan Verstovsek.

We’re going to have a discussion, first about myelofibrosis, then about polycythemia vera. Patients with myelofibrosis are quite heterogenous. It’s amazing what a mix this disease can be for individuals. Jamile, why don’t you walk us through how we think about risk and burden for these patients with myelofibrosis?

Everybody would agree that risk assessment is so important to identify those who have low vs high risk. Anybody who’s taking care of those patients would have to be familiar with the prognostic scheme that looks at various clinical variables associated with overall survival. You have the IPSS [International Prognostic Symptom Score], you have the Dynamic International Prognostic Scoring System [DIPSS], and you have something called an enhanced prognostic scoring system. Those encompass variable clinical parameters that we all have to be familiar with, so you can concoct the score and say whether your patient is low risk or high risk. Clearly, high-risk patients must be considered for transplantation and those who have lower-risk disease—we can talk about the role of transplanting for this particular group. It’s extremely important because the survival rate for this group of patients varies. If you look at low-risk patients, the IPSS should be performed at diagnosis. You are looking at 11 years of overall survival vs the highest score possible, which is 2 years. That’s a huge difference if you look at the DIPSS Plus, which encompasses things like cytogenetics or platelet count. If there are poor cytogenetics, you’re looking at 15 years vs 2 years. That’s a huge difference. We need to become familiar with those prognostic schemes.

That’svery helpful. We know that some of the molecular markers are increasingly woven into some of these scores. Pankit, in your practice at UAB, you’re also on the NCCN [National Comprehensive Cancer Network] panel. Srdan and I had been on that group in the past. It rotated as things evolved. Where do you use those new NGS [next generation sequencing] panels? Where does NCCN suggest we do them for patients with myelofibrosis?

At present, we at UAB—and at most academic medical centers—use NGS panels at the time of diagnosis for patients who have myelofibrosis. With the typical risk-scoring stratification—IPSS, DIPSS, DIPSS Plus—that’s not incorporated into decision-making in the initial stats. However, we do get prognostic value out of those comprehensive NGS panels. For example, fine mutations like 

 mutations are high risk in nature for progression. This comes into play most when you’re dealing with patients with intermediate-1 risk myelofibrosis, when you’re wondering if you should send them to transplant early. That’s an additional piece of information that you can get to risk stratify. On the other hand, if you were using a DIPSS or an IPSS risk-scoring stratification, that would be crucial over there as well.

That’s very helpful. As I sit with patients, this discussion of risk and prognosis is important. It’s a very heterogeneous disease. Indeed, individuals can have very short- or long-lived disease. I’m also very mindful of the concept of their symptoms as part of the burden they face. Do they have splenomegaly? Do they have symptoms of splenomegaly? Many of the constitutional symptoms we can now question them about using the standardized questionnaires that my team—with many collaborators’ help—developed. We can determine whether that’s a baseline, how that evolves, and how that impacts therapy.

A panel of experts in myeloid malignancies begins with a discussion on risk assessment criteria, next-generation sequencing, and symptom burden questionnaires to assess prognosis for patients with myelofibrosis. 

Pankit Vachhani, MD

Articles

Recent Updates to NCCN Guidelines on MF Treatment

Therapeutic Decision-Making for Primary Myelofibrosis

Diagnosis and Prognosis of Primary Myelofibrosis