Patient Scenario 1: A 72-Year-Old Man With Primary Myelofibrosis


Moving on to review the first patient scenario of primary myelofibrosis, panelists elucidate the decisionmaking process when selecting JAK inhibitor therapy.


John O. Mascarenhas, MD: In this next segment, we’re talking about myelofibrosis treatment, it’s going to be a case-based discussion, this is patient case No. 1. This is a 72-year-old gentleman who presents with a diagnosis of high-risk primary myelofibrosis, we’ll say it’s JAK2 mutated, ASXL1 mutated, large spleen, and high symptom burden. Platelets are 145,000, and the hemoglobin is a robust 14.1 [g/dL], highlighting the idea that not everyone presents with significant anemia. This gentleman is coming to you, first visit. What are your thought processes in an older gentleman, obviously symptomatic, big spleen, and pretty good blood counts?

Gabriela S. Hobbs, MD: Based on what we have been discussing, the first thing I do for a patient like this is to risk stratify. We havea lot of the information we need to do risk stratification with the MIPS [Mutation-Enhanced International Prognostic Score System] model because we have the JAK2 mutation as well as the ASXL1. I would also want to know if he has circulating blasts, and what the bone marrow showed in terms of fibrosis, etc. Assuming this is a higher-risk patient, along with our discussion about treatment, there’s also a discussion about referral to a transplant soon. Even though the blood counts don’t look that terrible, the hemoglobin, like you said, is robust, and it’s possible this patient may experience lots of benefit from a JAK inhibitor, this is somebody who makes us concerned with that ASXL1 mutation. Then short term, right in front of me, it sounds like the patient is symptomatic and has splenomegaly. I think he would be a good candidate for ruxolitinib initiation, whether that be by itself or if there’s a clinical trial available.

This patient highlights one of the challenges of taking care of patients with myelofibrosis, where you may see somebody who up front looks like they’re high risk, but potentially is somebody who you start on ruxolitinib, and all of a sudden, you make them feel wonderful. Then you have to have this discussion of, “Even if you feel great, we know that outcomes after ruxolitinib, aren’t that great. A transplant is still where we want to get you.” Those are discussions that can take many visits until we finally agree to when the transplant needs to happen.

John O. Mascarenhas, MD: Excellent. In this patient, Kristen, with a pretty good hemoglobin platelet count, what would be your drug of choice?

Kristen M. Pettit, MD: I think it’ll probably evolve over time. We’re fortunate to have 3 approved JAK inhibitors now, and as we had mentioned previously, potentially a fourth coming with momelotinib. In somebody with this robust of blood counts to start with, my first choice is usually ruxolitinib, given the long-term data we have with that, both as far as safety and efficacy, and that most of the data with some of the other agents, like fedratinib, are in the second-line setting. We have data going from ruxolitinib to fedratinib, but not necessarily so much the other way around. Generally, my first-line treatment option, unless there’s a reason not to, such as cytopenias, is usually ruxolitinib, unless a clinical trial is available to the patient, like for example, an upfront trial of a JAK inhibitor plus a novel agent. Then that would be my first approach, but as standard of care, ruxolitinib is still my go-to.

John O. Mascarenhas, MD: With a platelet count of 145,000, how would you dose ruxolitinib?

Kristen M. Pettit, MD: I take this on a case-by-case basis. According to the package insert, we’re dosing based on starting platelet count and then dose-reducing based on platelet count changes down the road. There are a few other things to consider as well; he’s 72 years old, so he’s a little on the older side, and we don’t know much about his comorbidities or performance status or anything like that. I would start at an intermediate dose, probably around 10 mg twice daily. The most important thing is to follow the blood counts over time, and if blood counts stay stable on an intermediate to lowish dose, then to dose escalate quickly, not to be stuck at a relatively low dose. Whereas the opposite is also true, if we were to start a higher dose, then I would be very cautious to watch for cytopenias. The platelet count usually does drop relatively quickly when you start ruxolitinib. I’d be careful to monitor over those first 3, 4, 5 weeks to watch for a platelet count decrease and dose reduce if we need to.

John O. Mascarenhas, MD: Andrew, is there any value to delaying therapy? Do you use up your benefit with ruxolitinib if you use it too early in the disease course, or is there additional benefit to using it earlier rather than to allow patients to get sicker before you start using a JAK inhibitor?

Andrew T. Kuykendall, MD: No, we don’t have any evidence to this point to suggest that starting ruxolitinib induces any kind of clinical progression or resistance mechanisms that occur there. We have good long-term data that patients with polycythemia vera are able to stay on ruxolitinib for a long time with good disease control. We don’t see that it induces any unnecessary clonal evolution. Alternatively, any trial that’s looked at earlier stage patients, so intermediate or lower risk patients, suggests that those patients have a better chance of getting a benefit from ruxolitinib than patients who have intermediate to high risk or more complex disease. In reality, it’s probably because it’s a more JAK2-driven disease, or JAK/STAT-driven disease. Early in the disease process, you’re more likely to get benefit with a JAK inhibitor rather than if you wait for the disease to progress. It’s usually not progressing because there’s more of a JAK mutation, it’s usually progressing because there are additional mutations that are not as responsive to a JAK inhibition approach. So, no reason to wait. If they have symptoms or splenomegaly or something you think could benefit from a JAK inhibitor, then we typically offer it up front.

That being said, as we’ve referenced earlier, if they don’t have anything you think would benefit from a JAK inhibitor approach, perhaps it is someone you could monitor for a bit. But I would say oftentimes patients underestimate the amount of symptoms they have at first presentation as well. So you’ll have patients who may not think they’re going to benefit from a JAK inhibitor until they’ve started it, or until maybe they were started and they come off of it, and you realize they had a far higher symptom burden than they previously appreciated. Which goes to Gabby’s point as well, of performing validated symptom scoring assessments as well in these patients, and utilizing something like the MPN-10 [myeloproliferative neoplasm 10-symptom assessment] in practice can be helpful to objectively measure a patient’s symptom burden and maybe uncover symptoms they didn’t realize they had.

John O. Mascarenhas, MD: There are recent retrospective analyses from the full COMFORT study suggesting that the duration from disease diagnosis to initiation of ruxolitinib matters. Patients who have a longer duration tend not to enjoy the full benefit of JAK inhibitor therapy in terms of usually worsening treatment-related cytopenias, the durability of the spleen response is usually lower, and the survival is lower. There is probably benefit, I would agree, in not waiting for that perfect moment to start the therapy, but probably starting it sooner rather than later to maximize the benefits.

Transcript edited for clarity.

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