Rami Komrokji, MD: I have a couple of cases, and I’m interested in how you would manage those cases, putting into practice what we’ve been discussing. The first case is a 67-year-old gentleman who presented with splenomegaly, constitutional symptoms, borderline cytopenia, a hemoglobin of 9.5 g/dL, and a platelet count of 160,000 per μL. A bone marrow [biopsy] confirms myelofibrosis. What would you recommend for this patient as initial treatment?

Jeanne Palmer, MD: Did you say what the spleen was? I’m sorry.

Rami Komrokji, MD: He had splenomegaly on physical exam and constitutional symptoms.

Jeanne Palmer, MD: In a patient like this with splenomegaly and symptoms, especially with platelets well within the normal range, I think JAK inhibition. Starting with something like ruxolitinib is a good idea. In patients who are somewhat anemic, because we know that they can have a pretty significant anemia response, I’ve been starting them on a slightly lower [dose]. I base the starting dose on the hemoglobin rather than on the platelets necessarily. Sometimes that helps prevent them from really dropping.

If they have a huge spleen, the 20-mg twice-a-day dosing is much more beneficial for shrinking the spleen. But if we aren’t trying to rapidly shrink that spleen, I’ll often use a bit of a lower dose so I can potentially avoid some of that significant anemia. I see a number of patients who come in who were just diagnosed with myelofibrosis, feel fine, and don’t have any symptoms, and they’re put on a JAK inhibitor just because you treat them with ruxolitinib. It’s important to emphasize that the symptoms and the spleen prompt treatment more than the diagnosis by itself.

Rami Komrokji, MD: Absolutely.

Ruben Mesa, MD: [I have] a slightly alternative view as it relates to dose. This is something that Srdan Verstovsek, MD, PhD, [of The University of Texas MD Anderson Cancer Center] and I have discussed many times. When we did the studies with COMFORT-I [clinical trial (NCT05410470)] in particular, the goal was a rapid response because it was a 24-week readout on the study. Everyone was on 15 mg twice a day or 20 mg twice a day.

Jeanne is definitely right. If you’re concerned about the hemoglobin dropping from 9.5 to 7 g/dL and needing a transfusion, then you start them a little lower. However, according to the product label, at a platelet count of 160,000 per μL, you’d start them on 15 mg twice a day. What’s the plus for that? It might be a deeper response. It might be better for the long term. We don’t know, but it’s possible. But they’ll have more anemia up front. We manage anemia through a variety of other treatments. If we give someone azacitidine, we wouldn’t think twice if we needed to give them a transfusion after their first cycle, so it’s a point of discussion. I don’t think we know for certain what the better approach is. If you start them lower, don’t be afraid to increase it, because the anemia is pretty front-loaded. If you increase that from 10 mg twice a day to 15 mg twice a day after 10 or 12 weeks, you aren’t necessarily going to see a second subsequent decrease.

Another lesson we’ve learned about ruxolitinib is that there are probably too many patients who are underdosed on ruxolitinib and using levels well below ideal. If you start them lower, don’t be overly timid about increasing it. And don’t be overly timid about a short period of support for the anemia. We have data showing that if you develop anemia briefly from a drug adverse effect, that isn’t the same as having anemia in the DIPSS [Dynamic International Prognostic Scoring System] risk. It doesn’t mean that the prognosis for the patient has changed. I’ve had that same question: “I started the patient on ruxolitinib 2 weeks ago, and now they’re anemic. I recalculated their DIPSS. Should I take them to transplant now?” No, that isn’t the setting of the DIPSS. It didn’t factor that factor in.

Rami Komrokji, MD: Our approach has been similar, especially starting at a slightly lower dose when there’s borderline cytopenia. But to your point, the key is to escalate those patients, not to keep the dose static if there’s no profound cytopenia. Would you think of a transplant for this 67-year-old patient with constitutional symptoms, splenomegaly, and anemia?

Jeanne Palmer, MD: The white blood cell count and the blasts are what I pay attention to a lot in this setting. Because if you look at the DIPSS score—recognizing some of its limitations—based on the anemia and the age by itself, they would fall into an intermediate-2 risk category. If it’s only the anemia and the age, that by itself probably wouldn’t make me want to proceed with transplant. I wouldn’t be thrilled to push them forward. If they’re having some symptoms, especially if their white blood count is going up and their blast percentage is a little higher, those are the patients [for] whom we need to be thinking about transplant.

That becomes a shared decision-making process, because this is something that can really impact a patient’s quality of life. It’s important to have them involved and say, “These are the things we know, and these are the things we don’t know.” A number of patients are fairly sophisticated and good at helping make decisions. This is also where some of that next-generation sequencing may help me. If I see a patient who’s in that intermediate-2 risk category based on age and anemia, and maybe their white count is up at 18,000 or 22,000 per μL, in which case they don’t get a point but we know they’re up there, a high-risk mutation helps me decide about transplant. It isn’t a very straightforward answer, unfortunately, but it’s an ongoing discussion to have with the patient.

Rami Komrokji, MD: Absolutely. And the variables you mentioned are the things that we think of. As we mentioned before, you want to get a sense of the disease kinetics.