Real-World Strategies for Managing Anemia in Patients With Myelofibrosis

Natasha Johnson

Hi, Katie! So glad to be talking to you today about a topic that is very familiar to both of us: anemia. Approximately 40% of patients with myelofibrosis have anemia at diagnosis, and many will require transfusions.¹ Both anemia and transfusion dependence are associated with a poor prognosis in myelofibrosis, so this is a major concern that impacts a large proportion of the patients that we see.²

However, it is important to understand that myelofibrosis-related anemia differs from treatment-related anemia, which is a common side effect of JAK inhibitor treatment and does not appear to negatively impact overall survival.³ When the COMFORT studies were conducted, there was a pooled analysis demonstrating that earlier treatment with the JAK inhibitor ruxolitinib is actually associated with improved outcomes.⁴ Historically we had been waiting to start treatment with ruxolitinib until our patients were very symptomatic, but this analysis suggested that intervening sooner might actually benefit our patients.

So, with treatment-related anemia, we generally start seeing a 2-g/dL decrease in hemoglobin around 8 to 12 weeks into treatment. When that happens, we usually keep the patient on treatment, even if that means having to transfuse them. And then, what tends to happen is that their hemoglobin counts gradually improve—not back to baseline, but close. It’s important to remember that anemia is very much expected, but if we keep our patients on their JAK inhibitor treatment and their spleen and symptoms are improving, we can treat through it. Treatment-related anemia does not negatively impact overall survival.

Kathryn Herricks

That’s so true, Natasha. Are there tools that you recommend when trying to determine whether to continue treatment with ruxolitinib in a patient who developed anemia while on treatment?

Natasha Johnson

I find the RR6 prognostic model to be very helpful. This model is used to predict survival in patients with myelofibrosis based on their response to ruxolitinib after 6 months of treatment.⁵ It assigns a risk category to patients based on three variables—ruxolitinib dose, spleen size, and red blood cell transfusion need—from data collected at baseline, 3, and 6 months. As advanced practitioners, we see these patients after they start treatment and on follow-up, so this model is a great tool to have in our back pockets to help identify patients who are having an inadequate response to ruxolitinib and to figure out whether we need to consider another treatment option.

Of course, there can be other causes for a patient’s anemia that are unrelated to JAK inhibitor treatment or their myelofibrosis. Especially when you have a patient with polycythemia vera, for instance, whose disease has progressed to myelofibrosis, it’s important to consider whether there’s an iron deficiency that needs to be addressed. I know we’ve both had patients whose iron deficiency was caused by a small gastrointestinal (GI) bleed; we ordered the colonoscopy, found the GI bleed, started iron replacement therapy, and all of a sudden the anemia that we thought was related to myelofibrosis significantly improved—and there was no longer a need for transfusion!

Other causes of anemia that are important to consider include things like folate deficiency, vitamin B12 deficiency, and abnormal thyroid levels. You once had a patient whose hypothyroidism was contributing to their anemia, right?

Kathryn Herricks

Yes, I did. I feel like sometimes it’s the things that we rarely see that can be most impactful once addressed. For the patients I’m thinking about, going on levothyroxine or folic acid resulted in a robust improvement in their anemia, and they ended up not requiring the expected treatment changes after all.

Natasha Johnson

Now that I’m thinking about this, our patients with myelofibrosis often have early satiety or loss of appetite; they’re not eating well, so it makes sense that they could have nutritional deficiencies. We really need to think about checking those levels on a routine basis to see if they need iron replacement and to rule out other causes before we decide to change treatments.

But what if it truly is myelofibrosis-related anemia? What if we have a patient who is suffering from splenomegaly-related symptoms and constitutional symptoms? Can you tell us how you would take care of those patients, Katie?

Kathryn Herricks

That’s when it becomes a little trickier and when we really start to benefit from the newer JAK inhibitors. One option is to first lower the dose of ruxolitinib. If they did have that drop in hemoglobin and it didn’t come back to a level that was tolerable for that patient, sometimes we can lower the ruxolitinib dose and still get the symptom response that we need—along with a little less anemia.

Another option is to add an erythropoiesis-stimulating agent or luspatercept to the JAK inhibitor to help boost the anemia response; that way you’re getting both the anemia response and that spleen and symptom response. Alternately, sometimes adding danazol to help get that anemia response, or using thalidomide in combination with prednisone, can be effective.

Of course, for some patients, the best option is to switch to an alternative JAK inhibitor like momelotinib, which is our newest JAK inhibitor. We saw that momelotinib is effective in patients with anemia in the MOMENTUM trial, where it demonstrated durable anemia responses compared with danazol.⁶

Like all drugs, there are advantages and disadvantages to momelotinib. Some side effects that we see in our patients treated with momelotinib include diarrhea, fatigue, and acute kidney injury, which can be difficult for patients to tolerate. In those cases, we have found that dose reduction can be really effective and can still lead to very durable anemia responses. What has your experience been, Natasha?

Natasha Johnson

I’ve definitely had patients who have had those durable responses after dose reduction, just like you said. They seem to still be responding to the reduced dose of momelotinib, and importantly they’re able to tolerate it and stay on the drug.

I actually have a patient with post–polycythemia vera myelofibrosis who developed pretty significant anemia after being on ruxolitinib—she became transfusion-dependent. So, we switched her to momelotinib, and you wouldn’t believe the difference! Her hemoglobin and hematocrit improved so much that she had to go back to needing phlebotomies because of the response that she had. Of course, at that point we did pull back on the momelotinib dose, but it was very interesting to see.

Kathryn Herricks

Wow! Was she feeling well at that point, or was she starting to feel symptomatic from her hemoglobin and hematocrit getting so high?

Natasha Johnson

The latter—it reminded her of back when she had polycythemia vera and needed phlebotomies, many years ago. It was a unique case for sure.

Kathryn Herricks

In patients like that, I wonder if you were to check their bone marrow, if you would see a reduction in fibrosis.

Natasha Johnson

We don’t know for sure. Unfortunately, we didn’t repeat a bone marrow biopsy, but it was a very unique situation.

Kathryn Herricks

Absolutely. Well, Natasha, this was a great discussion that I think really underscores why it’s so important to improve treatment options for our patients with anemia and myelofibrosis. With 40% of patients with newly diagnosed myelofibrosis presenting with anemia at baseline, and knowing that anemia is a side effect of a lot of these drugs, it’s obviously an issue that we still need to find ways to overcome. No two patients are the same, and there are important nuances to utilizing the therapies that we already have so that we can determine the right dose for each patient.