Why JAK inhibitors worsen anemia in myelofibrosis—and how one agent changes the equation
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Patients treated with momelotinib were less likely to become anemic and less likely to require transfusions compared with ruxolitinib. So, we often think of it as a kind of ‘one-stop shop’... it treats both the disease manifestations and the anemia.
—Aaron Gerds, MD, MS, hematologist-oncologist at Cleveland Clinic
Nearly all patients with myelofibrosis (MF) develop anemia, with approximately 40% presenting with anemia at diagnosis and 60% manifesting it in the first year after diagnosis.[][] For many, it becomes one of the most clinically consequential aspects of the disease, shaping prognosis, symptom burden, and, increasingly, therapeutic strategy.
It’s important to recognize that MF-associated anemia is not only mediated by bone marrow dysfunction but also by hepcidin-mediated dysregulation of iron homeostasis and other factors. Understanding what’s driving the anemia is critical for accurate classification and for selecting therapies that avoid exacerbating it.
Why treating anemia in MF is so complex
The many potential causes of anemia make it difficult to treat, Cleveland Clinic hematologist-oncologist and American Society of Hematology (ASH) media expert Aaron Gerds, MD, MS, tells MDLinx.
“It can be drug-related: JAK inhibitors can cause anemia,” Dr. Gerds says. “It can be due to mutations that impair red cell maturation in the bone marrow. It can be driven by inflammation. It can also be due to splenic sequestration, since the spleen is often enlarged in this disease and can destroy or trap red blood cells.”
Worsening anemia is a poor prognostic sign, predicting worse survival, and is included in diagnostic (WHO, ICC) and prognostic models such as DIPSS (Dynamic International Prognostic Scoring System) and MIPSS70 (Mutation-Enhanced International Prognostic Scoring System). Additionally, worsening anemia increases symptom burden and transfusion dependence, according to Dr. Gerds.
A key mechanism: Hepcidin and iron restriction
Chronic inflammation leads to an increase in cytokines, especially in levels of IL-6. In turn, the cytokine IL-6 increases hepcidin production. Hepcidin is a peptide hormone, serving as the master regulator of iron entry into the plasma.
Hepcidin acts almost like a cork—it blocks the release of iron from storage sites. As a result, iron isn’t available for red blood cell production, which leads to anemia.
—Aaron Gerds, MD, MS, hematologist-oncologist
The unavailability of iron results in anemia of chronic inflammation (ie, iron-restricted erythropoiesis).
The signaling pathway behind iron-restricted erythropoiesis
Inflammation links directly to iron-restricted erythropoiesis via the IL-6/JAK/STAT3 signaling pathway.
Following an inflammatory stimulus, IL-6 is released and binds to form a complex of the IL-6 receptor α and gp130. This interaction activates Janus kinases (JAKs) that phosphorylate signal transducers and activators of transcription (STAT) proteins—in particular STAT3. STAT3 then translocates to the nucleus, where it mediates the transcription of various target genes, including the production of hepcidin.[][]
Related: IL-6, hepcidin, and the hidden driver of anemia in MF: Are you targeting the right pathway?A better approach to managing MF-associated anemia
Dr. Gerds explains why iron-restricted anemia in MF has been underrecognized: “Historically, we focused more on bone marrow dysfunction and drug effects. But therapies like momelotinib have helped bring a greater attention to the role of hepcidin and iron restriction as a therapeutic target,” he says.
Momelotinib is an oral, once-daily kinase inhibitor approved in 2023 for adults with intermediate or high-risk MF and anemia. It has changed the treatment landscape for MF by addressing both disease burden and anemia, whereas other JAK inhibitors control disease but often worsen anemia.
“In clinical trials,” says Dr. Gerds, “patients treated with momelotinib were less likely to become anemic and less likely to require transfusions compared with ruxolitinib. So, we often think of it as a kind of ‘one-stop shop’—it treats both the disease manifestations and the anemia.”
SIMPLIFY-1 was a randomized phase 3 clinical trial of momelotinib vs ruxolitinib in JAK inhibitor–naïve patients.[] In commenting on the study, the authors highlighted the novelty of momelotinib.
“Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population,” they wrote. “In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib."
The growing recognition of hepcidin-driven iron restriction reframes how clinicians think about both disease biology and therapeutic strategy. In the past, treatment decisions often required tradeoffs between controlling splenomegaly and symptoms vs worsening anemia. But a deeper understanding of the IL-6/JAK/STAT3–hepcidin axis is beginning to shift that paradigm, highlighting anemia as a targetable component of the disease.