Evolving Strategies for Myelofibrosis-Associated Anemia Highlight Persistent Gaps in Biomarker Guidance

Although the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for myeloproliferative neoplasms outline several options for the management of myelofibrosis-associated anemia, sparse biomarker data that could help predict response to certain therapies and define the limited efficacy of current treatment approaches has left unanswered questions.

“One of the challenges of treating [patients with] anemia is the fact that we don’t know which [treatment] is going to work the best, outside of erythropoietin [EPO] levels predicting response with erythropoiesis-stimulating agents [ESAs],” Aaron Gerds, MD, MS, said in an interview with OncLive^®. “We’re often just shuffling the deck to see what [treatment] works. More efficacious medications and predictors for which ones are going to work [would] help us make more efficient treatment decisions.”

Gerds is an assistant professor in the Department of Medicine in the School of Medicine, deputy associate director for Clinical Research, and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center, as well as a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic, in Ohio.

What are the challenges of myelofibrosis-associated anemia?

Anemia represents one of the key manifestations in myelofibrosis, with a significant proportion of patients presenting with anemia at diagnosis and the majority ultimately experiencing anemia over the course of their disease.^1,2 Myelofibrosis-associated anemia has been linked with lower survival rates for this patient population, along with diminished quality of life [QOL] stemming from transfusion burden.²

“Splenomegaly, constitutional symptoms, and anemia are the 3 key [manifestations of myelofibrosis] that we tend to face in the clinic,” Anthony M. Hunter, MD, told OncLive. “[A patient] may [have] all those things or just 1 of them. [This varies] from patient to patient, but anemia is a key part of myelofibrosis. Studies have suggested [that approximately] 50% to 60% of patients [are anemic at] diagnosis or within the first year [after diagnosis]. Some of that depends on what you define anemia as…but throughout the course of the disease, essentially every patient is going to become anemic at some point.”

Hunter is an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, medical director of the Immediate Care Center, and leader of the Myeloproliferative Neoplasm Program at Emory Winship Cancer Institute in Atlanta, Georgia.

Anemia is also a prognostic factor within myelofibrosis, with transfusion dependence associated with reduced overall survival outcomes and survival worsening with an increased severity of anemia.²

Notably, multiple factors play into the development of anemia in patients with myelofibrosis. Along with the displacement of hematopoietic elements driven by the underlying disease, splenomegaly can also contribute directly to anemia via sequestration and red cell destruction. Furthermore, anemia can also be an adverse effect of JAK inhibition.

“[Anemia] affects both quantity and quality of life. Anemia is one of the strongest factors in our risk-stratification systems, like the Dynamic International Prognostic Scoring System model—it’s the only [criterion] that gives [a patient] 2 points,” Hunter said. “It’s a big factor for prognosis and health-related QOL. Patients get profound fatigue, they come into the clinic a lot, they have all these issues, and it’s a big burden.”

What are some potential treatment avenues for anemia in myelofibrosis?

The 2026 NCCN Guidelines divide the management of myelofibrosis-associated anemia into 3 patient subgroups³:

• Patients with ongoing symptomatic splenomegaly and/or constitutional symptoms
• Patients with no splenomegaly or constitutional symptoms
• Patients with splenomegaly and constitutional symptoms well controlled by their current JAK inhibitor

For patients with ongoing symptomatic splenomegaly and/or constitutional symptoms, momelotinib (Ojjaara) holds a category 1 recommendation as a preferred option within the NCCN Guidelines. However, the only other preferred option listed for all 3 patient subgroups is clinical trial enrollment.

Other recommendations for patients with ongoing symptomatic splenomegaly and/or constitutional symptoms include pacritinib (Vonjo) or a ruxolitinib (Jakafi)–based regimen in combination with luspatercept-aamt (Reblozyl), danazol, or an ESA (for patients with an EPO level < 500 mU/mL). For patients with no splenomegaly or constitutional symptoms, other recommended options include danazol, ESAs (for patients with an EPO level < 500 mU/mL), luspatercept, momelotinib, and pacritinib; lenalidomide (Revlimid) plus prednisone is listed as useful in certain circumstances for patients harboring 5q deletions. In patients with splenomegaly and constitutional symptoms well controlled by their current JAK inhibitor, the other recommended option comprises a JAK inhibitor combined with an ESA (for patients with an EPO level < 500 mU/mL), luspatercept, or danazol; switching the JAK inhibitor to momelotinib or pacritinib is also listed as useful in certain circumstances.

“We don’t have a lot of agents that directly improve anemia. We have ESAs, luspatercept, and danazol that are all commercially available and used, but [they] have limited efficacy,” Gerds said. “They don’t work for [all patients] all the time. We also have ACVR1 inhibitors like momelotinib, [which is also a JAK inhibitor], that can also help anemia in a different way. Again, none of these are perfect, and they all have their shortcomings.”

Regarding luspatercept, the FDA approved the agent for the treatment of anemia without prior ESA use in adult patients with very low– to intermediate-risk myelodysplastic syndrome who may require regular red blood cell (RBC) transfusions.⁴ However, despite its inclusion in the NCCN guidelines, luspatercept is currently not approved by the regulatory agency for the treatment of anemia in patients with myelofibrosis.⁵

In the phase 2 ACE-536-MF-001 trial (NCT03194542), luspatercept improved anemia and transfusion burden across 4 cohorts of patients with myelofibrosis, with patients assigned based on transfusion dependence status.⁶ However, topline data from the phase 3 INDEPENDENCE trial (NCT04717414) showed that luspatercept plus concomitant JAK inhibition did not lead to a statistically significant improvement in RBC transfusion independence during any consecutive 12-week period compared with JAK inhibition plus placebo, missing the trial’s primary end point (P = .0674).⁷

“We have the phase 2 data that have been published, along with all the long-term data, so we got a good idea there with [luspatercept]. It works, and I would say that my real-world experience using luspatercept [for myelofibrosis-associated anemia] reflects what we saw in the ACE-536-MF-001 study,” said Gerds, who also noted that luspatercept remained in the same spot in the 2026 NCCN Guidelines following the announcement of the topline results from INDEPENDENCE. “INDEPENDENCE was a negative trial for its primary end point...and it highlights 2 issues. It highlights the issue of how difficult it is to measure anemia, even at baseline and even within a trial. What truly is anemia? And then how does anemia improve? [Anemia] is one of these things [that when] you see it, you know it, you understand it, [and] as you’re taking care of patients, [you could say their] anemia is better. But how do you quantitate that in a consistent manner across a trial? There is a whole other layer of complexity that’s very, very difficult. Anemia is hard to measure.

“Secondly, [INDEPENDENCE] brings up some of the challenges of doing a global trial. This study was open all over the world, [with] some patients enrolled in North America, then a lot of patients enrolled in Europe, Asia, and other areas where care may be subtly different. The treatment approach and the therapies available are…different from country to country.”

Detailed findings from the primary analysis of INDEPENDENCE will be presented at the 2026 EHA Congress in June.

What future research could help improve anemia management in myelofibrosis?

Hunter underscored that one issue with current treatment approaches for myelofibrosis-associated anemia is that these therapies are intended to address the anemia specifically, rather than the underlying disease.

As such, the focus of ongoing and future research will hinge on novel agents that could deliver improved disease modification, or combination strategies that could work synergistically to address the underlying myelofibrosis.

“The goal is: How can we more robustly manage the disease? Even JAK inhibitors like ruxolitinib can prolong survival, both in real-world studies and long-term trial follow up, although they don’t cause bone marrow responses or decrease leukemia transformation,” Hunter said. “[Even with] improved survival, we’re maybe not truly targeting the disease in that sense, and that’s where we hope to see some of these JAK inhibitor combination approaches, [where] we target multiple pathways and modify the disease more. As an outcome of that, hopefully we’ll see anemia improve as well if we’re targeting that malignant clone in the marrow. [As we improve] marrow function over time, hopefully anemia benefit will come along with that as well.”

Gerds highlighted several ongoing research avenues for myelofibrosis-associated anemia, including combination approaches using JAK/ACVR1 inhibitors, such as momelotinib or pacritinib in combination with luspatercept. For example, the ongoing phase 2 ODYSSEY trial (NCT06517875) is evaluating momelotinib plus luspatercept in patients with transfusion-dependent myelofibrosis.⁸ He also explained that agents similar to luspatercept, such as elritercept (KER-050), are also being investigated, along with other hepcidin-directed therapies.

He also agreed that agents or combinations with improved disease modification traits could ultimately affect how myelofibrosis-associated anemia is managed.

“By rooting out disease, we can improve anemia. I hope there is a day when anemia-supportive agents are not really a thing, where we’re just treating the disease, and as a happenstance, the anemia gets better,” Gerds said. “I hope these conversations about myelofibrosis-associated anemia become antiquated someday soon.”

References

1. Personalizing treatment of myelofibrosis-associated anemia. News release. Cleveland Clinic. March 18, 2025. Accessed May 13, 2026. https://consultqd.clevelandclinic.org/personalizing-treatment-of-myelofibrosis-associated-anemia
2. Jain AG, Gerds AT. How I treat anemia in myelofibrosis. Blood. 2025;145(16):1738-1746. doi:10.1182/blood.2023022414
3. NCCN clinical practice guidelines in oncology: myeloproliferative neoplasms. Version 1.2026. NCCN. January 22, 2026. Accessed May 13, 2026. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
4. US FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed May 13, 2026. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx
5. Reblozyl. Prescribing information. Bristol Myers Squibb. Updated February 2026. Accessed May 13, 2026. https://packageinserts.bms.com/pi/pi_reblozyl.pdf
6. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis. Blood Adv. 2024;8(17):4511-4522. doi:10.1182/bloodadvances.2024012939
7. Bristol Myers Squibb announces topline results from phase 3 INDEPENDENCE trial for Reblozyl (luspatercept-aamt) in adult patients with myelofibrosis-associated anemia. News release. Bristol Myers Squibb. July 18, 2025. Accessed May 13, 2026. https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-INDEPENDENCE-Trial-for-Reblozyl-luspatercept-aamt-in-Adult-Patients-with-Myelofibrosis-Associated-Anemia/default.aspx
8. Study of momelotinib in combination with luspatercept in participants with transfusion dependent myelofibrosis (ODYSSEY). ClinicalTrials.gov. Updated April 20, 2026. Accessed May 13, 2026. https://clinicaltrials.gov/study/NCT06517875