The Management of Myelofibrosis-Related Anemia

History of Presentation

An 82-year-old male with a past medical history of hypertension, coronary artery disease, hyperlipidemia, and JAK2-positive primary myelofibrosis diagnosed 5 years prior was receiving ruxolitinib 20 mg twice daily. His initial presenting signs and symptoms included mild anemia (hemoglobin [Hgb] 10.2 g/dL), leukocytosis (white blood cell count [WBC] 14.6 k), splenomegaly (3 cm from left costal margin [LCM] on physical exam) and reports of early satiety, unintentional weight loss, and profound fatigue. Platelets were normal. A total symptom score (TSS) calculated at the time of diagnosis was 32 (of a possible 100). A bone marrow biopsy revealed World Health Organization (WHO) grade 2 fibrosis with megakaryocytic atypia and no increase in blasts. Molecular testing revealed an ASXL1 mutation. Karyotype was normal (46 XY). The calculated MIPSS70+ score was 7, consistent with high-risk disease, and first-line treatment with ruxolitinib was initiated.

While receiving ruxolitinib, the patient’s splenomegaly, weight loss, and early satiety resolved. He experienced mildly improved but persistent fatigue. The patient’s WBC and Hgb normalized (8-10 k and 9.5 g/dL, respectively). After 6 months of treatment, the TSS improved to 10/100.

After 4.5 years of treatment, the patient presented with worsening fatigue, dyspnea on exertion (DOE), dizziness with standing, and a 3-day history of rhinorrhea and low-grade fevers (Tmax 100.7 F). A complete blood count (CBC) revealed a WBC 16 k, Hgb 6.9 g/dL, and a normal platelet count. Upon physical exam, his spleen was just palpable at the LCM. A respiratory pathogen panel was positive for COVID-19 infection. He reported no obvious blood loss. He received 2 units of packed red cells and had a subjective improvement in fatigue, DOE, and orthostasis. For COVID-19, he was treated with molnupiravir. At this visit, his TSS was 40; during the preceding 4.5 years, his TSS was monitored at each visit and was stable in the 10-15/100 range.

He returned to the clinic 1 month later with concerns of ongoing weight loss (10 lbs in the last 8 weeks), early satiety, abdominal discomfort, recurrent fatigue, DOE, and orthostasis. At that time, CBC was significant for WBC 13 k, Hgb 7.4 g/dL, and a normal platelet count. His spleen was newly palpable at 4 cm below LCM, raising the concern for disease progression. The low-grade fevers and rhinorrhea had resolved. His TSS had increased to 33/100 on this visit. Vitamin and mineral studies were assessed including zinc, copper, B12, folate, and iron, which were all within normal limits. Total bilirubin was normal; for completeness, an autoimmune hemolytic anemia work-up was performed including lactate dehydrogenase, haptoglobin, and reticulocyte count, which were unrevealing. Given the patient’s symptoms, age, and history of coronary artery disease, he received 1 unit of packed red cells for Hgb 7.4 g/dL.

Two weeks later, his CBC was largely unchanged (WBC 13.6k, Hgb 7.3g/dL, PLT 174k). A bone marrow biopsy was performed and revealed overall WHO grade 2 fibrosis with continued megakaryocytic atypia and no increase in blasts. There was no change in karyotype or gene mutations.

Management and Outcome

In the absence of an available and appropriate clinical trial for this patient, ruxolitinib was discontinued, and he began treatment with momelotinib 200 mg daily. After 6 months, he achieved transfusion independence with Hgb consistently 9.5-10 g/dL. He also achieved resolution of splenomegaly on physical exam as well as improvement of his abdominal discomfort, early satiety, and weight loss. TSS had also improved to 12/100.

Discussion

Management of myelofibrosis-related anemia starts with identifying the underlying cause and assessing concurrent signs and symptoms. Any vitamin deficiencies should be corrected, and signs of bleeding or hemolysis should be addressed prior to considering other interventions.¹ However, anemia in patients with myelofibrosis can often be attributed to the myelosuppressive effects of currently approved myelofibrosis therapies, including JAK inhibitors such as ruxolitinib. For patients already on JAK inhibitor therapy with uncontrolled symptomatic splenomegaly and/or other constitutional symptoms in addition to anemia, transitioning to an alternative JAK inhibitor should be considered. Momelotinib is a JAK inhibitor that is U.S. Food and Drug Administration (FDA) approved for the treatment of intermediate- or high-risk primary or secondary myelofibrosis in adult patients with anemia. In addition to targeting JAK1/JAK2, momelotinib additionally inhibits activin A receptor type 1 (ACVR1). ACVR1 inhibition decreases hepcidin levels and increases the availability of iron, leading to increased red blood cell production.^2,3 In clinical trials, patients who received momelotinib experienced spleen volume reduction, symptom improvement, and significant improvements in hemoglobin and red blood cell transfusion requirements.^4-6

Pacritinib is another JAK inhibitor that also inhibits ACVR1 as well as interleukin 1–associated receptor kinase (IRAK1).⁷ IRAK inhibition suppresses downstream nuclear factor kappa light chain enhancer of activated B cells (NFkB), which can decrease cytokine production and chronic inflammation.⁸ The phase 3 PERSIST-2 study of patients with myelofibrosis and baseline thrombocytopenia showed that pacritinib was superior to best available therapy (including ruxolitinib) in spleen volume reduction and improvement in symptoms. Additionally, patients who received pacritinib also had lower red blood cell transfusion requirements than patients receiving best available therapy. Although pacritinib is recommended in the National Comprehensive Cancer Network Guidelines for myelofibrosis-related anemia, it is important to note that anemia is not currently an approved indication for pacritinib. Pacritinib is currently FDA approved for the treatment of intermediate- or high-risk primary or secondary myelofibrosis in adult patients with a platelet count below 50x10^9/L.⁷

If patients with myelofibrosis experience anemia without concurrent splenomegaly or constitutional symptoms, treatments specifically to increase red blood cell counts should be considered. These treatments include erythropoiesis-stimulating agents, luspatercept-aamt, or danazol and may be used either alone or in combination with JAK inhibition.⁸

Key Takeaways in the Management of Myelofibrosis-Related Anemia

1. Investigate and determine the underlying cause of anemia in patients with myelofibrosis prior to deciding on management.
2. Consider JAK inhibitors with ACVR1-inhibitory properties for management of myelofibrosis treatment–related anemia.
3. Calculate the total symptom score to help monitor the effectiveness of treatment for patients with myelofibrosis.

References

1. National Comprehensive Cancer Network. Myeloproliferative Neoplasms. NCCN Clinical Practice Guidelines in Oncology. Published 2025. Accessed August 4, 2025. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf.
2. OJJAARA (momelotinib) [prescribing information]. GSK; 2025.
3. Chifotides HT, Bose P, Verstovsek S. Momelotinib: an emerging treatment for myelofibrosis patients with anemia. J Hematol Oncol. 2022;15(1):7. doi:10.1186/s13045-021-01157-4.
4. Mesa RA, Kiladjian JJ, Catalano JV, et al. Simplification of therapy with momelotinib in myelofibrosis: results from a phase 3 trial. J Clin Oncol. 2017;35(34):3844-3850. doi:10.1200/JCO.2017.74.4723.
5. Harrison CN, Vannucchi AM, Platzbecker U, et al. Momelotinib versus best available therapy in patients with myelofibrosis and anemia (SIMPLIFY-2): a phase 3 randomized trial. Lancet Haematol. 2018;5(2):e73-e81. doi:10.1016/S2352-3026(18)30004-5.
6. Gerds AT, Vannucchi AM, Kosiorek HE, et al. Phase 3 MOMENTUM study: momelotinib versus danazol in symptomatic and anemic myelofibrosis patients previously treated with a JAK inhibitor. Lancet Haematol. 2023;10(9):e735-e746. doi:10.1016/S2352-3026(23)00178-0.
7. VONJO (pacritinib) [prescribing information]. Sobi, Inc; 2024.
8. Jain AG, Kuykendall A, Rampal RK, et al. Efficacy and safety of momelotinib in patients with myelofibrosis and thrombocytopenia: results from the phase 3 MOMENTUM study. 2025;145(16):1738-1746. doi:10.1182/blood.2023011236.