What Are The Differences Between Cytopenic And Proliferative Myelofibrosis?

Myelofibrosis (MF) is a chronic bone marrow condition that affects how blood cells are made. It can appear in two main forms: cytopenic and proliferative. These terms describe opposite blood count patterns and describe how the bone marrow is functioning.

What is cytopenic myelofibrosis? 

Cytopenic myelofibrosis is a form of the disease where blood counts are low. “Cytopenia” means a deficiency of one or more types of blood cells. In this type, patients often experience anemia (low red blood cells), thrombocytopenia (low platelets), and sometimes neutropenia (low white blood cells). 

During cytopenic myelofibrosis, the bone marrow becomes fibrotic, or scarred. Fibrotic bone marrow cannot produce as many healthy blood cells. Cytopenic MF behaves more like a bone marrow failure disorder. It is associated with more genetic complexity, higher rates of infections and bleeding, and an increased risk of turning into acute leukemia.

What is proliferative myelofibrosis? 

Proliferative myelofibrosis refers to cases where the bone marrow is still actively producing blood cells, but often too many. These patients may have high or normal white blood cell and platelet counts and less severe anemia. This overproduction is driven by mutations such as JAK2 V617F. It leads to symptoms like an enlarged spleen, called splenomegaly, and fatigue from inflammation and abnormal blood flow.

Although these two phenotypes differ at diagnosis, they exist on a spectrum. Over time, some people with proliferative MF may progress to the cytopenic form as the disease and bone marrow scarring advance.

The molecular differences of cytopenic and proliferative myelofibrosis

Both MF types arise from mutations in JAK2, CALR, or MPL. These genetic changes activate the JAK/STAT pathway that causes abnormal blood cell growth. 

Cytopenic MF often carries additional mutations in genes such as ASXL1, SRSF2, and U2AF1. This affects RNA splicing and epigenetic regulation (how genes are modified to adapt to environments). These mutations contribute to defective blood cell production and genetic instability. Patients with cytopenic MF are more likely to have primary MF and not MF that has evolved from another condition, like polycythemia vera or essential thrombocythemia. They also have lower JAK2 V617F mutation burden.

How is proliferative MF treated compared to cytopenic MF

Proliferative MF is typically treated with JAK inhibitors that improve spleen size and symptoms. These include ruxolitinib (Jakafi, Incyte Corporation) and fedratinib (Inrebic, Bristol Myers Squibb). JAK inhibitors can worsen anemia and thrombocytopenia. These therapies were studied mainly in patients with higher platelet counts, limiting their use in cytopenic populations.

Cytopenic MF requires therapies that stabilize or improve low blood counts without excessive bone marrow suppression. Two JAK inhibitors, pacritinib (Vonjo, CTI BioPharma Corp) and momelotinib (Ojjara, GSK), have expanded the options for these patients.

• Pacritinib (Vonjo, CTI BioPharma) inhibits JAK2, IRAK1, and ACVR1, showing benefit even in patients with platelets below 50×10⁹/L. It also improves anemia by modulating ACVR1 signaling.
• Momelotinib (Ojjaara, GSK) targets JAK1/2 and ACVR1 and is approved for MF with anemia. In the MOMENTUM study, it improved symptom burden and led to higher rates of transfusion independence compared with danazol.

Ancillary and emerging therapies

Several supportive treatments can improve anemia or platelet counts, though the benefit does not always last. Danazol (an androgen) and erythropoiesis-stimulating agents (ESAs) may reduce the number of blood transfusions some patients need. Immunomodulatory therapies like lenalidomide and thalidomide have shown modest benefits in improving anemia and thrombocytopenia.New biologic therapies are also being studied:

• TGF-β inhibitors such as luspatercept and elritercept promote red cell production in anemic MF.
• Telomerase inhibitors such as imetelstat and Bcl-2 inhibitors such as navitoclax are under investigation for modifying disease biology.
• Other agents, such as anti-hemojuvelin antibodies (DISC-0974) and MDM2 inhibitors (navtemadlin), target molecular pathways involved in iron regulation and tumor suppression.

Cytopenic myelofibrosis represents a complex form of the disease compared to its proliferative counterpart. Understanding the molecular and clinical differences helps guide treatment decisions. It can also help you look out for new advancements. The arrival of new JAK inhibitors that don’t interfere with the formation of new blood cells, such as pacritinib and momelotinib, along with ongoing trials exploring non-JAK targeted approaches, marks a significant step toward more individualized care for MF patients.

Stay tuned for more updates on new treatment advances, FDA approvals and clinical trials for myelofibrosis with the HealthTree News site.

READ MORE NEWS

Sources: 

• https://www.dovepress.com/the-ongoing-challenges-of-managing-cytopenic-myelofibrosis-in-2025-the-peer-reviewed-fulltext-article-BLCTT 
• https://www.cancer.gov/types/myeloproliferative/patient/chronic-treatment-pdq#:~:text=for%20primary%20myelofibrosis.-,Primary%20myelofibrosis%20is%20a%20disease%20in%20which%20abnormal%20blood%20cells,support%20the%20blood%2Dforming%20tissues.