Thrombocytopenia is a common manifestation in patients with myelofibrosis, and its presence is influenced by both disease severity and the treatments that are used. Since there are few treatment options for thrombocytopenia, there is an urgent need for the identification of new management strategies.

Thrombocytopenia is a relatively common manifestation of myelofibrosis. It can be graded as mild (100-150×10³/µL), moderate (50-100×10³/µL), or severe (<50×10³/µL). There are data from retrospective studies demonstrating that thrombocytopenia is an adverse prognostic marker for survival. Generally, the incidence of thrombocytopenia increases and the severity worsens as the disease progresses, and survival decreases as the severity increases. There are also data suggesting that patients who start ruxolitinib with platelet counts of less than 260×10³/µL or who discontinue ruxolitinib with platelet counts of less than 100×10³/µL do particularly poorly.

The etiology of myelofibrosis-associated thrombocytopenia is complex. It may result from the disease process, as there may be a poor production of platelets, a sequestration of platelets in the spleen, and some destruction of circulating platelets. Myelofibrosis-associated thrombocytopenia may be worsened by many therapies that are used for treatment. For example, thrombocytopenia is a dose-limiting toxicity of JAK inhibitors such as ruxolitinib and fedratinib.

However, thrombocytopenia is also a consequence of the myelodepletive phenotype in myelofibrosis, such that both anemia and thrombocytopenia are often present. Usually, we think of anemia as driving symptoms such as shortness of breath and fatigue and as driving a reduction in patient quality of life. An interesting pooled analysis of data from the phase 3 PERSIST-1 and the phase 2 PAC203 trials was presented at the 64th American Society of Hematology Annual Meeting and Exhibition in 2022. The analysis evaluated baseline symptom burden to assess the individual contribution of thrombocytopenia and anemia on symptom burden. Patients with isolated thrombocytopenia had a greater symptom burden and a higher severity of most symptoms than those with isolated anemia. This was interesting because we have not traditionally considered thrombocytopenia to be a laboratory biomarker of symptomatology. These recent data provide insight into the biology of myelofibrosis, how patients are feeling, and how well they are clinically doing.

A significant unmet need for patients with myelofibrosis is that we do not have a great intervention for thrombocytopenia. Historically, we have tried to use a few different therapies without much success. For example, the thrombopoietin mimetics that are used in patients with idiopathic thrombocytopenic purpura have not been very effective. In fact, there is a concern that you could be stimulating the clone and even augmenting bone marrow fibrosis. If patients are bruising or having mucosal bleeding, I use antifibrinolytic agents such as tranexamic acid, but there are limited data. In general, symptoms of thrombocytopenia often persist, and we are left supporting the patient with platelet transfusions. There remains an urgent need for new therapies that can improve platelet counts.

Agents that have shown some potential for addressing thrombocytopenia in myelofibrosis include pomalidomide and AVID200. Pomalidomide, currently being used in multiple myeloma, was tested in patients with myelofibrosis, and, while the study failed to meet its primary end point of red cell transfusion independence, 22% of patients achieved a platelet response. The other agent is AVID200, a TGF-β 1/3 trap that is expected to improve megakaryopoiesis and megakaryocyte maturation. In a phase 1b trial in patients with advanced myelofibrosis, there were platelet responses—some pretty dramatic—to AVID200. Further evaluation of these agents is warranted, as thrombocytopenia is a persisting unmet need.