Unveiling population heterogeneity in health risks posed by environmental hazards using regression-guided neural network.

Myelofibrosis (MF) is a rare hematological neoplasm characterized by clonal myeloproliferation, leading to the production of abnormal megakaryocytes and a buildup of fibrosis in the bone marrow, which impairs the normal production of blood cells [–]. This cancer is driven by genetic mutations in hematopoietic stem cells, the most common being Janus kinase () 2, calreticulin (), and myeloproliferative leukemia virus () [, , ]. The clinical hallmarks of MF include splenomegaly, constitutional symptoms (fever, night sweats, and fatigue), severe anemia, thrombosis, bleeding, bone pain, and pruritus [, ]. Management of MF depends on the risk stratification and symptom burden of the patient [, ]. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potential cure for MF, but its use relies on donor availability and is limited by the risk of life-threatening complications [, , ]. When allo-HSCT is not possible, treatment aims to control symptoms and complications and to reduce the risk of progression []. JAK inhibitors (JAKis) are a standard-of-care option for patients ineligible for allo-HSCT [, ]. However, issues of poor tolerability and drug resistance limit the use of particular JAKis, such as ruxolitinib or fedratinib, and anemia can also develop owing to their mechanism of action [, , ]. Momelotinib is a novel JAKi that was approved by the European Medicines Agency in January 2024 for patients with primary MF who have moderate-to-severe anemia []. Momelotinib has a different mechanism of action to that of previously available JAKis, and includes potent inhibition of type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2). This unique mechanism of action stimulates erythropoiesis and, therefore, has a beneficial effect on anemia []. Momelotinib improves anemia in MF and prevents or reverses red blood cell transfusion dependence [–]. Other treatment options for MF include immunomodulators, interferon alpha, hydroxycarbamide/hydroxyurea, androgens, corticosteroids, and blood transfusions [–, ]. Anemia represents a particular management challenge in MF [, ]. It is typically present at diagnosis in around one-third of patients and almost all patients become anemic over the course of their disease [, , ]. Moderate anemia in MF has previously been treated with supportive agents primarily to prevent worsening and progression to transfusion need []. However, supportive care may only provide transient benefit and the dose of first-line JAKis that have a negative impact on anemia may need to be lowered []. Regular blood transfusions are typically needed for severe anemia []. Around half of patients with MF require blood transfusions within 1 year of diagnosis, and many become dependent on regular transfusions [, ]. Importantly, progression to transfusion dependency negatively affects prognosis, reducing quality of life, worsening comorbidities, increasing the risk of leukemic transformation, and shortening survival [, ]. The impact of anemia and associated fatigue on patients is substantial and increases alongside worsening anemia severity []. Similarly, by worsening prognosis and quality of life, anemia also increases healthcare resource utilization (HCRU) and costs in patients with MF, causing increased hospital admissions, emergency department visits, and treatment expenditure [].