MYELOFIBROSIS: CURRENT MANAGEMENT AND THERAPEUTIC STRATEGIES

Abstract

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, and bone marrow fibrosis, frequently associated with aberrant JAK/STAT pathway signaling. Mutations in JAK2 V617F, CALR, MPL, and other myeloid-associated gene variants play crucial roles in MF pathogenesis, diagnosis, and prognosis. Accurate diagnosis and risk stratification are paramount for guiding treatment decisions. HSCT is preferred for high-risk patients, while JAKis form the backbone of therapy for symptomatic, transplant-ineligible patients, aiming to ameliorate splenomegaly, constitutional symptoms, and improve quality of life. Ruxolitinib, the first FDA-approved JAK1/2 inhibitor, demonstrated significant reductions in spleen size and symptom burden in the COMFORT-I and COMFORT-II trials, extending overall and progression-free survival, though not consistently reducing leukemic transformation risk. Common adverse events include anemia and thrombocytopenia, typically manageable with dose adjustments. Fedratinib, a selective JAK2 inhibitor, approved for ruxolitinib-failure/intolerance, also shows efficacy in splenic and symptom responses in JAKARTA studies. Pacritinib, selectively targeting JAK2/FLT3, is particularly beneficial for patients with severe thrombocytopenia (<50x10^9/L) without exacerbating platelet counts. Momelotinib, a JAK1/2 and ACVR1 inhibitor, offers additional benefits in ameliorating anemia by modulating hepcidin. Each JAKi possesses distinct targets and safety profiles, allowing for personalized treatment approaches. However, current JAKi have not consistently demonstrated the ability to reverse bone marrow fibrosis or achieve deep molecular or complete responses, nor have they significantly altered the natural history of the disease. While JAKis have markedly improved patient quality of life, there remains a significant unmet need for novel therapies capable of deeper disease control and natural history modification.

Keywords: myelofibrosis; myeloproliferative neoplasms; JAK inhibitors; hematopoietic stem cell transplantation; gene mutations; prognosis