Current treatment landscape of Myelofibrosis

Details

Supervisors

Zhu, Jingjing

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [60] en sciences biomédicales

Abstract

enMyelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm driven by muta tions in JAK2, CALR, or MPL, leading to constitutive JAK-STAT activation, bone marrow fibrosis, extramedullary hematopoiesis, and a severe symptom burden. Additional non driver mutations in ASXL1, SRSF2, U2AF1, and EZH2 further influence prognosis and dis ease progression. Risk stratification through scoring systems such as MIPSSv2 and GIPSS guides therapeutic decisions, most critically the timing of allogeneic hematopoietic stem cell transplantation (AHSCT), the only potentially curative option, with 5-year overall sur vival now approaching 60% reflecting advances in patient selection, conditioning regi mens, and supportive care. Other treatment options remain largely palliative. Hydroxyurea serves as the standard cytoreductive agent for splenomegaly and hyperproliferative manifestations in the ab sence of anemia. Four JAK inhibitors are approved: ruxolitinib for symptomatic spleno megaly and constitutional symptoms, fedratinib as second-line after ruxolitinib failure, pacritinib for severe thrombocytopenia, and momelotinib when anemia is dominant, ow ing to its unique ACVR1 inhibition and hepcidin suppression. Despite meaningful sympto matic improvements, none has demonstrated reversal of bone marrow fibrosis or con vincing survival prolongation. Emerging therapies offer considerable promises. Pelabresib combined with ruxolitinib achieved SVR35 rates of 66% in the phase 3 MANIFEST-2 trial. Selinexor showed striking early results with SVR35 reaching 79% in combination, now evaluated in the phase 3 SEN TRY trial. Imetelstat, assessed in the ongoing IMpactMF trial, is the first agent to use over all survival as a primary endpoint in JAK inhibitor-refractory disease. These developments suggest the coming years may finally deliver evidence of survival prolongation in this ag gressive malignancy.