Myelofibrosis (MF) in 2026: Matching Therapy to the Dominant Clinical Problem
Key claim: In myelofibrosis, matching therapy to the dominant clinical problem is increasingly feasible through mutation-specific CALR-directed agents (INCA033989, bispecific antibodies) and the pelabresib plus ruxolitinib combination, which improved outcomes in JAK inhibitor-naïve intermediate-1 or higher-risk patients in the phase 3 MANIFEST-2 study.
Abstract
CALR-directed therapies are emerging as mutation-specific approaches. INCA33989, a monoclonal antibody targeting mutant CALR-positive CD34+ cells, shows preclinical potential. Early clinical trials are developing bispecific antibodies that bind CD3 and mutant CALR cells. Pelabresib (bromodomain inhibitor) plus ruxolitinib in the phase 3 MANIFEST-2 study improved clinical outcomes in JAK inhibitor-naïve patients with intermediate-1 or higher-risk MF.
Why this matters
This review crystallizes a problem-matched treatment paradigm specific to PMF — distinct from PV/ET where cytoreduction and thrombosis prevention dominate — by pairing CALR-genotype subpopulations with neoepitope-directed agents and JAKi-naïve higher-risk disease with BET-combination therapy. It reinforces PMF’s growing subtype-specific therapeutic stratification, where driver mutation and dominant clinical problem (anemia, splenomegaly, symptoms, cytopenias) increasingly dictate regimen choice rather than a uniform JAKi-monotherapy approach.