All Eyes Are on Novel Combination Therapies and Molecular Targets in MPN at ASH 2025
Key claim: At ASH 2025, 96-week MANIFEST-2 phase 3 data confirm durable spleen volume reduction, symptom improvement, and anemia benefit with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis, alongside growing focus on mutant CALR-targeted therapies.
Abstract
At ASH 2025, a major focus is on developing therapies specific to the mutant calreticulin (CALR) protein. 96-week data from the phase 3 MANIFEST-2 trial confirm durable benefit in spleen volume reduction, symptom reduction, and anemia improvement with pelabresib plus ruxolitinib in JAK inhibitor-naive myelofibrosis.
Why this matters
Durable 96-week MANIFEST-2 data strengthen the case that adding pelabresib to ruxolitinib upfront delivers sustained spleen, symptom, and anemia benefits in JAK inhibitor-naive myelofibrosis — directly informing the natural history and frontline treatment paradigm for PMF, where ruxolitinib monotherapy responses typically wane. Coupled with the ASH 2025 spotlight on mutant CALR-targeted agents, the finding reinforces a subtype-stratified PMF therapeutic future split between pathway-combination (BET+JAKi) and genotype-specific (CALR-mutant) strategies.