A new clinical trial is evaluating selinexor, a non-JAK inhibitor, as a first-line therapy in myelofibrosis, with a JAK inhibitor added later only if needed. This innovative sequencing challenges the current, long-standing paradigm of initiating all treatments with a JAK inhibitor.
The development of agents targeting specific mutations like CALR and JAK2V617F marks a move away from the "one size fits all" JAK inhibitor approach. This enables a more personalized, molecularly-driven treatment strategy that was previously not possible for MPN patients.
Unlike therapies that only manage symptoms, the CALR antibody INCA033989 reduces hematopoietic stem and progenitor cell pools. This suggests the drug targets the root clonal source of the disease, indicating a potential for genuine disease modification rather than just killing off downstream cancer cells.
In a Phase 1 trial, the CALR antibody INCA033989 was escalated to a very high dose (2,500mg) without reaching a maximally tolerated dose or showing significant toxicities. This exceptional safety profile suggests a highly targeted mechanism with minimal off-target effects, a major advantage in chronic disease management.