Dr Harrison on Investigational JAK Inhibitor–Based Combinations in Myelofibrosis

“All these [trials] are trying to find a better frontline therapy because many of us were taught that we should give the best treatment first for patients when the disease is less complicated. [In doing so, we can] try to achieve the best outcomes [early in the treatment course].”

Claire Harrison, MD, FRCP, FRCPath, professor, Guy’s and St. Thomas’ Hospital, discusses ongoing research with JAK inhibitor–based combination regimens in the frontline setting for patients with myelofibrosis.

Ongoing clinical trials in myelofibrosis aim to identify more effective first-line treatments beyond ruxolitinib (Jakafi), Harrison begins. Notably, clinical efficacy in myelofibrosis trials is primarily measured by the proportion of patients achieving spleen volume reduction of at least 35% (SVR35) and symptomatic improvement, she explains.

The nonrandomized, United Kingdom–based, phase 2 FEDORA trial (EudraCT 2021-004056-42) is evaluating the JAK inhibitor fedratinib (Inrebic) in combination with ropeginterferon alfa-2b-njft (Besremi) in the frontline setting in patients with JAK2 V617F–positive primary or secondary myelofibrosis. Preclinical data from animal models have shown the potential biological activity of this combination, although further validation is required, Harrison says.

Furthermore, the phase 3 SENTRY/XPORT-MF-034 trial (NCT04562389) is assessing selinexor (Xpovio) plus ruxolitinib vs ruxolitinib alone in treatment-naive patients. Selinexor is of interest in myelofibrosis due to its effects on NF-κB, JAK-STAT signaling, p53-mediated apoptosis, and nuclear export mechanisms, Harrison reports. Selinexor is also being investigated for patients with thrombocytopenic myelofibrosis, she notes.

The POIESIS trial (NCT06479135) is investigating navtemadlin (KRT-232) as an add-on to ruxolitinib in patients with JAK inhibitor–naive myelofibrosis. This trial has a unique design in that all patients initially receive ruxolitinib and are then randomly assigned to receive navtemadlin or placebo if they do not achieve SVR35 or at least a 50% symptom response, according to Harrison.

Additionally, the phase 3 TRANSFORM-1 (NCT04472598) and MANIFEST-2 (NCT04603495) trials investigated navitoclax and pelabresib (CPI-0620), respectively, as potential frontline agents. These studies uphold the clinical practice of initiating the most optimal therapy early in the disease course to maximize long-term outcomes, Harrison concludes.