<p>Myelofibrosis presents significant therapeutic challenges due to its progressive nature. Although current therapies may alleviate disease-related symptoms, substantial unmet needs remain that require new therapeutic strategies and agents. Investigational agents and combination therapies that are in development could help transform the management of myelofibrosis in the coming years.</p>

While current myelofibrosis therapies can help a patient’s disease-related symptoms, we are lacking therapies other than allogeneic stem cell transplant that can reliably improve anemia, provide more durable responses, or truly modify the disease. I think that there are a few ways to accomplish these goals. For patients with anemia, an agent that is in development is luspatercept, which is US Food and Drug Administration (FDA) approved for myelodysplastic syndromes. However, the phase 3 INDEPENDENCE trial of luspatercept in combination with a JAK inhibitor did not meet its primary end point, according to a recent press release. In addition, elritercept, which acts on the activin pathway, and DISC-0974, which is an anti-HJV antibody, are also focused on anemia and are currently entering later-phase clinical trials.

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For deeper, more durable responses, the thought is that we may need to use combination therapies. There are a number of different combination therapies that are being evaluated with good preclinical rationale. The best example is the combination of pelabresib, a BET inhibitor, and ruxolitinib, which is being studied in the ongoing phase 3 MANIFEST-2 trial. Results at 24 weeks showed that the pelabresib combination nearly doubled spleen responses (65.9% in the pelabresib-plus-ruxolitinib arm vs 35.2% in the placebo-plus-ruxolitinib arm) and mildly improved symptom responses, while causing less anemia than ruxolitinib. However, we are not sure if doubling the spleen response is clinically important, although we think that it is encouraging. Additionally, navitoclax is a BCL-XL inhibitor that, in combination with ruxolitinib, also doubled spleen responses compared with placebo plus ruxolitinib but is associated with significant thrombocytopenia, which makes administration quite challenging. Neither of these combinations has received FDA approval.

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Two additional combination therapies in later-phase trials that are generating a lot of excitement are the XPO1 inhibitor selinexor in combination with ruxolitinib and the MDM2 inhibitor navtemadlin in combination with ruxolitinib. Selinexor plus ruxolitinib is being evaluated in the front line against ruxolitinib alone in the phase 3 SENTRY study. Navtemadlin plus ruxolitinib is being evaluated in the ongoing, randomized, phase 3 POIESIS trial. POIESIS is enrolling treatment-naive patients to receive ruxolitinib. Those who respond suboptimally to ruxolitinib alone are then randomized to the addition of either navtemadlin or placebo to see if additional benefits can be obtained.

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I think that another way to start getting into disease modification is to more selectively target the underlying core of the disease. At least 90% of patients with myelofibrosis have a driver mutation, and, if we could target and eliminate this, the hope is that we could potentially eliminate some disease. CALR mutations are present in approximately 30% of patients with myelofibrosis. CALR-targeted therapies are gaining momentum in clinical trials with monoclonal antibodies, and T-cell–redirecting antibodies targeting CALR-mutated cells are under evaluation. Most patients with myelofibrosis have JAK2 mutations, and more specific JAK2 inhibitors are entering trials too.

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The telomerase inhibitor imetelstat is worth mentioning because it is being evaluated in the phase 3 IMpactMF trial in relapsed/refractory myelofibrosis, with a primary end point of overall survival. This is the first time that overall survival has been a primary end point in a myelofibrosis study. Imetelstat is FDA approved for myelodysplastic syndromes in patients with anemia, but it would be used in myelofibrosis more as a disease-modifying agent.