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Rational combination therapies, new-generation drugs, and new therapeutic targets will push treatment for myelofibrosis beyond the current focus on the Janus kinase (JAK) inhibition, a specialist said during the .

Within the next three to five years, as many as four new drugs for myelofibrosis could reach the U.S. market, said Srdan Verstovsek, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston. The new options will give clinicians more flexibility to tailor therapy to specific clinical scenarios.

"We definitely need more therapies, and we have the ability to identify new targets," he said. "It is no longer about the JAK-STAT pathway. There are many other epigenetic abnormalities. Other parts of the biology of the disease are being explored as targets for therapy."

Evidence of the impending therapeutic evolution can be seen in the large number of ongoing and planned phase III clinical trials of myelofibrosis therapy, Verstovsek added.

Seeking to provide a "flavor" for where therapeutic development is headed, Verstovsek showed a list of single-agent trials that included some familiar names, such as anti-PD-1 antibodies and the recently approved nuclear export inhibitor selinexor (Xpovio). More numerous were investigational agents, including inhibitors of telomerase, BET, LSD1, HDM2, CD123, and AURKA, as well as a Smac-mimetic and recombinant human pentraxin-2.

Building off the success of JAK inhibitors, multiple studies are evaluation combination strategies. Some studies pair a JAK inhibitor with some familiar names -- azacitidine, decitabine, thalidomide, pomalidomide (Pomalyst), and interferon. Other strategies include investigational drugs with novel targets -- heat shock protein 90, BCL2, PI3K-gamma, MDM2, BET, and NAE.

Despite the interest in new targets and combinations, JAK inhibitors will retain a key role in myelofibrosis. Phase III trials have begun for at least two new agents in the class -- momelotinib for symptom control and anemia and pacritinib for patients with low platelet counts and a focus on reducing spleen volume and symptoms.

Investigators in the ongoing phase III trial are comparing pacritinib and physician's choice of therapy for patients with myelofibrosis and severe thrombocytopenia (platelet count <50,000 μL). The primary outcome is reduction in spleen volume at 24 weeks. Secondary endpoints are total symptom score at 24 weeks and overall survival.

Momelotinib is being evaluated as second-line therapy in the phase III trial for patients with myelofibrosis and anemia (hemoglobin <10 g/dL), previously treated with a JAK inhibitor. Patients receive a placebo and either momelotinib or danazol, which has been shown to ameliorate anemia in patients with myelofibrosis, said Verstovsek.

Among other agents in phase III clinical evaluation, Verstovsek singled out several for more detailed discussion.

Luspatercept

A first-in-class erythroid maturation agent, luspatercept targets TGF-beta ligands secreted by bone marrow stroma that inhibit terminal erythropoiesis, thus helping to improve anemia in patients with myelofibrosis. In a , single-agent luspatercept demonstrated potential to reduce the need for transfusion in patients with and without transfusion dependence, including patients already on ruxolitinib (Jakafi). The results provided the basis for the phase III, placebo-controlled INDEPENDENCE trial involving patients with myelofibrosis and require red blood cell transfusions despite JAK2-inhibitor therapy.

CPI-0610

A BET (bromodomain and extraterminal domain) protein inhibitor, CPI-0610 targets inflammation and bone marrow cells that drive myelofibrosis. In a of CPI-0610 added to ruxolitinib, 63% of patients with no prior JAK inhibitor treatment had at least a 35% reduction in spleen volume (SVR35, the primary endpoint) and an average reduction of 53%. Additionally, 59% of patients had at least a 50% reduction in total symptom score (TSS50, median 64%).

The results provided the basis for a global phase III trial involving patients with myelofibrosis (including post-polycythemia vera and post-essential thrombocytopenia myelofibrosis) and no prior exposure to a JAK inhibitor. All patients receive ruxolitinib and are randomized to CPI-0610 or placebo. The primary endpoint is SVR35 response at 24 weeks.

Navitoclax

Targeting BCL-X₁, BCL-2, and BCL-W, navitoclax offers a potential antifibrotic effect in bone marrow, synergistic activity with JAK inhibition against JAK2-mutated cells, and ability to overcome resistance to JAK2 inhibition. The drug is being evaluated in combination with ruxolitinib, said Verstovsek. In a , the combination led to an SVR35 response rate of about 30% in patients with primary or secondary myelofibrosis and suboptimal response to single-agent ruxolitinib. A similar proportion had improvement in TSS. Only two of 30 patients had progression of spleen volume as best response.

Two phase III trials of the combination therapy have been planned, said Verstovsek. One trial will involve patients with previously untreated myelofibrosis. All patients will receive ruxolitinib and randomization will be to navitoclax or placebo. The second trial will involve patients with relapsed or JAK2 inhibitor-refractory myelofibrosis. Patients assigned to the control arm will receive best available therapy.

Imetelstat

A first-in-class telomerase inhibitor, single-agent imetelstat achieved an SVR35 response rate in 10% of patients with relapsed or refractory myelofibrosis in a . Overall, 37% of patients had at least a 10% improvement in spleen volume at 24 weeks. Patients treated with the higher of two doses evaluated in the trial had a median overall survival (OS) of 29.9 months, which compared favorably with historical data for patients with relapsed/refractory myelofibrosis, said Verstovsek.

The results led to a phase III trial to compare single-agent imetelstat and best available therapy (excluding a JAK inhibitor) in 320 patients with relapsed/refractory myelofibrosis. The trial has a primary endpoint of OS and has the statistical power to detect a 40% reduction in the survival hazard for the imetelstat arm. Enrollment is expected to begin during the first quarter of 2021.

"This is a really important new development," said Verstovsek. "Not only are we talking about patients who are refractory to JAK inhibitors, but we are talking about upping the bar. This is a moment in drug development when we are going from anemia as the endpoint ... to talking about for the first time ever a randomized trial of treatment to prolong survival."

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