Looking Beyond Conventional JAK Inhibition in Myelofibrosis Therapy

Raajit K. Rampal, MD, PhD

Currently available therapies offer meaningful clinical benefits to patients with myelofibrosis, but achieving remission will likely require new molecules targeting different pathways, a specialist in the field said at the 2016 Society of Hematologic Oncology annual meeting.

In the placebo-controlled COMFORT I trial, significantly more patients treated with ruxolitinib achieved the primary endpoint of at least a 35% reduction in spleen volume at 24 weeks. In COMFORT II, significantly more patients randomized to ruxolitinib met the spleen volume—reduction criteria at 48 weeks as compared with best available alternative therapy. Both trials demonstrated marked improvement in symptoms. Moreover, both trials showed a survival benefit among patients treated with ruxolitinib.

“Quite obviously, the drug has had a profound effect, but we must be cognizant of the drug’s limitations,” said Raajit K. Rampal, MD, PhD, a research fellow at Memorial Sloan Kettering Cancer Center.

One limitation is the durability of response, which declined steadily over time. Secondly, the trials showed only modest decreases in JAK2. The relative lack of effect on JAK2 has been evaluated in preclinical studies, leading to the concept of persistence.

“In normal JAK-STAT signaling, JAK2 homodimerizes and then signals through the STATs,” said Rampal. “What we think might be happening, with exposure to ruxolitinib, is that JAK is able to heterodimerize to other family members and allow for signaling to continue in the JAK-STAT pathway.”

Another potential limitation relates to the known mutational heterogeneity of patients with myelofibrosis. The number and type of mutations appear to affect clinical course, including response to treatment.

The recent emergence of information about the potential limitations of JAK inhibition has provided the impetus to examine other treatment strategies for myelofibrosis. Several concepts have emerged, including improved targeting of JAK2 by means of novel JAK inhibitors or other types of inhibitors that affect JAK2 activation, homing in on associated genetic and epigenetic targets, and strategies that involve novel mechanisms and new therapeutic targets.

In addition to ruxolitinib, several other JAK inhibitors are in clinical development, including momelotinib, pacritinib, and NS-018. Although structurally divergent, all of the agents in development are type I, ATP-competitive inhibitors, like ruxolitinib, said Rampal.

Novel agents in development include imetelstat, a telomerase inhibitor. A preliminary clinical trial involved 33 patients with myelofibrosis, about half of whom had already received a JAK inhibitor. The overall response rate was 21%, and some patients had reversal of bone marrow fibrosis. Adverse events of note included grade 4 thrombocytopenia in 18% of patients, grade 4 neutropenia in 12%, and grade 3 anemia in 30%. A phase II trial has begun, said Rampal.

PRM-151, recombinant pentraxin 2 protein, was initially evaluated in pulmonary fibrosis but more recently in myelofibrosis. The trial involved 27 patients, 20 of whom completed 24 weeks of treatment and 13 of whom completed 72 weeks.

Six patients met WHO criteria for response, ranging from 30% to about 70% improvement in bone marrow status. Reductions in spleen volume were also observed. The best responses occurred in patients who completed 72 weeks of treatment. Responses were seen in patients who received PRM-151 alone or in combination with ruxolitinib.

As a chaperone molecule for JAK2, Hsp90 has attracted interest as a target for therapy in myelofibrosis. Several drugs are in development, and early trials have provided preliminary evidence of activity.

HDAC inhibitors have been studied extensively in hematologic malignancies, and attention has turned to myelofibrosis. In a phase I trial, 34 patients received the HDAC inhibitor panobinostat (Farydak) and ruxolitinib. A majority of patients had reductions in spleen volume. Additionally, 4 of 12 evaluable patients had improvement in bone marrow fibrosis, and 5 of 17 evaluable patients had a greater than 20% decrease in JAK2 allele burden.

Potential epigenetic strategies have included evaluation of hypomethylating agents. Single-agent activity has been observed, but responses have generally been modest, said Rampal.

More recently, decitabine was given with ruxolitinib to a group of patients with myelodysplastic/myeloproliferative neoplasms. Two-thirds of patients had objective responses, and reductions in spleen size were also observed. Rampal and colleagues are conducting a phase I/II trial of ruxolitinib and azacytidine in patients with myelofibrosis and hope to report initial findings at the 2016 American Society of Hematology annual meeting in December.

CHZ868, a novel type II JAK inhibitor, demonstrated inhibition of JAK signaling in preclinical studies involving cells that exhibit persistence, activation of JAK signaling when exposed to a conventional JAK inhibitor. Another agent that has shown promise in preclinical evaluation is LSD1, a lysine-specific HDAC inhibitor.

“The achievement of remission on a molecular and biologic level will likely require targeting of other pathways aside from JAK-STAT,” said Rampal. “Combinatorial studies, utilizing agents with non-overlapping toxicities, represent a reasonable and rational approach to ongoing and future investigations.”

Two randomized phase III trials provided evidence supporting the approval of the selective JAK 1/2 inhibitor ruxolitinib (Jakafi) for myelofibrosis.