Pemmaraju Reviews Potential Combination Regimens With Ruxolitinib for Myelofibrosis

Naveen Pemmaraju, MD

JAK inhibition has already been cemented in the treatment paradigm for patients with myelofibrosis as a standard of care and new research has turned to combination approaches with JAK inhibition. Naveen Pemmaraju, MD, put it to the audience in a presentation at the Society of Hematologic Oncology’s Seventh Annual Meeting, what is the role for combinations with JAK inhibition, is it necessary, can it be done safely without substantial added toxicity, and at what stage of disease?

Although several newer JAK inhibitors are being investigated, such as pacritinib, momelotinib, and the recently FDA approved fedratinib (Inrebic), most combinations are being explored in combination with ruxolitinib (Jakafi), a JAK inhibitor that was approved for treating patients with intermediate or high-risk myelofibrosis in 2011. Current combination trials with ruxolitinib are looking to improve responses through potential combinations with hypomethylating agents (HMAs), immunotherapies, targeted therapies, and more.

Pemmaraju, an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said that the addition of HMAs to JAK inhibition is an intuitive combination for myeloproliferative neoplasms.

He pointed to a recent phase II study of ruxolitinib in combination with azacitidine in 46 patients with chronic-phase, intermediate- or high-risk primary myelofibrosis.¹Patients received ruxolitinib alone twice a day for 3 cycles with azacitidine added at cycle 4. Pemmaraju noted that the dosages were more variable in this study than some others.

The objective response rate was 72% with the combination with about one-fourth of the responses occurring after the addition of azacitidine. Significant bone marrow and spleen improvements (>50% reduction) were both noted with this combination.

Histone deacetylase (HDAC) inhibition in combination with JAK inhibition has been tougher to prove despite preclinical activity suggesting some synergy, Pemmaraju suggested. A phase II study explored pracinostat in combination with ruxolitinib in 20 patients with myelofibrosis.²Once again, the JAK inhibitor was given for 3 cycles and then the HDAC inhibitor was added, but most of the responses occurred prior to the initiation of pracinostat. Additionally, the HDAC inhibitor was poorly tolerated with patients experiencing many toxicities as well as treatment discontinuation with pracinostat.

Pemmaraju noted that investigators are looking for ways to harness or target the chronic inflammation and overproduction of cytokines found in myelofibrosis. As such, 2 phase II studies are being conducted in Europe to explore the combination of ruxolitinib with interferons which have already demonstrated safety for the regimen. He noted that Europeans are showing the feasibility for this potential combination with the use of ropeginterferon.

Immunomodulatory drugs including lenalidomide (Revlimid) and pomalidomide (Pomalyst) have shown mixed results in terms of some responses, but also toxicities of concern such as myelosuppression. In a phase Ib/II trial of ruxolitinib and pomalidomide in 37 patients with myelofibrosis who had anemia and splenomegaly, the objective response rate was 16% and clinical benefit was seen in about one-third of patients.³The combination was considered safe and feasible.

Combinations with immunotherapy, such as PD-1/PD-L1 checkpoint inhibitors, are still in the early stages of development. This potential combination is of interest asJAK2V617F mutations increase the expression of PD-L1 via STAT3 activation. However, toxicities with the combination have been noted in similar disease settings, such as acute myeloid leukemia. “In a chronic setting, I think these have to be approached cautiously because there’s no data yet to show for this approach. Many more iterations are needed to get to the point of safety,” Pemmaraju said.

PI3K inhibition plus JAK inhibition has been considered to be a combination of interest due to the activation of the PI3K/Akt signaling pathway in myeloproliferative neoplasms. Preclinical synergy between the 2 classes of agents was noted, leading to in-human trials; however, Pemmaraju noted “it has not shown a tremendous amount of promise yet.”

One study of ruxolitinib in combination with umbralisib looked at patients with primary or secondary myelofibrosis who had prior exposure to ruxolitinib.⁴The patients had prior loss of response, suboptimal response, or no response at all after a stable dose of ruxolitinib for ≥8 weeks. The combination led to modest improvements, including a median decrease in spleen volume by 13%, and the mean reduction in tumor symptom score was 33%. Additionally, umbralisib led to an increase in hemoglobin levels >2 g/dL in 5 patients.

“One of the fairly exciting, novel concepts for us is the concept of bromodomain (BET) inhibitors,” Pemmaraju said, as no agents in this novel class of drugs have yet been approved by the FDA, “but the science is engaging here. There are many theories on how these therapies work.”

Early data from a study of the BET inhibitor CPI-0601 in combination with ruxolitinib in patients with myelofibrosis was presented at the 2019 American Society of Clinical Oncology Annual Meeting and updated at the 2019 European Hematology Association Annual Meeting.⁵The combination appeared to be well tolerated and responses were seen. Improvements were also noted in terms of bone marrow fibrosis and transfusion dependence. Pemmaraju noted that this is a study that should be watched.

The androgen danazol was also of interest in combination with ruxolitinib for its potential mitigation of anemia. A phase II study explored the use of danazol with ruxolitinib in a small group of patients with intermediate- or high-risk myelofibrosis, some of whom had prior exposure to JAK inhibition.⁶Nine patients (64.2%) achieved stable disease and 1 (7.1%) had a partial response to the combination. Clinical improvement in terms of spleen response was also seen in 3 patients (21.4%).

In terms of setting, Pemmaraju discussed considerations for when combinations should be used such as in the salvage setting to manage patients who have inadequate responses or persistent or worsening symptoms like anemia.

Many other combination regimens with ruxolitinib are also being considered, including with use of newer JAK inhibitors. As such, Pemmaraju stressed the importance of clinical trials to support these potential combinations.

References

1. Masarova L, Verstovsek S, Hidalgo-Lopez JE, et al. A phase II study of ruxolitinib in combination with azacytidine in patients with myelofibrosis. Blood. 2018;132(16):1664-1674. doi: 10.1182/blood-2018-04-846626.
2. Bose P, Swaminathan M, Pemmaraju N, et al. A phase 2 study of pracinostat combined with ruxolitinib in patients with myelofibrosis. Leuk Lymphoma. 2019;60(7);1767-1774. doi: 10.1080/10428194.2018.1543876.
3. Stegelmann F, Hebart H, Bangerter M, et al. Ruxolitinib plus pomalidomide in myelofibrosis: updated results from the Mpnsg-0212 trial (NCT01644110). Blood. 2016;128(22):1939. bit.ly/2lLod1M.
4. Moyo T, Palmer J, Huang Y, et al. Resurrecting response to ruxolitinib: a phase I study testing the combination of ruxolitinib and the PI3K delta inhibitor umbralisib in ruxolitinib-experienced myelofibrosis. Presented at: 2018 European Hematology Association Annual Meeting; Stockholm, Sweden; June 14-17, 2018; Abstract S133. bit.ly/2mfPytf.
5. Hoffman R, Mascarenhas J, Kremyanskaya M, et al. CPI-0610, a bromodomain and extraterminal domain (BET) inhibitor, reduces pro-inflammatory cytokines, bone marrow fibrosis and the number of transfusions in myelofibrosis patients. Presented at: 2019 European Hematology Association Annual Meeting; Amsterdam, Netherlands; June 13-16, 2019; Abstract S831. bit.ly/2kajmXg.
6. Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leuk Res. 2017;60:31-35. doi: 10.1016/j.leukres.2017.06.005.