ONCAlert | 2018 ASCO Annual Meeting

Combination Strategies With Ruxolitinib Explored in Myelofibrosis Treatment

Angelica Welch
Published Online: 1:00 PM, Fri September 15, 2017

Srdan Verstovsek, MD, PhD
The treatment of myelofibrosis has changed significantly in the past few years, largely due to the approval of ruxolitinib (Jakafi). Although it provides durable improvements, the JAK inhibitor may be even more effective in combination—as inhibition of JAK-STAT signaling has not shown to be curative.

In his presentation at the 2017 Society of Hematological Oncology (SOHO) Annual Meeting, Srdan Verstovsek, MD, PhD, professor, Department of Leukemia, The University of Texas MD Anderson Cancer, delineated the current status of myelofibrosis therapy, and introduced the rationale for combination regimens with ruxolitinib, including early clinical studies.

Currently the National Comprehensive Cancer Network guidelines for the treatment of overt myelofibrosis are based on risk and symptoms. For low-risk patients, those patients who are asymptomatic undergo observation or are referred to a clinical trial, and those patients who are symptomatic are administered either ruxolitinib or interferon, or are referred to a clinical trial. Patients categorized as intermediate-1 are recommended for observation, or ruxolitinib if symptomatic, or allogeneic hematopoietic stem cell transplantation (HSCT) if they present with low platelets or complex cytogenetics, or again, a clinical trial.

Additionally, for patients who are either intermediate-2 or high risk, if eligible for transplant, they receive allogeneic HSCT—if they are ineligible or symptomatic, they are administered ruxolitinib, or referred to a clinical trial. For those patients who are intermediate-2 or high risk, and who are transplant ineligible, symptomatic, and anemic, managing the anemia is the course of therapy.

When using ruxolitinib in practice, Verstovsek recommends to base the starting dose on platelet number, for clinicians to avoid prophylactic underdosing or interruption of ruxolitinib if patients are responding well, and understand that the development of anemia does not affect the benefits of a JAK2 inhibitor, ie, anemia is not a contraindication.

Based on the brevity of these guidelines, additional treatments are needed, says Verstovsek—especially because some patients do not respond to ruxolitinib, and patients with platelets <50x109/L cannot take ruxolitinib due to the JAK inhibitor’s myelosuppressive effects. Less myelosuppressive JAK2 inhibitors such as NS-018 and pacritinib are in clinical trials, though.

There are still patients who do not respond to JAK inhibitors, and some lose their response, which builds on the argument for novel therapies and combinations with ruxolitinib, says Verstovsek.

“One strategy to overcome the myelosuppressive effects of ruxolitinib is to combine it with drugs that improve anemia,” said Verstovsek. “When given as monotherapy to patients with myelofibrosis and anemia, sotatercept has been shown to be well tolerated.”

Sotatercept (ACE-011) is a novel agent that has been shown to stimulate erythropoiesis. It is currently being evaluated in combination with ruxolitinib in a phase II study.

Another option that Verstovsek proposed is combining a hypomethylating agent with ruxolitinib in patients with myelofibrosis who show aberrant methylation. Specifically, the combination of ruxolitinib and azacitidine has shown promising early results, even though as monotherapy, hypomethylating agents have shown little activity in this disease. In a study by Daver et al, ruxolitinib in combination with 5-azacytidine as therapy for patients with myelofibrosis demonstrated an overall response rate of 69%.

Additionally, histone deacetylases inhibitors have shown synergy with ruxolitinib.

“Preliminary results of the combination of panobinostat with ruxolitinib were favorable, and the study has now entered the expansion phase,” noted Verstovsek.

Verstovek also listed antibodies and fusion proteins, telomerase inhibitors, hedgehog pathway inhibitors, Aurora kinase inhibitors, and immune checkpoint inhibitors as new molecules undergoing investigation as single agent therapy or in combination with ruxolitinib for the treatment of myelofibrosis.

Interestingly, upregulation of the JAK-STAT pathway can upregulate cell cycle progression of CKD 4/6, suggesting that inhibitors of CDK4/6 may work synergistically with ruxolitinib. Specifically, ribociclib (Kisqali)—which has seen success in breast cancer—and PIM447, are currently undergoing testing in combination with ruxolitinib in a European clinical trial.

The future for myelofibrosis is moving toward genetic subtypes and individualized treatment, according to Verstovsek. This means validating molecular signatures for use in clinical decision-making, defining new treatment strategies with JAK2 inhibitors and novel agents, and honing in on improving outcomes in patients with accelerated/blast-phase myeloproliferative neoplasms by developing new strategies.

Although ruxolitinib remains the only FDA-approved treatment for myelofibrosis, novel therapies and combination regimens are showing immense promise in clinical trials.
 
 
Reference:
Verstovsek S. Therapy of Myelofibrosis: Where are We and What Next. Presented at: 2017 SOHO Annual Meeting; Houston, TX; September 13-16, 2017.


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