Expert Discusses Potential Combos With Ruxolitinib in Myelofibrosis

Prithviraj Bose, MD

To date, the JAK inhibitor ruxolitinib (Jakafi) is the only FDA-approved therapy for the treatment of patients with myelofibrosis (MF); however, novel agents and combination regimens are in development to address some of the unmet needs in MF, including treating cases of anemia associated with MF and treatment with ruxolitinib, as well as increasing responses to the targeted therapy.

In an interview withTargeted Therapies in Oncology™(TTO), at the meeting, Prithviraj Bose, MD, assistant professor, The University of Texas MD Anderson Cancer Center, discussed the findings of 2 combination trials with ruxolitinib to optimize outcomes for patients with MF.

TTO:What are the unmet needs that still exist in MF that you would like to see be resolved?

BOSE:Ruxolitinib is a very well-established choice for JAK1/2 inhibition, but we also have some limitations. It is great at shrinking the spleen and improving symptoms, and it extends overall survival [OS], but certain things don’t get that much better. For example, ruxolitinib causes anemia, which can make it hard for patients to stay on or go up to the optimal dose.

The unmet needs are (1) to have a drug that could circumvent the anemia with ruxolitinib, and maybe even the thrombocytopenia, so that patients can stay on ruxolitinib at an optimal dose for an extended period of time, and (2) the fact that ruxolitinib is not a cure. Even though it extends OS, MF is still not curable without allogeneic transplant. We need disease-modifying drugs, which, in combination with ruxolitinib, for example, will hopefully give us more biology-altering benefits.

TTO:How is the study of sotatercept and ruxolitinib aiming to meet the first need?

BOSE:This is a single-arm phase II open-label study. Sotatercept alone and in combination with ruxolitinib (Jaka ) [was studied] in patients with myeloproliferative neoplasm—associated MF (MPN-MF).1 Sotatercept can be compounded with ruxolitinib because ruxolitinib initially causes a decrease in hemoglobin levels before they slowly improve to a new baseline. There are patients who are anemic from the disease and there are patients who are anemic because of both MF and ruxolitinib.

Sotatercept alone was given in patients who are anemic, and no other MF-directed therapy was permitted in that cohort. Separately, there is a cohort in which sotatercept was added to patients on ruxolitinib. They had to have been on ruxolitinib for at least 6 months and on a stable dose of ruxolitinib for the previous 2 months.

We have been very encouraged by what we’ve seen so far. In the monotherapy cohort, we had a 39% re- sponse rate with 7 out of 18 evaluable patients. In the combination cohort, we had a 30% response rate with 3 out of 10 evaluable patients.

I think this drug has the potential to ll a major unmet need. We had 2 groups of patients, one in whom anemia is the main manifestation of their MF. That is a space where there is a clear need for something that works in those patients. Then we had the larger group on ruxolitinib. Those are the patients who have splenomegaly or other symptoms and of course need their ruxolitinib. The problem is that the anemia that ruxolitinib initially causes or worsens can limit the ability to optimize the dose of ruxolitinib or to keep them on the drug for a suficient length of time. This is where you really need an agent that can help those patients stay on ruxolitinib and optimize the dose for optimal benefit.

TTO:How will the pracinostat and ruxolitinib combination study potentially ll the second unmet need?

BOSE:This was purely a combination study.²All patients received both drugs, ruxolitinib and the histone deacetylase [HDAC] inhibitor, pracinostat, which has gotten a lot of attention recently in acute myeloid leukemia, where the FDA gave it a breakthrough designation. There is a lot of preclinical data that support combining ruxolitinib with HDAC inhibitors and that formed the basis of the investigation.

You had ruxolitinib alone for 12 weeks and then pracinostat was added. This was to avoid any additive side effects, which might compromise the ruxolitinib dosing because the first 12 weeks is when the patients get the maximum benefit. This study enrolled 25 patients, of whom 20 were able to start pracinos- tat. Among those 20, unfortunately while we saw clinical activity, we did not see a very good tolerability of the combination. All 20 eventually ended up going o the study; however, there was 1 patient who was on it for 2 years and there was a near complete disappearance of the JAK2 mutation in that patient. Also, a marked improvement in his bone marrow brosis grade was noticed, from grade 3 to grade 1.

Overall, the spleen and symptom responses were quite high. There was about a 74% clinical improvement in his spleen and 80% clinical improvement in symptoms. This certainly looks higher than you would expect with ruxolitinib alone. But it seems a bit difficult to develop this combination further because of the tolerability concerns and the discontinuation rate.

References:

1. Bose P, Daver N, Pemmaraju N, et al. Sotatercept (ACE-011) alone and in combination with ruxolitinib in patients (pts) with myeloprolifera- tive neoplasm (MPN)-associated myelo brosis (MF) and anemia. Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 255. ash.confex.com/ash/2017/webprogram/Paper104189.html.
2. Bose P, Pemmaraju N, Schroeder K, et al. Phase II study of pracinostat in combination with ruxolitinib in patients (pts) with myelo brosis (MF). Presented at: 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 1632. ash.confex.com/ash/2017/webprogram/Paper105843.html.