Ruxolitinib Combos Are Making Strides in Myelofibrosis and MPNs

The highly potent and selective JAK inhibitor ruxolitinib (Jakafi), alone and in combination with other drugs, has helped to improve both survival outcomes and quality of life for patients with myelofibrosis and other myeloproliferative neoplasms (MPN), according to Marina Kremyanskaya, MD, PhD. However, progress still needs to be made in terms of addressing disease progression.

“These diseases are being attacked from all different angles possible,” Kremyanskaya said. “Hopefully, in the next few years, we will see some newer drugs that we can use and offer our patients that will have an impact on their disease course.”

In an interview with OncLive^®, Kremyanskaya, and assistant professor of medicine, hematology, and medical oncology at Mount Sinai Hospital, discussed potential new combinations for treating patients with myelofibrosis and other MPNs, with a backbone of ruxolitinib.

OncLive^®: In terms of disease modification, what is the current state of treatment in MPNs?

Kremyanskaya: MPNs are a group of heterogeneous disorders with variable disease scores and life expectancies. Although we talk about disease modifying agents, there is not really any medical therapy that is available that will offer patients a cure, except for stem cell transplantation. There are many agents that are in development that we are hoping will modify the disease course, but currently, there are no proven standard therapies that [can do that], as well as prevent disease progression, or offer patients a cure.

What add-on approaches with ruxolitinib are being explored to increase efficacy?

Ruxolitinib has been a standard-of-care treatment for patients with myelofibrosis, as well as patients polycythemia vera, since its approval. Most patients [with myelofibrosis] get ruxolitinib soon after diagnosis, or at least when they become symptomatic and develop other disease characteristics that make it reasonable to start them on therapy. Many newer [treatment strategies] are using the approach of combining additional therapy with a JAK inhibitor, such as ruxolitinib, to achieve a more lasting and disease modifying effect. Ruxolitinib is a great drug for our patients. It offers improvement [in terms of] quality of life, many patients feel a lot better, and there are some benefits in survival. [However], it is not disease modifying, in the sense that it is not offering a cure and disease progression still happens.

There are many therapies that are looking at an additional effect, and the backbone of ruxolitinib is a very common in clinical trials [for this patient population] right now. One is a drug by Constellation [Pharmaceuticals], CPI-0610, which is a bromodomain inhibitor. In a phase 2 trial [NCT02158858], CPI-0610 was used as monotherapy for those patients who progressed on ruxolitinib, or who were intolerant of it, as well as in addition to ruxolitinib for patients who had suboptimal responses to it. [A third arm of the study assigned] JAK-naïve patients or those recently diagnosed who have not had experience with JAK inhibitors [to CPI-0610 plus ruxolitinib].

This drug has demonstrated some clinical activity in all 3 arms. There were splenic responses [reported], and there are patients who were transfusion dependent at baseline who have become transfusion independent on therapy. [Additionally,] there have been anemia responses in those patients who were not transfusion dependent. [We have also seen] improvement in symptom scores for patients in all the [different study arms]. Specifically, for those JAK-naïve patients who are receiving the combination therapy, the total spleen response seemed to be better than [that seen with] ruxolitinib alone. [This was also the case when] looking at other secondary end points, such as improvement in fibrosis, improvement in anemia, and all the other usual end points that we look at in myelofibrosis.

This phase 2 trial led to the opening of the phase 3 MANIFEST-2 trial [NCT04603495], where patients are going to be randomized to receive either ruxolitinib plus CPI-0610 or ruxolitinib plus placebo. This will give us much more information about the efficacy of these 2 drugs together as an upfront therapy.

Another combination [under investigation] is navitoclax [previously ABT-263] plus ruxolitinib. [The] phase 2 trial [will examined navitoclax] as monotherapy, and combination with ruxolitinib in those patients have already had suboptimal responses to ruxolitinib. Additionally, a phase 3 trial is opening where navitoclax will be used upfront in JAK inhibitor–naïve patients. An additional combination [includes] a drug from Insight Pharmaceuticals, which is a PI3K-delta inhibitor. [Similarly, there has been a] phase 2 trial with some clinical activity and promising results, and it is moving on to a phase 3 trial where it will be offered both upfront for JAK-naïve patients, and as an add-on to those patients who are already on ruxolitinib and have had suboptimal responses. Ruxolitinib really is being used as the backbone for a lot of different combinations, so we will see it in combination with a lot of other drugs.

Are there any efforts being made with immunotherapy in this space?

Immunotherapy in myelofibrosis and other MPNs, in general, does not seem to be as advanced as in other fields, but this is a field that’s developing There are many treatment options that are being investigated and we will see them come up in early phase clinical trials, either as single-agent or in combination with JAK inhibitors.

What are some of the next steps for this area? Are there any efforts ongoing that you're excited about?

These trials I mentioned [that are investigating combinations with ruxolitinib are all in phase 3 right now. [As these read out] we will have a better understanding of where all these drugs fit into [the treatment paradigm] of myelofibrosis. Currently, we still only have 2 JAK inhibitors that are approved, and once patients progress on the JAK inhibitors, there is not a lot that we can offer them outside of clinical trials. Because all these drugs are going into phase 3 right now, it will give us additional options for upfront therapy, where hopefully we can get deeper, more meaningful responses. Additionally, for those patients who already experienced JAK inhibitor therapy, these agents can be added on for a next line of therapy.

It will be exciting, and we will have choices. We will see where all these drugs fit with each other, and we will perhaps see a specific phenotype of patients with myelofibrosis who can go in one treatment direction vs another. In addition, there are other JAK inhibitors in development, and some of them are hopefully getting close to approval, such as pacritinib. This is an agent that can be used for patients with cytopenias, specifically thrombocytopenia, which is a difficult to treat population where there is a lot of unmet need. Hopefully, we will see improvement in survival in these patients. This will be another exciting area that can offer us more information.

What is the focus for treating patients who are resistant to ruxolitinib?

In practice for these patients, outside of clinical trials, there is nothing. We go back to older drugs that were used for myelofibrosis before. They may get a hypermethylated agent, depending on their disease, and they should go to transplant if that is an option for them.