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Expert Underscores Importance of Gaining Better Understanding of Mutations in Myelofibrosis

Danielle Ternyila
Published Online:5:23 PM, Fri February 8, 2019

Angela G. Fleischman, MD, PhD

The understanding of mutations in patients with myeloproliferative neoplasms (MPNs), and myelofibrosis (MF) in particular, continues to progress. However, a patient’s mutational profile does not necessarily dictate treatment decisions at this time.

Mutations can play a role in the decision to evaluate a younger, fit patient for transplant, but there is still a lot to learn about these mutations before moving to more personalized treatment regimens.

“I think the next step would be personalizing treatment for the MF patient based on their specific mutational profile, but first we have to understand what these mutations mean,” said Angela G. Fleischman, MD, PhD.

In an interview with Targeted Oncology, Fleischman, an assistant professor in the department of medicine, division of hematology/oncology at UC Irvine Health, discussed a clinical trial at her institution investigating the JAK1 inhibitor itacitinib in patients with MF. She also highlighted other recent advancements for patients with MF, as well as advancements in other MPNs such as essential thrombocytopenia (ET) and polycythemia vera (PV).

TARGETED ONCOLOGY: How has our understanding of the genetics of MF evolved and how has this been used to inform prognosis?

Fleischman: One of the areas in MF where we made particular progress is in better understanding the clonal architecture of the disease and how certain high-risk mutations have prognostic importance. At the present time, understanding an MF patient’s full mutational profile is indeed very helpful and serves for prognostic purposes, but really, we don’t necessarily dictate treatment based on their mutational profile. In the future, this could potentially occur.

One instance where I think knowing someone’s mutational profile is extremely important would be in younger MF patients who would be excellent candidates for transplant. For example, if a younger person with MF has a high-risk mutation, at the present time in clinical practice, this is the type of person that would then be referred for transplant evaluation sooner rather than later.

We are learning a lot more about people’s mutations and what that means for their prognosis, but at the present time, we don’t have enough knowledge to say if they have X mutation, then they should have Y treatment. Where we are using it, however, is in the younger, fit population, helping to decide how aggressive it is to move toward transplant.

TARGETED ONCOLOGY: What are some of the agents that you see potentially getting approved in the field?

Fleischman: The most obvious drugs that are in line for FDA approval in the MF patient population would be another JAK inhibitor. There are a number of JAK inhibitors that have been in clinical trials for quite some time and are moving closer to FDA approval, for example, pacritinib, fedratinib, and momelotinib. There will likely be a new option for a JAK inhibitor available for MF patients in the near future.

The other realm in the non-JAK arena would be interferon. This might be more relevant for PV and ET patients, but there is a long-acting interferon being evaluated, pegylated interferon alfa-2a, which could become available for MPN patients in the near future. The unique feature of interferons is their ability to achieve molecular remission in MPN patients, as well as the potential to reduce fibrosis in patients with early MF.

In terms of what is coming to be available, this is it for MF patients: new JAK inhibitors and interferons. Potentially for anemia, which is a feature of MF that is very difficult to treat with limited options at the present time, luspatercept was recently FDA-approved for myelodysplastic syndromes and is also under evaluation in MF, but transforming growth factor–beta super family inhibitors such as luspatercept or sotatercept could be agents that could be used potentially in the near future in MF for the treatment of anemia.

TARGETED ONCOLOGY: What are some different classes of drugs that are currently under investigation in earlier clinical trials?

Fleischman: In terms of different classes of drugs, there are a number of different pathways being targeted in MF. There are anti-fibrotic agents such as PRM-151. There are telomerase inhibitors, like imetelstat, being investigated in MF. The aurora kinase inhibitor alisertib, is also being evaluated. Another agent called LCL161 which is an inhibitor of apoptosis protein-1, is being investigated in MF. The P53 pathway is also being investigated as a target in MF.

TARGETED ONCOLOGY: Taking all of that into account, how do you see the treatment paradigm evolving over the next several years?

Fleischman: In terms of learning about the mutational architecture of MF, the next step is we need to understand what these mutations mean in the disease. I think the next step would be personalizing treatment for the MF patient based on their specific mutational profile, but first we have to understand what these mutations mean. Then we can move on to tailoring personalized treatments based on a patient’s mutational profile.

TARGETED ONCOLOGY: Can you discuss the rationale for your trial with itacitinib?

Fleischman: Itacitinib is a JAK1 inhibitor. It doesn’t have significant JAK2 inhibitory potential, so the rationale is that many of the JAK inhibitors, for example ruxolitinib (Jakafi), inhibit both JAK1 and JAK2. The thought is that many JAK inhibitors benefit through reduction of the inflammatory cytokine, which could be mediated through JAK1 whereas the propensity to induce cytopenias such as thrombocytopenia, would be through the JAK2 activity. If we focused on a JAK1 inhibitor, that could potentially give the benefit of reduction of inflammation but would not give the side effect of causing thrombocytopenia or anemia.

It’s a very nice paradigm to really highlight that JAK inhibitors are not necessarily targeting the JAK2 mutation. They are targeting information. By demonstrating that a drug with JAK1 potential but devoid of JAK2 inhibitory could potentially work better than a JAK2 inhibitor, this could highlight a very different paradigm than other targeted therapies in terms of MF and MPNs. We are not targeting the mutation, we are targeting an abnormal inflammatory pathway.

TARGETED ONCOLOGY: Are there any advancements in PV or ET that you would also like to highlight?

Fleischman: At ASH 2018, there were a number of oral abstracts directly comparing interferons with hydroxyurea in the upfront setting for PV and ET. Although interferon is an old drug, it has been used in MPNs for many years, and this year’s ASH highlighted the benefits of interferon in the upfront setting. We’re potentially entering a renaissance of interferon. What’s interesting is we are searching for lots of new agents that impact disease course, but yet we have had an agent for many years that is able to induce molecular remissions in patients, which is interferon.

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