Abu-Zeinah Shares Next Steps for Research With Interferon-Alpha in Polycythemia Vera

Now that interferon-alpha (IFN) has been shown to prolong survival in patients with polycythemia vera (PV), it is important that investigative efforts focus on developing a better understanding on the biology of the disease and the mechanisms by which the agent actually improves outcomes, according to Ghaith Abu-Zeinah, MD.

“We recognize that IFN is not a curative treatment—not everyone will respond to it and not everyone is a candidate to receive it. [However, if we] at least know the mechanism or the biology by which it works, then we can develop drugs that could target some of these mechanisms or potentially combine IFN with a drug that can create a synergy that ultimately would lead to a cure for the disease,” Abu-Zeinah said. “On the pathway to developing a cure, we have to learn from what we know with IFN and apply that to the future to develop new drugs and combinations with IFN that could be promising.”

In a single-arm retrospective study, Abu-Zeinah and colleagues found that IFN significantly improved both myelofibrosis-free survival and overall survival (OS) over other standards of care such as hydroxyurea and phlebotomy; the agent was found to have benefit in both low- and high-risk patients. Although prior trials have compared the use of IFN with hydroxyurea, challenges regarding follow-up, the incorporation of certain necessary end points, and difficulty with determining OS benefit has made it difficult to determine whether the agent is beneficial to all patients with PV.

“You do have some follow-up [with some of these trials], but at the end of the day…are we going to wait 5 years to decide whether patients should receive IFN or not? This is a question that has persisted for 30 years and it needs to be buried,” Abu-Zeinah stressed. “This study had to happen because, although retrospective, it is really the only study at this point that can tell us right now whether IFN is a good [option] for everyone, or at least for high-risk patients.”

In an interview with OncLive®, Abu-Zeinah, a hematologist and oncologist at Weill Cornell Medicine, discussed strategies for overcoming challenges faced with clinical trials done in PV, the search for surrogate biomarkers of survival, and ongoing efforts being made to further understand the mechanisms of IFN in this population.

OncLive®: What challenges have previous trials comparing IFN with hydroxyurea faced and how was this overcome in this study?

Abu-Zeinah: The main issue goes back to the problem of [disease] chronicity. Some clinical trials have compared IFN with hydroxyurea head-to-head. The longest follow-up barely exceeds 5 years. As time accrues, we have more years of follow-up. These patients don't all stay on the study, so you don't follow them for 10 years. They [stay on study] for a couple of years and they might come off of it for several reasons. The number you begin with, whether it's 100 patients or 200 patients, atrophies over time.

The clinical trials [that have been done] are good in the sense that they have shown us that, at least in the beginning, there is no difference between hydroxyurea and IFN. They have affirmed what many people thought: efficacy with hydroxyurea and IFN is the same. However, as you follow the patients beyond the first year or 2, you will see that not only are blood counts better controlled [with IFN], but the JAK2 allele burden is also better controlled. Moreover, a higher rate of molecular response [has been observed with IFN]. Although bone marrow biopsies are not necessarily a routine measurement to follow, several studies have examined complete bone marrow responses on IFN in the long term. The clinical trials are missing some end points that we believe are very important for obvious reasons.

[In terms of] other challenges, although we cannot assess survival directly, we do not actually have a surrogate for survival. [If] MFS were a surrogate for OS, it would be great and maybe shorten the follow-up required to meet that end point. What we really need in these clinical trials is a surrogate end point or biomarker that can predict for OS in the long term; that is what I feel the issue is with clinical trials in PV in general, not specific to studying IFN vs hydroxyurea: We need a biomarker.

What efforts have been made to identify such a biomarker? What should this research look like?

The efforts really need to stem from laboratory research or translational research. There needs to be exploratory end points that clinical trials combine in their design. Currently, many of the clinical trials [that are done] primarily target blood counts, spleen size, and symptom burden. It is very important to patients to become symptom free or at least have a lower symptom burden.

I do not discount anything about blood counts being very important, but efforts looking at biological proxies are needed. How can you easily measure the biology of the disease? That is easier said than done. The biology of the disease may have initially seemed simple because we have 1 targetable mutation, JAK2, in 98% of cases. Can we monitor that mutation over time to see how patients are responding [to treatment]? What we have noticed over the past decade since JAK2 has been discovered, is that tracking JAK2 alone does not capture the biology of the disease. What I specifically mean by that is tracking JAK2, whether in the blood or bone marrow, which we use for molecular responses, is not a good surrogate for survival; or, at the very least, it has not proven to be.

We need some type of measurement that can capture the biology of PV and tell us whether the biology is getting better, worse, or if there is evolution. We could then look at treatments and determine whether it can potentially modify the biology of the disease; then, that translates into a clinical benefit, and eventually, survival.

We need to couple laboratory research with clinical trial research and explore these exploratory end points. We need to incorporate them into studies to be able to define a biomarker that we can routinely use. We are working on that currently at Weill Cornell. This is one of our research interests and research projects.

What are some remaining questions that need to be addressed?

They all go back to biology. We know that there is a drug in PV that prolongs survival. Let's look into why that is. There is research on the mechanism of IFN and [we have seen] some elegant studies [with the agent in] animal models. Some studies are now looking at primary patient samples to suggest that IFN has some stem cell–targeting activity.

The takeaway here is, now that we have a drug that prolongs survival, let's use that drug in a laboratory or translational [setting] to identify the mechanism by which it actually prolongs survival. What does it do at the cellular level or the bone marrow environment level that actually makes it modify the disease and lead to better survival outcomes?

Reference

1. Abu-Zeinah G, Krichevsky S, Cruz T, et al. Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival. Leukemia. Published online March 2, 2021. doi:10.1038/s41375-021-01183-8