Expert Discusses Challenges and Future Opportunities in Treating Myelofibrosis

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In an interview with <em>Targeted Oncology</em>, McCloskey discussed current treatment options for patients with myelofibrosis as well as further options in development in clinical trials. McCloskey recommended that community oncologists partner with specialists to improve the prognosis for these patients until new agents are approved, and for referrals to clinical trials for further research for this patient population.

James K. McCloskey II, MD

James K. McCloskey II, MD

James K. McCloskey II, MD

In the treatment of myelofibrosis, researchers still have not identified the best agent for both high-risk and low-risk patients. For low-risk patients, no agent currently makes a significant difference in improving survival and in high-risk disease, patients typically present with a declining performance status, which makes them less likely to respond to standard-of-care treatments.

Due to the lack of effective options, physicians have a different goal when treating patients with myelofibrosis. &ldquo;Oftentimes, our focus is around treatments that improve their quality of life but, we're not yet successful at changing progression or modulating their overall outcome,&rdquo; said James K. McCloskey II, MD, interim chief, Division of Leukemia, John Theurer Cancer Center. He highlighted 3 different therapies that have shown improvements for patients in quality of life: androgen therapy, telomerase inhibition, and Janus kinase (JAK) inhibition. Deciding which therapy to give, depends on whether the patient is high- or low-risk and what their primary symptom is, said McCloskey.

Patients with low-risk myelofibrosis whose primary issue is anemia may benefit from androgenic therapy with danazol and ruxolitinib (Jakafi), an FDA-approved JAK inhibitor.1Patients with high-risk disease, however, typically benefit from ruxolitinib early on but may not respond to this agent when certain complications develop.

JAK inhibition may also improve quality of life in high-risk patients. Results from the phase III COMFORT-1 trial, which looked at ruxolitinib versus placebo in patients with myelofibrosis, showed sustained clinical benefits in quality of life in addition to spleen size and debilitating symptoms. In the study, 41.9% of patients treated with ruxolitinib had a reduction in spleen volume of &ge;35% at 24 weeks compared with 0.7% in patients treated with placebo (P<.001).2However, high-risk patients who no longer respond to ruxolitinib may see a survival benefit from telomerase inhibition with imetelstat as well.3

Another JAK inhibitor being investigated in clinical trials is pacritinib,4and McCloskey noted that it may be a strong contender for treating patients with myelofibrosis in the community setting, once is it approved. In the meantime, patients who progress and are not responding to any of the approved agents should be referred for enrollment in clinical trials, said McCloskey.

In an interview withTargeted Oncology, McCloskey discussed current treatment options for patients with myelofibrosis as well as further options in development in clinical trials. McCloskey recommended that community oncologists partner with specialists to improve the prognosis for these patients until new agents are approved, and for referrals to clinical trials for further research for this patient population.

TARGETED ONCOLOGY: Could you speak to the challenges of treating patients with myelofibrosis?

McCloskey: The challenge of treating is a tough question. I think there are more questions than answers. Myelofibrosis remains a very challenging disease to treat. For low-risk patients, we have yet to have a clear treatment that improves survival. So, oftentimes, our focus is around treatments that improve their quality of life but, we're not yet successful at changing progression or modulating their overall outcome. I think there are some data that interferon may do that, but across the board, it's not something that we incorporate. [It depends] or your individual clinical practice and large-scale clinical trials haven't clearly shown a benefit, in my opinion.&nbsp;

For higher-risk patients, the challenge we face is that they're often older. They often have suffered the consequences of maybe having lived with low-risk disease for a period of time. So, they're coming to us with transfusion-refractory thrombocytopenia, massive splenomegaly, and a decline in their performance status. These [patients] are harder to treat anyways.

And certainly, some of those patients who progress to acute myeloid leukemia are some of the most challenging patients to treat. I also think that these patient are more difficult to transplant, which is the only curative therapy for these [patients].

TARGETED ONCOLOGY: What are the current treatment options for these patients?*

McCloskey: In terms of current FDA-approved therapies, it varies quite widely. The first thing to [consider] is, are they low-risk or high-risk. If they're low-risk, what is their primary issue or symptom? Patients who have a primary issue with anemia are those who would often benefit from danazol. [It helps to] incorporate that and growth factors in those patients selectively. [Also], selectively using interferon, depending on your clinical practice, can be appropriate.

Interferon remains quite controversial in this disease entity. But it's something we employ sometimes for patients who are symptomatic.

If the patient's primary issue is splenomegaly, then the use&nbsp;of ruxolitinib in those patients is certainly beneficial. If the patient is having systemic symptoms, like bone pain, night sweats, and things of that nature, then additionally,&nbsp;low doses of ruxolitinib also helps these patients.&nbsp;The&nbsp;caveat&nbsp;in low-risk patients is to remember that, if it's not one these issues with splenomegaly or systemic symptoms, then&nbsp;ruxolitinib is not going to help with your cytopenias.&nbsp;

Based on data from the COMFORT trial, high-risk patients may benefit from early implementation of ruxolitinib. So, we often will incorporate it there and certainly at the first evidence of&nbsp;splenomegaly.&nbsp;

Those are the currently approved therapies, which is a short list compared to other diseases we treat for sure.

TARGETED ONCOLOGY: Is there any recent data on JAK inhibition for the treatment of myelofibrosis.

McCloskey: In terms of recent therapy that's promising, there are several coming along. imetelstat has shown some benefit in these [patients] and we're hopeful that it may pan out. There are newer-generation JAK inhibitors as well that appear to be effective. I think we've seen some of these fail previously. But, some of them are coming closer to real-time clinical benefit.

TARGETED ONCOLOGY: What are the options for when a patient fails a JAK inhibitor?

McCloskey: It depends on how you define failure. The most common thing that we see is a patient who has responded to ruxolitinib over time develops worsening cytopenias and may no longer be able to take&nbsp;ruxolitinib. As the counts fall, we get into a&nbsp;conundrum where the patient can't safely take&nbsp;ruxolitinib because of their cytopenias. And for these [patients], there is not a great option for them. So, our approach would be to treat these patients in clinical trials.&nbsp;

I think wherever you're practicing in the community, there's an academic center that has a trial for patients who fail first-line JAK inhibition and this disease entity, given the rarity, is very hard to study. I think that the local universities and academic institutions would welcome these [patients] who don't have a great standard option [into] a clinical trial.&nbsp;

Outside of a clinical trial, if a patient is higher-risk and fit for transplant, we proceed with transplant. And some of the other options are danazol, testosterone, or growth factors might be something you can consider on a case-by-case basis.

TARGETED ONCOLOGY: What do you see evolving over the next several years with regards to the treatment landscape for myelofibrosis?

McCloskey: I would highlight again that it's been made challenging by the fact that the disease is relatively rare, so, it's been very hard for us to accrue to clinical trials. But we have seen promising agents come close to approval. We thought pacritinib would be approved by now for some of these cytopenic patients. Ongoing clinical trials are investigating that. I think that this new JAK inhibitor may come to us soon. I mentioned the telomerase inhibitor imetelstat as well.

There are a variety of other agents that are close to development. I think it will be potentially focusing outside of the JAK pathway [and] using targeted therapies that hopefully will spare patients some of the toxicities. And, we still need to figure out the appropriate time and place to implement stem cell transplant for these [patients].

TARGETED ONCOLOGY: What advice would you want to share with an oncologist seeing patients with myelofibrosis in a community setting?

McCloskey: I think this must be a particularly challenging patient to see because it's very rare, so these patients don't come along every day. There are a lot of nuances to treating them that can be hard to glean from the research that we have. We're limited in that regard.&nbsp;&nbsp;

What's fascinating with someone who does this is that the way I manage a patient may be completely different than the way one of my colleagues does. And, we're both right because there's not a lot of data about what to do.

In my opinion, it never hurts to have that patient seen by a tertiary care center, an academic center, or a specialist who treats myelofibrosis. This is beneficial to both the patient and the provider in the community because at least it plugs that patient in. It gets an initial evaluation that makes sure that we get the appropriate molecular testing. Then, a periodic visit helps us know when we should pull the trigger on transplant and when to change treatments to address some of these cytopenias or quality-of-life issues. Timing the transplant is important because we would like to transplant a patient [who is] truly progressing and failing other lines of therapy before they have end-stage disease, before they develop complications, or before they develop acute myeloid leukemia. A tertiary&nbsp;referral helps accomplish all of that and in many cases, they don't need to see us all the time. One visit once a year would be enough and we can all work together that way.

References

  1. Gowin KL, Kosiorek HE, Dueck AC, et al. Final Analysis of a Multicenter Pilot Phase 2 Study of Ruxolitinib and Danazol in Patients with Myelofibrosis. Blood. 2015;126(23):1618.
  2. Verstovsek S, Mesa RA, Gotlib JR, et al. A double-blind, placebo-controlled trail of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807. doi: 10.1056/NEJMoa1110557.
  3. Wang X, Hu CS, Petersen B, et al. Imetelstat, a telomerase inhibitor, is capable of depleting myelofibrosis stem and progenitor cells. Blood Advances 2018 2:2378-2388; doi: https://doi.org/10.1182/bloodadvances.2018022012.
  4. Mascarenhas J, Hoffman R, Talpaz M, et al. Pacritinib vs Best Available Therapy, Including Ruxolitinib, in Patients With Myelofibrosis. A Randomized Clinical Trial. JAMA Oncol. 2018;4(5):652-659. doi: 10.1001/jamaoncol.2017.5818

*Editor&rsquo;s Note: This interview occurred before the recent FDA approval of fedratinib (Inrebic) in patients with myelofibrosis.

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