In an interview with Targeted Oncology, Douglas Tremblay, MD, discussed the significance of cytoreductive therapy in mitigating thrombotic risk in myeloproliferative neoplasms.
According to Douglas Tremblay, MD, cytoreductive therapy has emerged with a pivotal role in mitigating thrombotic risk in the treatment landscape of myeloproliferative neoplasms (MPNs), specifically essential thrombocytopenia (ET) and polycythemia vera (PV).
Despite the evident benefits, each therapy carries unique adverse effects, requiring the careful consideration of patient-specific factors in treatment administration. Deciding when to initiate cytoreductive therapy in patients with chronic MPNs relies on accurate risk assessment, with parameters such as age and prior thrombotic events often guiding treatment decisions.
Frontline therapies, such as hydroxyurea and interferon, manage blood counts for patients with ET and PV, and newer options are emerging, according to Tremblay, assistant professor of medicine at the Icahn School of Medicine at Mount Sinai. However, the long-term implications focus on thrombosis prevention and disease progression.
Ongoing research endeavors aim to delve deeper into surrogate end points and novel therapeutic avenues, promising to further refine and revolutionize the management of MPNs.
In an interview with Targeted OncologyTM, Tremblay discussed the significance of cytoreductive therapy in mitigating thrombotic risk in MPNs, specifically ET and PV.
Targeted Oncology: What are the potential benefits and risks of cytoreduction in this space?
Tremblay: Cytoreductive therapy refers to multiple medications which are given with the purpose of reducing blood counts in both essential thrombocythemia and polycythemia vera but are also given for the purpose of reducing thrombotic risk. Thrombosis is the leading cause of morbidity and mortality in patients with polycythemia vera and essential thrombocytopenia, and these medications are given in order to mitigate that risk.
Cytoreductive therapy is given in order to reduce thrombotic risk, and that's really its purpose. It is associated with some [adverse] effects in different medications, including hydroxyurea, pegylated interferon, anagrelide for ET, or ruxolitinib [Jakafi] for PV, [which] have unique [adverse] effect profiles, but they all carry some risks and [adverse] effects. They're not curative therapies. They are really done to reduce risk of thrombosis and therefore, it is important to understand what someone's baseline risk is for thrombosis. That way you can decide if the benefits of cytoreductive therapy outweigh the risks in those patients.
What factors influence the decision to recommend cytoreduction for these patients?
The discussion around when to start cytoreductive therapy around chronic MPN patients with PV and ET really has to do around risk stratification. There are risk stratification schemas available, largely used through the [European LeukemiaNet] risk classification, which dictates high-risk patients older than the age of 60 or those who have a prior thrombosis. In ET, there are additional risk stratification schemas, including the IPSET-Thrombosis and the revised subset thrombosis score. These can dictate which patients are high-risk for thrombosis and then who will be benefiting from cytoreductive therapy.
But many of these different factors exist on a continuum, such as age in particular, and what I highlighted in my talk is that there is not a difference in your risk stratification the day that you turn 61 years old, and it is very important to understand someone's biological age, including their cardiovascular risk factors that can inform their overall risk of having a blood clot in these diseases.
What are the different cytoreduction approaches available to patients?
The different set of cytoreductive approaches available for patients depends on which disease you have. If you have ET, the frontline therapies include hydroxyurea or pegylated interferon. If you have polycythemia vera, it is hydroxyurea, pegylated interferon, or ropeginterferon alfa-2b [Besremi] given at a once every 2-week dose. These options are available in the frontline.
In second-line settings, there are additional options available such as the JAK 1/2 inhibitor ruxolitinib in polycythemia vera, as well as the the selective platelet reducer anagrelide in patients with essential thrombocythemia.
What do the safety profiles of these agents look like? How can clinicians manage the toxicity?
In terms of safety profile, I'll focus first on hydroxyurea and interferon-based therapy. Hydroxyurea is an oral pill that is frequently taken once a day. [Adverse] effects of this include hematologic toxicity [in]other cell lines, including reducing white blood cell count, as well as reducing platelet count or hemoglobin, which is desirable in some patients, but also can introduce toxicities where you could try to control the blood count that is abnormally elevated in and PV or ET. [Adverse] effects of hydroxyurea outside of hematologic toxicities include some mouth ulcers, particularly in higher doses, or skin ulcers, particularly around the medial malleolus that can lead to discontinuation of the drug. There is also an increased risk of non-melanoma skin cancer that is induced with hydroxyurea.
In terms of pegylated interferon, it is an injectable medication and a frequent [adverse] effect is a flu-like syndrome that happens after the first dose. It usually gets better over time. Concerning [adverse] effects that informed selection of this agent vs other agents include its neuropsychiatric [adverse] effects in patients who have severe depression or anxiety or psychiatric disorders. It is largely contraindicated in those diseases, as well as exacerbating autoimmune diseases. There is also hepatotoxicity and ocular toxicity which require monitoring as well. Importantly, in younger patients, particularly those who are trying to conceive or trying to get pregnant, pegylated interferon is safe in that setting and hydroxyurea cannot be used.
What are the long-term implications of cytoreductive therapy for these patients with MPNs?
The long-term implications of cytoreductive therapy for PV and ET is of particular concern. Ultimately, the goal is to reduce risk of thrombosis. That is done to reduce this very fatal complication of these diseases. There is also a concern that we want to prevent these diseases from progressing and there, there are some distinctions too. There is hydroxyurea vs pegylated interferon. When you look at certain potential surrogate biomarkers like JAK2 V617F allele burden, interferon in particular is much better at trying at reducing those numbers and the burden of JAK V617Fallele burden, particularly over long-term treatment. Whether or not that really translates into decreased disease progression is still an unanswered question, but it is clearly more anti-clonal in that respect.
Ultimately, there are also safety concerns about treating someone for years and years. Every patient has to have a discussion with their physician as it relates to what those safety concerns are and the potential benefits in the long-term.
What research is being done currently to combat these challenges?
There are multiple research avenues that are trying to address these challenges. Firstly, there is additional work trying to understand how we can identify surrogate end points for thrombosis in these diseases in order to accelerate development of novel therapeutics in these stages. There are also new drugs coming into the market that are cytoreductive therapies that can be used, particularly in ET, trying to control platelet counts and may have some distinct benefits in terms of understanding the disease clone.
I think a lot of exciting data comes from 2 separate avenues. One is new antibody or immune-mediated activity against calreticulin-mutated patients [with ET]. There is also a whole new class of drugs that work on the hepcidin and pathways to perform almost like a chemical phlebotomy in patients and obviate the need for phlebotomy in these [patients with] polycythemia vera.
What should community oncologists know about using cytoreduction therapy for their patients?
The key takeaways about cytoreductive therapy in polycythemia vera and ET is that right now, I do not think there's enough evidence to recommend 1 cytoreductive agent over the other, particularly hydroxyurea vs interferon-based therapies. For every patient, it is a discussion regarding the pros and cons of each approach that incorporates discussions regarding route of administration, toxicities, efficacy, safety and I think that is a conversation that needs to happen with each patient.
In the second-line setting, I think that in polycythemia vera, ruxolitinib is an excellent choice, particularly for patients who fail hydroxyurea or are intolerant who have a heavy symptom burden. Anagrelide can also be a choice in select patients without cardiac comorbidities.
Another key takeaway is that platelet count of controlling blood counts has not been correlated with end points like survival or thrombosis. While we try to reduce people to almost a normal level, the relevance and the ability to translate that goal into real, important outcomes has not been established. Further work needs to be done to understand what are the target blood counts for the cytoreductive therapies.
What support services can be made available for patients during an after cytoreductive treatment?
I think a lot of support services for patients with PV and ET during cytoreductive therapy revolve around mitigating toxicities and trying to understand what some of these toxicities are. I think it is helpful to partner with your physician to try to understand what sort of additional resources are available. Some of these medications can also have a high financial cost. There are support services available to help patients who are eligible to try to enjoy the benefits of some of these newer medications to improve their outcomes. A lot of treatment of PV and ET involves more of a holistic approach and not just focusing on the blood counts, but focusing on other parameters that each patient has and trying to optimize those in order to ensure the best long-term outcomes.
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