Aims of Treatment and Choice of First-Line Therapy for Patients With Polycythemia Vera
Expert Roundtable Part 2
Expert Roundtable Part 2
In this expert roundtable series, Claire Harrison, MD, Guy's and St Thomas' NHS Foundation Trust leads a 4-part roundtable panel discussion on polycythemia vera (PV) and the importance of hematocrit control with Jean-Jacques Kiladjian, MD, Saint Louis Hospital, Paris, and Alessandro Rambaldi, MD, University of Milan.
In the second video of the series, the members of the panel discuss aims of treatment and choice of first-line therapy for patients with PV.
Transcript:
Claire Harrison: Welcome everyone, and thank you for joining us today. For our second discussion, we'll be covering aims of treatment and choice of first line therapy for PV.
So, let's leap right in. Alessandro, why don't I ask you to comment about the aim of therapy today in 2023 for patients with p. vera. Is it just thrombosis risk reduction? Is it just controlling the hematocrit? What do you have in mind when you see a patient?
Alessandro Rambaldi: It's clear that we have also new and more appealing needs and aims for the future, and we would really impact on the natural history of the disease. And we know that we have some drugs, interferon first, that can impact on the biology of the disease, and so I think that the current perspective [] when we initiate the treatment in this patient has changed and the possibility to modify the natural history of disease is now a reality.
Claire Harrison: I'm really interested to hear you say that. I think in my mind, first and foremost, I would always say aspirin and venesection and patient education, documenting symptoms. And then of course thrombosis risk reduction. But of course we want to change the natural history of the disease, or at least do no harm to the patient where possible. So I mean, clearly we're at this point where when we're choosing to start a treatment, if we're choosing to start it for thrombosis risk reduction, we would be choosing between interferon or hydroxycarbamide.
It's quite clear now that the state of play in the field has shifted a little bit, and Jean-Jacques, you've been a huge part of that. So for yourself, with a patient in front of you, and there's some evidence that at least in the short term that when we control blood counts, we can control them equally well with these 2 treatments, but they are different in terms of what they might do to the JAK allele burden, and maybe what they might do in the longer term, better stability of control might be achieved with interferon, especially the better-tolerated longer acting forms. So, when you are talking to a patient, what would you say about these drugs and which one—which would you maybe disqualify a patient for hydroxycarbamide or disqualify one for interferon?
Jean-Jacques Kiladjian: Yes. Obviously, as you said, we have now these 2 drugs available as first line therapy for PV, and I would say that, first of all, there are some contraindications for interferon in particular, very few for hydroxyurea, but for interferon you have some contraindication that, for example, active autoimmune diseases, active psychiatric problems, et cetera. So, we have a series of contraindications.
This drug is not possible to give to every patient. For example, those with an active autoimmune disorder or active psychiatric problem, et cetera, cannot be eligible for interferon alpha, at least until these conditions are controlled. On the other hand, we have this, as you mentioned, maybe long-term effects that are more, let's say evidence for interferon rather than with hydroxyurea—in particular the reduction of the JAK2 allele burden, and we hope that this may translate to a lower risk of evolution of the disease, in particular to myelofibrosis, because as we know, the higher the high-yield burden of JAK2, the higher the incidence of occurrence of fibrosis.
So, we hope that this may be the preferred drug if there's no contraindication. If the patient is okay, also, because this is a different administration. The hydroxyurea is an oral drug, the other one is subcutaneous. And also, if the drug is well-tolerated, and as you stressed, it's clear that the new formulations over time, pegylated and now the ropeginterferon, [have] better and better tolerance, and this is a key point because this was the main limitation for the use of interferon, at least for the long term or at a high dose, because it was poorly tolerated. But now with these new forms, the tolerance is much better and we can propose this drug more frequently, I think.
Claire Harrison: And just to touch on, Alessandro, would you mind telling me, do you think there's a patient who should definitely not have hydroxycarbamide? We touched on who shouldn't have interferon, but for you is a patient who should not have hydroxycarbamide?
Alessandro Rambaldi: Well, I believe that the younger patient, particularly a young female, should avoid [starting] hydroxycarbamide, and now the availability of pegylated interferon is a valuable option. I personally confirm what Jean-Jacques just said, that the tolerability of these new formulations of interferon are significantly better-tolerated. So, that's represent a significant advantage for patients in whom the expected period of treatment in their life is very long. So, young patients should avoid [starting] hydroxycarbamide too early.
Claire Harrison: I think I agree. So interestingly, recently we've also seen a lot of data focusing on symptom burden and use of treatment to control symptoms. I must admit that I do sometimes do a trial of treatment to control symptoms, but in that situation I often find myself using hydroxyurea and then maybe switching to interferon.
But I do find that pruritus can be particularly difficult, and pruritus can get worse sometimes with interferon. Any comments on that from you, Jean-Jacques, that could be practically important for colleagues?
Jean-Jacques Kiladjian: Yes, you are right. It's kind of a double-edged sword because sometimes you can have a nice response on pruritus, in particular with interferon. On the other hand, interferon can induce pruritus by itself.
So the mechanism is different, but at the end of the day the patient still has itching, so how can we manage that? And then hopefully we have another drug now that can help us in that particular situation, namely ruxolitinib, but it's clearly a symptom that is sometimes difficult to manage for the patient, and can be very boring for them.
Claire Harrison: And just maybe a word from you about starting interferon and how do you start? Do you start with a full dose or do you start with a low dose and ramp up? And lastly, just one thing. Occasionally we have a few concerns about starting interferon in someone that's had a recent thrombotic event, a cardiac event or splanchnic vein thrombosis. Any quick comments on that?
Jean-Jacques Kiladjian: Yeah. Interferon, at least in the short term, has a kind of inflammatory effect because it's a compound that we produce when we are infected by virus, et cetera, that produces inflammation, to help us to fight the infection. So, we have this effect, and for patients who just had the thrombotic events, sometimes you can be afraid that it may increase the risk of recurrent thrombosis. In these cases, sometimes I start with hydroxycarbamide for a few weeks or months and then the patients get used to the diagnosis, you can discuss the treatments difference, [] because usually it's very well-tolerated in the short term, gives nice results, and then you have the time to switch to interferon alpha and avoid this effect of inflammation.
I usually start at low dose and increase gradually until I achieve the response, and then stop hydroxycarbamide, of course, if it was a combined treatment for the beginning. But I would say that there's no hurry at the beginning because you can always manage the patients with phlebotomy to reduce your hematocrit. You can start hydroxyurea, that works within a few days usually to control the leukocytes, the platelets when they are elevated, and then you switch to interferon, and usually it works very well and the tolerance is much better than starting upfront with a high dose.
Claire Harrison: That's really helpful. Alessandro, anything that you would add?
Alessandro Rambaldi: No. I would like to comment your point about pruritus because it's true: the paradoxical effect that sometimes interferon can induce pruritus. So, unfortunately, we do not have yet a key for understanding the patients in whom this can happen. Our recent experience with the pegylated, the ropeginterferon, was overall positive.
I would say that this is in general a promising issue that we can derive from this clinical trial. On the other hand, in the standard of care, in the daily practice, what Jean-Jacques suggested to start with hydroxyurea and then gradually to move to interferon may be a wise approach and practically feasible.
Claire Harrison: Yeah. I think taking a time with the patient is really important because these are treatments we want them to take for a long time.
Alessandro Rambaldi: Yeah.
Claire Harrison: Well, that was great. Thank you very much for joining us for that discussion about aims of treatment and choice of first-line therapy. Please join us for our next discussion on how do we know when treatment is failing and what treatment we should choose next.
