Second-Line Therapy for Patients With Polycythemia Vera: A Review of Data on Ruxolitinib

Expert Roundtable Part 4

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 fourth and final video of the series, the members of the panel review the available data and discuss the selection and management of second-line therapies, particularly ruxolitinib, for patients with PV. 

Transcript:

Claire Harrison: Welcome everyone and thank you for joining us today for our fourth discussion where we'll be covering the topic of data in regard to second-line therapies, particularly ruxolitinib and the management of this drug in patients with PV. 

I first of all want to ask you, Alessandro—if you have a patient who's failing therapy, either interferon or hydroxycarbamide, as we previously discussed would be our first-line therapy. The choice [for second-line] is sometimes to switch to one of those other drugs, or switch to ruxolitinib. What would make you decide one way or the other?

Alessandro Rambaldi: Well, first of all, the age of the patient is important, and the presence also of systemic symptoms is important. If pruritus is a major issue of the patient, say for example in a patient under hydroxyurea, 65 years of age, I would definitely consider switching to ruxolitinib. Also, as in the first trial performed in a PV patient with ruxolitinib, I would consider the presence of concomitant splenomegaly—though not that huge, but if present, that in my opinion [] an important suggestion to switch to ruxolitinib.

Claire Harrison: Yeah, that's true. So I'm thinking about the RESPONSE studies, that's the one you are referencing, isn't it?

Alessandro Rambaldi: Yes.

Claire Harrison: So the first response study, the patients had to have splenomegaly and the endpoint was built around splenomegaly, wasn't it? We know that ruxolitnib is very effective at that.

Alessandro Rambaldi: Exactly. Which is not very typical for a true PV patient, but it may happen, and this is something that should be considered as a guide to choose ruxolitinib as the next treatment option.

Claire Harrison: Yeah. And often patients in these studies that have already been on hydroxycarbamide and interferon. 

But maybe I can turn to you now, Jean-Jacques, and ask you just to—you were one of the lead investigators on both of these studies and have contributed a lot and have a vast experience. Could you maybe just summarize what we've learned about ruxolitinib from the RESPONSE studies and how you would be cautious about what things you would check before you started a patient on the drug?

Jean-Jacques Kiladjian: The RESPONSE studies showed that ruxolitinib was very efficient to restore response in terms of control of hematocrit that was achieved in more than 60% of patients who were previously intolerant or resistant to hydroxycarbamide, so it clearly established the role of this drug as a second-line therapy after failure of hydroxycarbamide. 

What we learned about safety also and efficacy, it may help us also to choose, as Alessandro said, between interferon or ruxolitinib as second line. For example, some symptoms we mentioned earlier, pruritus, was very, very efficiently treated with ruxolitinib. So if your patient failed because he has a lot of pruritus, I would choose this drug first.

On the other hand, in the RESPONSE trial we showed a slight increase in the risk of skin cancers in patients receiving ruxolitinib versus best available therapy, and this was particularly true for those who had a previous history of skin cancer or problems or long exposure to hydroxycarbamide. So, this may also be if you change your treatment because of the occurrence of skin problems in your patients, maybe interferon would be a better choice than ruxolitinib, at least for beginning. 

But may I ask you, Claire? In turn, you also presented recently beautiful results of an academic trial, MAJIC-PV trial, that also tested ruxolitinib in PV patients. Can you highlight the results of this study?

Claire Harrison: Sure. I think you highlighted very nicely the data from the RESPONSE studies, but what we wanted to look at with the MAJIC-PV study, which was an academic study we did in the UK, was what happens in the longer term? 

So the RESPONSE studies had a crossover, and in MAJIC-PV we didn't permit crossover between the 2 arms of the study, so we had patients who met the ELN criteria for hydroxycarbamide resistance or intolerance. Many of them had already had interferon and we randomized them to either ruxolitinib or best available therapy. We showed essentially the same data as the RESPONSE studies and other studies with ruxolitinib. 

But importantly, we found not only did patients have more chance of having better control of their blood count and their hematocrit, but we also saw that, first of all, if patients achieved a good control with ruxolitinib and maintained on that drug, then patients had less chance of a major event, so a thrombosis, a hemorrhage, disease transformation, or death. We also showed a correlation between achieving a good control of all parameters of the disease. So spleen, white count, platelets and hematocrit, and reduced occurrence of these events. 

We've had long discussions, in these discussions we've been having and also in the field, about the importance of controlling the white cell count and the platelet count. Then we also showed that looking at control of the disease from the perspective of lowering the JAK allele burden, which we know can be done very well with interferon. We found that this was also achievable over time with ruxolitinib, and tended to be durable, not to the same level that we see in CML, but a 50% reduction in allele burden, and that this was associated again with a better outcome for a patient. Regardless of whether the patient achieved that with interferon or with ruxolitinib, we saw that the patients were less likely to have thrombosis, hemorrhage, transformation and they had a better overall survival.

So, this may be challenging a bit the way we think about monitoring this disease—not just perhaps the blood count, but maybe also the JAK allele burden needs to be thought of. We also did pick up again these risks of skin cancers, infections, which are well known with ruxolitinib, and would like to look as well about cardiovascular risk, because we know especially in PV patients that the cholesterol level goes up. We didn't look at that specifically in this study, but this is something we need to look at again in the future, so thank you for bringing that up. 

I'm wondering now where will we use ruxolitinib in the future? We are running this study between the French and the UK networks asking about should it be used earlier. Beautifully named study called MITHRIDATE. You are responsible for the name, Jean-Jacques.

Jean-Jacques Kiladjian: Yes, I admit.

Claire Harrison: Yes. See, in the future there's still a lot to learn, isn't there? So maybe I could come to you both for a message about what you think we still need to learn in the future about this disease and how to manage our patients. 

Maybe I could come to you first, Jean-Jacques, and then yourself, Alessandro.

Jean-Jacques Kiladjian: Yeah. Thank you. I would say that we have now I think good drugs and good strategies to reduce to a very low level the risk of cardiovascular events in these patients that reach almost the risk of the general populations once they are followed and properly treated. 

Then we have these long-term endpoints. This is transformation to myelofibrosis, transition to myelodysplasia or even sometimes acute leukemia, and we still don't know well how to avoid this or reduce this risk, in particular for younger patients who are more and more often diagnosed now, especially young women. We need to address this issue in the long term, and maybe molecular data will help us to better define the strategy in the future.

Claire Harrison: Thank you so much. Alessandro, words from you for the future?

Alessandro Rambaldi: Yeah. I think that we have achieved important results over the last years but there is still a lot of to be done for the future. And again, the possibility to have disease-modifying drugs in terms of impacting on the biology. We know that both interferon and ruxolitinib can have an impact on the allele burden, but at the cost of some toxicity. And so for the near future, we would really welcome a new drugs impacting on the biology, for the mid and long-term side effects associated invariably to the available treatment. There is a big future ahead to be investigated.

Claire Harrison: Beautifully said. Thank you so much. I would say we learned a lot today. I want to thank both of you so very much for this wonderful discussion. I think we all learned that careful individual patient care which is evidence-based is really, really important. 

I want to thank you both, thank our audience for taking the time to listen, and thank you to Oncology Learning Network for organizing this discussion series.