Expert perspectives on long-term management of patients with polycythemia vera, with regard for the risk of developing secondary MF or AML.
Prithviraj Bose, MD: Coming back to our patient, to make a data-driven, evidence-based recommendation, I’d treat this patient with ruxolitinib [Jakafi]. That’s what I go to in situations of hydroxyurea resistance and intolerance. Clearly this is a high-risk patient with proliferative disease, needing phlebotomies a lot, symptoms, a big spleen—all things that are amenable to being nicely controlled by ruxolitinib. That’s where the data are as well. As I said, after 5 years, we have no new safety concerns and sustained efficacy. To me, it would be a no-brainer to go with ruxolitinib in this setting.
There are discussions regarding disease modification and the long-term risks of myelofibrosis and acute myeloid leukemia, which unfortunately are real even though they’re quite small. The risks at 10 and 15 years are relatively low, but they’re there. To give you some ballpark numbers, at 10 years, there’s a 4.9% to 6% chance of developing post–PV [polycythemia vera] myelofibrosis and a 2.3% to 14% chance of developing AML [acute myeloid leukemia]. At 15 years, these go up a little to 6% to 14% chance of developing post PV myelofibrosis and a 5.5% to 18% chance of developing AML. These are numbers I’m quoting from 1 study, but this study looked at the literature as a whole and tried to summarize the incidence.
These are problems, and we don’t have good evidence that any of our therapies modify this risk, unfortunately. We don’t know that. It has been said that interferons may have a role. That remains to be proven, but they do lower the JAK2 allele burden. That might be extrapolated into as a measure of disease modification. But this hasn’t been shown to clearly translate into clinical outcomes. However, some data from certain groups suggest that pegylated interferon regimens may be able to retard the progression to myelofibrosis. It’s far from settled, and this is something that needs further investigation.
The reduction of the JAK2 allele burden is clearly a strength of interferons, but this is also seen with ruxolitinib. In the RESPONSE trial, over time there was a clear reduction in JAK2 allele burden, and that ended up being about a 50% reduction in a good number of patients, with the mean reduction of the allele burden being around 40% in the long term follow-up, which was up to 4 years at the time this was reported.
In terms of what to tell patients with regard to MF [myelofibrosis] and AML [acute myeloid leukemia] risks, as well as overall goals and thrombosis reduction, we don’t have proven interventions to change the risk of myelofibrosis and AML. The ropeginterferon alpha-2b is recently approved, and interferons may not have the potential to do this. That remains to be seen. However, in terms of long-term disease control, in terms of controlling the blood counts, symptoms, the spleen—things we know are important in terms of quality of life and clotting risk—ruxolitinib has the most robust data in the second-line setting after hydroxyurea failure to achieve those end points.
We didn’t talk about clot reduction with ruxolitinib, but that was shown as well. It wasn’t an efficacy end point in the RESPONSE trials. Thrombosis reduction wasn’t 1 of the end points the trials were powered for, but they were definitely looked at as safety end points. It was shown that there were fewer thromboembolic events on the ruxolitinib arm than in the best-available-therapy arm: 1.8 vs 8.2 in the RESPONSE trial per 100 patient-years of exposure. That’s definitely a signal, and from other studies in MPNs [myeloproliferative neoplasms], that ruxolitinib reduces thrombotic risk even though it may not have been shown as a clearly defined efficacy end point.
Transcript edited for clarity.