During a Targeted Oncology™ Case-Based Roundtable™ event, Jonathan Abbas, MD, discussed data on therapies for a patient with polycythemia vera who did not adequately respond to hydroxyurea.
Targeted OncologyTM: What are the preferred therapy options in uncontrolled polycythemia vera (PV)?
ABBAS: We can use the NCCN [National Comprehensive Cancer Network] guidelines to look at therapy options in the setting of inadequate response or loss of response to hydroxyurea [Hydrea] plus phlebotomy. Peginterferon alfa-2a [Pegasys] is on the list, and the preferred category 1 treatment is ruxolitinib [Jakafi].1
During decision-making for patients with inadequate response/loss of response to cytoreductive therapy, do you consider the NCCN or other guidelines?
I usually don’t unless it’s more of an outlier situation. In this clinical case, I don’t think I would have gone to it…. If you’re down to every 6 to 8 weeks on phlebotomy and on a low to intermediate dose of hydroxyurea that’s well tolerated—no leg ulcers, no concerns, no other effects of the hydroxyurea— then that’s not a terribly burdensome disease for the patient if they agree with that assessment and say they are fine with getting phlebotomies done every 6 to 8 weeks.
One should keep an eye out for an increased frequency of phlebotomies. That might be where real-world experience and the NCCN guidelines don’t perfectly align. I don’t know if phlebotomy independence needs to be an end point. I think what’s considered an acceptable degree of phlebotomy is a perfectly fine end point to use.
Which data support the use of ruxolitinib as second-line treatment for PV?
The RESPONSE trial [NCT01243944] was the trial looking at ruxolitinib vs best available therapy [BAT]. It was a 1:1 [randomized trial] with about 200 patients. It does have data from a longer, 5-year follow-up that came out in around 2020.2
The study had an interesting composite end point of hematocrit control and spleen volume reduction, which was a challenging end point to meet. It met that end point in only 1 in 5 patients, so 20%, compared with BAT, [which met the end points] in less than 1% of patients. About 40% of patients had the reduction in spleen volume and about 60% had hematocrit control with ruxolitinib.
[Total] symptom scores…were grouped into 3 different clusters and compared with the BAT arm, there was dramatic improvement in all 3 arms with ruxolitinib.3 So this was the trial that led to the FDA approval for ruxolitinib in the second-line setting. [Using] BAT in many cases unfortunately [meant] continuing what we knew wasn’t working and keeping patients on hydroxyurea and phlebotomy because there were so few options.
What did the long-term follow-up of the RESPONSE trial show for these patients?
[We have] the long-term safety and efficacy data, and this is about durability. For the responders, most patients—over 70%—have maintained their response now 5 years out.2 So, it is key that we tell patients this is a chronic, lifelong disease, but we’re getting very durable responses with ruxolitinib.
A complete hematologic remission [CHR] is a nice thing to get. Is it certainly necessary? By no means, but it is lovely when we do achieve it. CHR means complete normalization of the complete blood count.
While some patients fall off, long term, about 55% of patients at 5 years have maintained a CHR. Again, [this shows] excellent durability. For hematocrit control now, most patients 5 years out have been able to maintain their hematocrit. [The 2 groups of patients] with or without splenomegaly showed no appreciable differences. We don’t see it breaking it down by the group with or without splenomegaly, so there is no tremendous variability.3,4
How did the dosing of ruxolitinib affect toxicity in RESPONSE?
It is important to remember dosing here. In PV, we’re now at 10 mg twice daily, not 20 mg twice daily. We’re not using a thrombocytopenia-based dosing, so we’re using a lower dose. Predictably, the degree of anemia and thrombocytopenia is better. We don’t see too many cases where ruxolitinib is driving the red blood cell count down so much that you’re creating new issues. The BAT had 23% fatigue of all grades vs 5% for ruxolitinib, and 12% for night sweats vs 3%, respectively, which are suggestive data. I don’t think there’s anything that’s going to jump out as a major flag here. Infections should be noted. There were more infections in the BAT group [59.8%] than in the ruxolitinib group [18.9%].2 But the point here is that ruxolitinib tolerability is, like we’ve seen across all other disease states, excellent.
There was a low rate of thrombotic events, at 5% for all grades, and 3% for grades 3 or 4. So getting good control of the disease is what we’re doing to decrease them. A secondary malignancy is not something we think about as often with ruxolitinib as you do with some other classes of drugs, like immunomodulatory drugs, but it is important to note that it was 7 [per 100 patient-years of exposure].
Most of these were non-melanoma skin cancers.2 There are, however, more serious hematologic malignancies and even solid tumor malignancies that have been seen after prolonged JAK2 [drug] exposure. So it’s something to think about and counsel patients on. For patients who are already [diagnosed] with basal cell or squamous cell carcinoma, you want to keep an eye on that and make sure they’re staying on top of it.
What data support the use of pegylated interferon as second-line treatment for PV?
The studies of hydroxyurea vs ropeginterferon alfa-2b [Besremi] include PROUD-PV [NCT01949805] and CONTINUATION-PV [NCT02218047]. The PROUD-PV study was looking at 1 year of treatment randomized to hydroxyurea or ropeginterferon. Patients who had been on hydroxyurea were randomized to continue it vs peginterferon or ropeginterferon. Then the CONTINUATION-PV study moved further [out], to 3 to 5 years.5
While it might take time to work, the CHR rate of the interferon vs control group—the group continuing hydroxyurea, which we knew wasn’t working well—[at months 24 and 36] was 70% vs 50%, respectively.5 So compared with the control group, we are seeing some clinical benefit that was statistically significant at the molecular level where they were measuring JAK2 allele burdens.
In the setting of hydroxyurea failure, interferon is an excellent treatment. It is better than continuing hydroxyurea? Has it been pushed [back in] the line of therapy behind ruxolitinib? I think so, but it is an excellent treatment. If you run into a ruxolitinib-intolerant patient, it is something to absolutely keep in mind. Adverse events [AEs] were very low. There is a lot of concern about things like some of the psychiatric AEs, but ropeginterferon had 4% of psychiatric AEs of all grades.
Endocrine events and musculoskeletal events were low, too.5 It’s a drug that we have heard nightmares about from the days before the pegylated versions of it, but it does have an impressive safety profile. I have not been forced into using this in several years, which is a great testament to how good something like ruxolitinib is, but when I have had to use it, I was a believer. One of my myeloproliferative neoplasms mentors, Ruben Mesa, MD, is an enormous believer in it, and he probably at any given point has 200 patients on interferon who are doing great.
1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms; version 3.2022. Accessed March 6, 2023. https://bit.ly/2E77tIB
2. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
3. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435. doi:10.1056/NEJMoa1409002
4. Passamonti F, Griesshammer M, Palandri F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18(1):88-99. doi:10.1016/S1470-2045(16)30558-7
5. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020;7(3):e196- e208. doi:10.1016/S2352-3026(19)30236-4