Anticipating the Future of Polycythemia Vera Treatment: Weighing Efficacy and Toxicity


An expert presenting at the Society of Hematology Oncology 2021 Annual Conference shared important updates in polycythemia vera (PV) treatment and weighed in on the direction of future treatment.

Future polycythemia vera (PV) treatment plans should be modeled around available criteria and anticipated molecular targets, explained an expert in the field. Additionally, researchers anticipate that interferons or ruxolitinib (Jakafi) will continue to be mainstays in PV treatment due to their demonstrated efficacy in their respective lines.

“Treatment of patients with PV should be, in my opinion, tailored based on the risk,” Francesco Passamonti, MD, said in his presentation at the Society of Hematology Oncology 2021 Annual Conference. “This is quite important. In the future, we will probably have to work more on additional mutations and the role of additional mutations in the prediction of events in PV.”

Until these mutations are found, criteria such as being above 60 years old and history of thrombosis have to be considered according to Passamonti, a professor at Universita dell'Insubria in Varese, Italy.

When managing PV, it’s important to take into account the natural history of the disease. There is a median of 3.3% of people a year who experience thrombosis. The risk of myelofibrosis is 0.9% at 1 year, 5% at 5 years, and 34% at 10 years. Lastly, the risk of blast phase is 0.4% and the incidence stays at this rate over time.

According to the National Comprehensive Cancer Network (NCCN) guidelines, the initial indication for low-risk disease is to monitor for and manage cardiovascular risk factors, give 81 to 100 mg of aspirin per day, and use phlebotomy to maintain a hematocrit level of less than 45%. Passamonti said “the first question is if there is evidence for an alternative to this approach.”

One option comes from phase 2 trial data published in 2021 of ropeginterferon alfa-2b (Besremi; ropegIFN) in low-risk PV (NCT03003325). The study enrolled 127 patients randomized 1:1 to phlebotomy plus aspirin (n = 63) versus phlebotomy, aspirin, and ropegIFN (n = 64). The median follow-up was 12.1 months, and the primary end point was the proportion of responders—patients with median hematocrit level of less than 45% without disease progression—at 1 year of treatment.

More patients in the experimental arm achieved the composite primary end point than the standard arm, with 84% versus 60% responding by 1 year (odds ratio [OR], 3.5; 95% CI, 1.3-10.4; P = .008). Additionally, 84% of patients receiving ropegIFN had hematocrit control compared with 66% receiving only phlebotomy and aspirin. No patients in the experimental arm had disease progression, however 8% of patients in the standard arm progressed. RopegIFN also demonstrated better symptomology for patients versus the standard of care.

After a patient with low-risk PV experiences symptomatic disease with potential indications for cytoreductive therapy, their disease is considered high risk and they need therapy. In high-risk disease, the NCCN guidelines recommend hydroxyurea or peginterferon alfa-2a in addition to the options suggested for low-risk PV.

Multiple studies have looked into using interferon treatments in PV, including the phase 3 PROUD-PV (2012-005259-18) and CONTINUATION-PV (2014-001357-17) trials. Treatment-naive patients who required cytoreduction were randomized 1:1 to receive ropegIFN (n = 127) versus hydroxyurea (n = 130) for 12 months in PROUD-PV. Twenty-one patients given ropegIFN discontinued treatment and 19 discontinued standard therapy.

In the CONTINUATION-PV trial, patient either continued on ropegIFN (n = 95) or best available therapy (BAT; n = 76). There were 16 patients who discontinued ropegIFN and 7 who discontinued BAT.

Patients treated with ropegIFN achieved complete hematologic response (CHR) at a higher rate than those on the standard arm after 3 years of therapy. The rate of phlebotomy-free patients was higher with ropegIFN, at 79.8% at 4 years compared with 60.0% (P = .007).

“The most relevant of the responses obtained with interferon was the rate of patients who obtained a molecular response during the 3 years. It was clearly higher with ropegIFN versus hydroxyurea,” Passamonti said. The patients with lower JAK2 AB had a higher number of CHR at 1, 2, and 3 years as well.

The rate of major thromboembolic adverse events (3%) and myelofibrosis (1 case each) was similar between the 2 arms.

If a patient with high-risk PV experiences inadequate response or loss of response, physicians must decide on a second-line treatment. Options include clinical trial or ruxolitinib as preferred regimens, or hydroxyurea or ropegIFN as other recommendations if not previously used.

Peg-interferon-α2a (pegIFN) was investigated in the second line in the phase 2 MPD-RC 111 trial (NCT01259817) of 50 patients with high-risk disease. After 1 year, complete response was achieved in 22% of patients with PV, 46% had a hematocrit level of less than 45%, 37% were phlebotomy independent, 32% had splenomegaly normalization, and 41.3% had more than 20% variant allele frequency reduction. There were 2% of patients with major vascular events at 1 year and 5% at 2 years. Even after discontinuation of pegIFN, data have shown patients can have CHR over time.

“Interferons, either pegIFN or ropegIFN, provided evidence of efficacy in first- and second-line setting within 1- to 3-year follow-up, so the question is: Is 1- to 3-year follow-up enough for me to decide to use ropegIFN in a patient with PV,” Passamonti asked. “Probably not in [all patients], but I think in young patients, interferon is a good option for high risk.”

Currently, the only therapy approved for second-line treatment of high-risk PV is ruxolitinib. The RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) trials enrolled patient who were resistant or intolerant to hydroxyurea, required phlebotomy every 3 months, had palpable spleen with MRI-confirmed volume of over 450 cm3, and platelet count of less than 100,000. Patients were randomized 1:1 to ruxolitinib at 10 mg twice daily (n = 110) versus BAT (n = 112). There was a primary composite end point of hematocrit control in the absence of phlebotomy and 35% or more spleen volume reduction (SVR35) at week 32 in the RESPONSE trial.

In RESPONSE-2, patients did not have splenomegaly and did not require SVR35 as an end point. The end point in this trial was assessed at week 28.

There were 21% of patients who achieved the primary composite end point in the ruxolitinib arm versus 1% in the BAT arm (OR, 28.64; 95% CI, 4.50-1206; P < .001). Separately, SVR35 was seen in 38% of patients receiving ruxolitinib and 1 patient receiving BAT; 60% and 20% achieved hematocrit control, respectively.

The RESPONSE-2 trial confirmed data for hematocrit control, with 62.2% of patients given ruxolitinib achieving control compared with 18.7% given BAT (OR, 7.28; 95% CI, 3.43-15.45; P < .0001).

After 5 years of follow-up for the RESPONSE trial, 83% of patients on the ruxolitinib arm did not require phlebotomies. There were 41% with normalization of leukocytosis and 46% with normalization of thrombocytosis. There was a 67% 5-year probability of maintaining clinic-hematological response and 72% 5-year probability of maintaining SVR35.

In the ruxolitinib arm, the rate of thromboembolic events was 1.2 per 100 patient-years, 8.2 in the BAT arm, and 2.7 in patients who crossed over from BAT to ruxolitinib. Ruxolitinib also improved rates of second malignancies or nonmelanoma skin cancer compared with BAT but did not improve rates of transformation to myelofibrosis and acute myeloid leukemia, according to Passamonti.

Passamonti concluded that he hoped that in the future, new drugs will be able to control thrombosis as well as control the evolution from PV to post-PV myelofibrosis considering that is a more difficult condition to treat.


Mora B, Passamonti F. Polycythemia Vera: Is it Time to Rethink Treatment? Presented at: 62nd American Society of Hematology Annual Meeting and Exposition. December 5-8, 2020. Accessed Sep

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