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Pegylated Interferon Leads to High Response Rates in Essential Thrombocythemia and Polycythemia Vera After Hydroxyurea

December 30, 2021

According to results of a phase II study published in Blood, treatment with pegylated-interferon-α (PEG-rIFN-α) was associated with an overall response rate (ORR) of approximately two-thirds in patients with high-risk essential thrombocythemia (ET) and polycythemia vera (PV) that is resistant or intolerant to hydroxyurea. Researchers also found that, in patients with ET, the presence of a CALR mutation was associated with higher complete response (CR) rates to PEG-rIFN-α, suggesting that mutational status may help identify which patients would benefit most from this therapy.

Patients who demonstrate either resistance or intolerance to hydroxyurea often have disease with unfavorable biology and a higher risk of mortality, complications, and transformation to leukemia. This subset of patients represents between approximately 25% to 35% of the ET and PV population, lead author Abdulraheem Yacoub, MD, of the University of Kansas Medical Center, explained to ASH Clinical News.

"Identifying active treatments in this population is a critical medical need," he added. "PEG-rIFN-α has shown good clinical activity in a large subset of these patients with clinical improvement in symptoms, cytoreduction, and some molecular and bone marrow responses. This study provides a practical and realistic criterion for patient selection and dose titration that can be applied in clinical practice."

This prospective, open-label, phase II clinical trial was conducted across sites in North America and Europe. A total of 115 patients were enrolled: 65 patients with ET and 50 patients with PV. All participants had disease that was either resistant (32.5%) or intolerant (67.5%) to hydroxyurea.

"This study provides a practical and realistic criterion for patient selection and [PEG-rIFN-α] dose titration."

—Abdulraheem Yacoub, MD

The investigators also evaluated response rates according to driver mutational status and observed that the presence of a CALR mutation was associated with superior clinical, but not molecular, response (56.5% vs. 28.0%, respectively; odds ratio = 3.34; 95% CI 1.28-8.67; p=0.01).

Patients also had high-risk clinical features, defined as one or more of the following:

  • history of a thrombosis
  • significant or symptomatic splenomegaly
  • presence of diabetes or uncontrolled hypertension
  • age >60 years
  • history of bleeding (ET only)
  • platelet counts >1,500×109/L in ET and >1,000×109/L in PV
  • vasomotor symptoms (e.g., erythromelalgia, severe migraine headaches)

PEG-rIFN-α was administered subcutaneously at an initial dose of 45 µg per week, then titrated monthly in 45-µg increments to a maximum of 180 µg per week. Per study protocol, the researchers performed an intention-to-treat response evaluation every 12 months. Patients who achieved at least a partial response (PR) at these timepoints continued treatment and were followed for up to four years. Treatment was discontinued in patients with no response or stable disease at 12 months.

The primary endpoints of the study were rates of CR and PR at 12-month follow-up. At baseline, three months, six months, nine months, and 12 months, patients completed a comprehensive assessment of myeloproliferative neoplasm (MPN)–associated symptoms using the MPN Symptom Assessment Form (MPN-SAF).

"The toxicities associated with PEG-rIFN-α may have abrogated some of those benefits [such as improvement in MPN-related symptoms]."

—Abdulraheem Yacoub, MD

CR was defined as correction of hematocrit (<45% without phlebotomy for PV), platelet count (<400×109/L), white blood cell count (<10×109/L), and resolution of splenomegaly and disease-related symptoms.

The median follow-up across the study population was 19.6 months (range = 0.6-56.6 months). At 12 months, the ORR in the ET population was 69.2%, which included:

  • 28 patients with CR (43.1%)
  • 17 patients with PR (26.2%)

In patients with PV, the 12-month ORR was 60%, which included:

  • 11 patients with CR (22%)
  • 19 patients with PR (38%)

Across the entire study follow-up period, the ORRs were 70.8% in the ET population and 64.0% in the PV population. Most clinical responses (96.2%) were achieved within the first 12 months of therapy.

During the study, 72% of patients remained on therapy for longer than 12 months; the most common causes for treatment discontinuation were study closure (30.4%) and completion of the planned four-year follow-up (26.1%). Discontinuation of PEG-rIFN-α due to adverse events (AEs) occurred in 13.9% of patients. Grade ≥3 AEs occurred in 50 patients (43.8%); the most common grade ≥3 AE was neutropenia in the ET group (7.8%) and lymphopenia in the PV group (6.0%). No deaths occurred during treatment, but three patients died after they were taken off study.

According to patient responses to MPN-SAF surveys, PEG-rIFN-α treatment was associated with improvements in MPN-related symptoms, such as Total Symptom Score, fatigue, dizziness, numbness/tingling, and weight loss (all p<0.05).

However, "the toxicities associated with PEG-rIFN-α may have abrogated some of those benefits," the authors noted. Participants reported increases in the following PEG-rIFN-α–related side effects: flulike symptoms, injection site irritation, blurry vision, and vision changes (all p<0.05).

"There is a scarcity of active agents that are approved for PV and ET, but fortunately many active agents are in clinical trials," Dr. Yacoub noted. "Ruxolitinib was evaluated and is approved for treatment of PV after hydroxyurea therapy. Whether pegylated interferon or ruxolitinib or a combination of these two drugs, is more effective therapy for patients with PV or ET clearly requires additional clinical trials. Given the heterogenous diseases patterns after hydroxyurea therapy and the variable clinical needs for patients, both agents are of great clinical need and utility."

Dr. Yacoub noted that the findings from this study may be limited by the lack of a comparator arm and by the fact that enrolled patients had high-risk clinical and molecular features, and the findings may not generalize to patients with lower-risk features. The study's relatively short follow-up period and the researchers' inability to determine how molecular responses impact patients' outcomes are additional limitations.

The study authors reported relationships with Roche, which sponsored this trial.


Yacoub A, Mascarenhas J, Kosiorek H, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood. 2019 September 12. [Epub ahead of print]

This study provides valuable information for a common situation in the care of patients with myeloproliferative neoplasms (MPNs). Many clinicians use pegylated interferon at some point in the treatment trajectory of patients with MPNs, often in patients for whom hydroxyurea has been inadequate or not tolerated well. The documented responses here are reassuring, although not earth-shattering … Interestingly, there was a higher overall response rate in patients with essential thrombocythemia (ET) than in those with polycythemia vera (PV), despite the fact that, historically, interferons have been more commonly used in patients with PV.

Interferon does have some toxicities, although they may be manageable. Patients should be informed that MPN-related symptoms like fatigue, dizziness, or neurologic manifestations may improve with cytoreduction, but they might experience flulike symptoms, headache, pruritis, or injection-site reactions as a trade-off.

In the past several years, consensus opinion has shifted to a risk-stratification syndrome where patients with ET who are CALR-positive are less likely to require cytoreductive therapy because of a lower vascular complication risk rate. While the data on patients who are CALR-positive responding favorably to the interferon is fascinating, it's not clear that this is enough information for us to say anything definitive about the timing of interferon in this subgroup. It's possible that in established treatment paradigms these patients might not require therapy.

When one is choosing second-line therapy for ET, interferon will need to be weighed against, for example, anagrelide or even, in some cases, a JAK-STAT pathway inhibitor. This study provides some hard data with which to make that choice with a patient.
The biggest limitation with this study is that it is single-armed. Randomized data would be helpful, especially in interpreting adverse events. Once a patient requires second-line therapy, it can be a challenge to appropriately attribute symptoms to underlying disease or to the treatment. A control arm would be particularly useful in interpretation of quality-of-life endpoints.

Nevertheless, this is a well-designed study in diseases that are both uncommon and indolent – making them a challenge for clinical research. The researchers have clearly demonstrated safety and efficacy in patients with higher-risk features – not only having advanced through first-line therapy, but also a population that was older, more likely to have splenomegaly, and had a relatively high frequency of mutations in TP53 and ASXL1. Further improvements in the tolerability of interferon through reformulations or with careful clinical interventions, as suggested by the authors, may mean more and more patients can receive this as a treatment option.

Laura Michaelis, MD
Medical College of Wisconsin
Milwaukee, WI


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