Pooled Analysis Shows Cytoreduction to Be Safe, Tolerable in Younger Patients With PV

Ghaith Abu-Zeinah, MD

Cytoreductive therapy with interferon alfa (rIFNα) or hydroxyurea is safe and well tolerated in patients with polycythemia vera (PV) under the age of 60 years and induces annualized discontinuation rates comparable to those reported with these agents in older patients with PV, for whom cytoreductive therapy is routinely used, according to findings from a meta-analysis that were published in Blood Advances.¹

Across the 14 studies included in this analysis, rIFNα discontinuation rates ranged from 4.6% to 37% over median durations of 0.4 to 6.3 years. Hydroxyurea discontinuation rates ranged from 2.6% to 17% over median durations of 0.5 to 14 years.

Although the use of cytoreductive agents, such as rIFNα and hydroxyurea, is associated with reduced thrombosis risk in PV, these agents are not routinely recommended by the European LeukemiaNet (ELN) or the National Comprehensive Cancer Network (NCCN) for patients with PV under the age of 60 years. The ELN recommends cytoreductive therapy for patients with PV who are younger than 60 years of age and have not had prior thrombotic events provided that they have strictly defined phlebotomy intolerance, symptomatic progressive splenomegaly, persistent or progressive leukocytosis, extreme thrombocytosis, persistently high cardiovascular risk, inadequate hematocrit control requiring phlebotomies, and/or persistently high symptom burden.² The NCCN does not recommend cytoreductive therapy as initial treatment for patients with low-risk disease.³

“Unfortunately, effective and potentially life-prolonging cytoreductive therapy is often deferred in younger patients who are considered ‘low-risk’ because of their age and lack of thrombosis history,” senior study author Ghaith Abu-Zeinah, MD, an instructor in medicine at Weill Cornell Medical College and an assistant attending physician at the NewYork Presbyterian Hospital in New York, New York, and coauthors, wrote in the paper.1 “The rationale for withholding cytoreductive therapy is data-sparse and driven by theoretical concerns for toxicity and unknown benefits from early treatment. Yet, there is some evidence that early treatment is both well tolerated and potentially useful.”

Investigators conducted a systematic review and meta-analysis to evaluate toxicity and disease-related complications in patients with PV under the age of 60 years who received rIFNα or hydroxyurea. The goal of this study was to support recommendations for the use of these agents in younger patients with PV.¹

Through searches of PubMed, Scopus, Web of Science, and Embase, investigators identified 693 unique studies with relevant keywords for PV and cytoreductive drugs. Studies were included in this analysis if they evaluated patients diagnosed with PV, reported a median age of 18 to 60 years, and included patients treated with rIFNα, hydroxyurea, and/or ruxolitinib (Jakafi). Case reports; case series with 20 patients or fewer; abstract-only studies; articles that did not include primary data; studies reporting results with cytoreductive agents other than rIFNα, hydroxyurea, and/or ruxolitinib; studies that did not report drug toxicity data; and studies that focused on post-PV myelofibrosis (MF), pregnancy in PV, or accelerated/blast-phase myeloproliferative neoplasms were excluded.

Of the 693 studies initially identified, 14 met these inclusion criteria and were selected for analysis. Only 2 studies reported on the use of ruxolitinib in patients with PV under the age of 60 years and were therefore not included in this meta-analysis.

The final analysis included 2,141 patients from the 14 studies, 744 of whom received rIFNα across 12 studies and 1,397 of whom received hydroxyurea across 8 studies. Patients who received rIFNα or hydroxyurea had weighted average ages of 48 years and 56 years, respectively. The weighted average duration of treatment for both agents was 4.5 years. The most frequently prescribed hydroxyurea dose ranged from 0.5 g per day to 1.5 g per day. The dosing of rIFNα agents, including pegylated interferon alfa-2a, recombinant interferon alfa-2a/2b, and ropeginterferon alfa-2b, varied between studies.

Adverse effects (AEs) were reported at different rates across each study. The incidence of grade 3/4 toxicities in patients who received rIFNα ranged from 0% to 11%; liver enzyme dysfunction and flu-like symptoms were the most commonly reported grade 3/4 AEs. Grade 3/4 toxicities in patients who received hydroxyurea were reported in 2 studies included in this analysis; dermatologic and hematologic toxicities were the most commonly reported grade 3/4 AEs.

Investigators observed significant heterogeneity in discontinuation rates across the rIFNα studies (Cochran’s Q = 29; P < .001; I2 = 70%), which they suggested may be related to differences in rIFNα formulation and dosing. However, significant heterogeneity in discontinuation rates were not observed across the hydroxyurea studies (Cochran’s Q =6.4; P < .03; I2 = 27%).

Among 587 patients who received rIFNα across 10 studies that reported treatment discontinuation, the overall discontinuation rate was 13% (95% CI, 2.7%-23.0%), and the annual rate of discontinuation was 5.2% (95% CI, 2.2%-8.2%). Of the 1097 patients who received rIFNα across 5 studies that reported treatment discontinuation, the overall discontinuation rate was 15% (95% CI, 6.9%-24.0%), and the annual discontinuation rate was 3.6% (95% CI, 1.0%-6.2%).

In the rIFNα and hydroxyurea arms, the pooled annual rates of thrombotic events were 0.79% and 1.26%, respectively; for progression to secondary MF (sMF), respective rates were 1.06% and 1.62%. Annual rates of progression to acute myeloid leukemia (AML) were 0.14% and 0.26%, respectively, and annual rates of death were at 0.87% and 2.65%, respectively. Investigators reported no treatment-related deaths.

The average complete hematologic response rates for patients receiving rIFNα and hydroxyurea, respectively, were 62% and 52%,; partial hematologic response rates in these respective populations were 27.9% and 43.0%. Moreover, the frequency of hematologic response increased over time in patients who received rIFNα but not in those who received hydroxyurea. Among 284 patients who received rIFNα across 7 studies, the estimated frequency of thrombotic events was 3.2%, with an annual rate of 0.79%. Of 842 patients who received hydroxyurea across 4 studies, the estimated frequency of thrombotic events was 5.4%, with an annual rate of 1.26%. The estimated frequency of progression to sMF was 11% with an annual rate of 1.06% among 267 patients who received rIFNα across 3 studies. These rates were 27% and 1.62%, respectively, among 1206 patients who received hydroxyurea across 5 studies. The annual rates of progression to AML were 0.14% and 0.26%, respectively, among 267 patients who received rIFNα across 3 studies and 908 patients who received hydroxyurea across 3 studies. Among the 9 rIFNα studies (n = 592) and 6 hydroxyurea studies (n = 1223) that reported deaths, the annual mortality rates were 0.87% and 2.65%, respectively. None of these deaths were attributed to treatment toxicity.

Four of the 14 studies compared cytoreduction with a phlebotomy-only control arm. Although the authors note that the data were limited, these studies showed improved symptoms, hematologic responses, and histomorphologic responses, as well as lower MF incidence, with rIFNα vs phlebotomy. Additionally, no significant differences in MF incidence were observed between the hydroxyurea and phlebotomy alone arms. Overall survival data for patients younger than 60 years of age who received cytoreduction vs phlebotomy alone were either not significantly different or not reported.

The authors noted that limitations of this research include the unavailability of patient-level raw data, leading to the pooled summary statistics across heterogeneous studies. Furthermore, heterogeneous dosing of the agents, the type of rIFNα agent used, and follow-up durations may have led to variabilities in AE rates and outcomes. Moreover, the short overall duration of follow-up limited the assessment of long-term efficacy and safety in this analysis, and the available data from these studies did not allow for the identification of younger patients with a history of thrombosis. Lastly, the number of studies conducted on this topic is limited, making it challenging to evaluate the quality of each study according to JBI criteria.

“These findings suggest that ELN/NCCN recommendations result in undertreatment of patients with PV [younger than 60 years of age] since there is no clear evidence to support concerns that risk of toxicity exceeds potential benefit,” the authors concluded. “Future investigation of cytoreductive agents should prioritize the inclusion of [patients with] PV [younger than 60 years of age], allowing for the development of new, evidence-based clinical guidelines that can improve their management.”

References

• Chamseddine RS, Savenkov O, Rana ST, et al. Cytoreductive therapy in younger adults with polycythemia vera: a meta-analysis of safety and outcomes. Blood Adv. Published online March 20, 2024. doi:10.1182/bloodadvances.2023012459
• Marchetti M, Maria Vannucchi A, Griesshammer M, et al. Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations. Lancet Haematol. 2022(4):e301–e311. doi:10.1016/S2352-3026(22)00046-1
• NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms, version 1.2024. Accessed May 6, 2024. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf