Interferon-Alpha Improves MFS and OS Over Standard Approaches in Polycythemia Vera

Ghaith Abu-Zeinah, MD

Interferon-alpha (IFN) has been shown to significantly improve both myelofibrosis-free survival (MFS) and overall survival (OS) over hydroxyurea and phlebotomy only in patients with polycythemia vera, according to data from a retrospective study published in Leukemia.¹

In all patients, the median MFS was 23.8 years, while the OS was 26.3 years; the 20-year MFS rate was 61% and the 20-year OS rate was 69%.

When broken down by risk category per European LeukemiaNet (ELN), low-risk patients had a 20-year MFS of 84% with IFN vs 65% and 55% with hydroxyurea and phlebotomy only, respectively (P <.001). Moreover, the 20-year OS in these patients was 100% with IFN, 85% with hydroxyurea, and 80% with phlebotomy only (P = .44).

In high-risk patients, the 20-year MFS rates with IFN, hydroxyurea, and phlebotomy only were 89%, 41%, and 36%, respectively (P = .19); the 20-year OS rates in these groups were 66%, 40%, and 14%, respectively (P = .016).

In a time-on-treatment multivariable analysis, longer treatment with IFN was shown to reduce the risk of myelofibrosis by 9% per year of treatment (HR, 0.91; 95% CI, 0.87-0.95; P <.001); it was also shown to reduce the risk of mortality by 6% per year of treatment (HR, 0.94; 95% CI, 0.9-0.99; P = .012), independent of other risk factors.

“The results of this study may support the use of IFN in the early treatment of well-defined polycythemia vera in order to prevent post–polycythemia vera myelofibrosis [PPVMF] and possibly prolong survival,” lead author of the study Ghaith Abu-Zeinah, MD, who is also a hematologist/oncologist at Weill Cornell Medicine, and colleagues, wrote. “Randomized clinical trials are required to confirm these findings.”

Previous studies have indicated that recombinant IFN has elicited complete and durable histomorphologic responses and reverse marrow fibrosis in patients with polycythemia vera, but no prospective or retrospective work has identified whether the agent can improve MFS or OS over other primary options that are available, such as hydroxyurea and phlebotomy only.

“This is important because phlebotomy only remains widely used for low-risk patients and hydroxyurea for high-risk patients, although IFN is also recommended for treating high-risk polycythemia vera by national and international guidelines,” the authors write.

Although some trials have compared the use of IFN with hydroxyurea and have found that both approaches can be used as initial cytoreductive treatment for those who are high risk, no long-term follow-up data are available to examine differences with regard to MFS and OS benefits. Moreover, some of the end points utilized in these studies were not surrogates of PPVMF or mortality.

To address this gap, in the single-center, retrospective study conducted at Weill Cornell Medicine, investigators set out to compare MFS and OS with IFN to hydroxyurea and phlebotomy-only approaches in a total of 470 patients with polycythemia vera.

Patients were identified by the International Classification of Diseases, code versions 9 and 10 or by the Systemized Nomenclature of Medicine – Clinical Terms for the diagnosis of polycythemia vera. All patients were diagnosed to have polycythemia vera per the Polycythemia Vera Study Group criteria, the Weill Cornell Medicine criteria, or the World Health Organization 2016 criteria.

Moreover, the ELN risk category at the time of diagnosis was identified for each patient. Those included in the high-risk subset were 60 years or older and/or had a history of thrombosis at the time of diagnosis, while those in the low-risk subset were younger than 60 years and had no previous history of thrombosis at diagnosis.

An intention-to-treat (ITT) analysis of MFS and OS organized patients to IFN, hydroxyurea, phlebotomy only, or other cytoreductive regimens. Patients were classified by the first cytoreductive treatment that they had received for at least 1 year. If patients did not receive cytoreductive agents, they fell into the phlebotomy-only cohort. If they had follow-up of less than 1 year, patients were classified per the treatment they had received for the longest.

A total of 480 patients were identified, although 10 were excluded because they did not meet the criteria specified for a polycythemia vera diagnosis. Among the 470 patients, the median age at diagnosis was 54 years, 49% were female, and 44% were considered to be high risk. The majority of patients were White (86%), 21% had cardiovascular risk factors, and 14% had a history of thrombosis. The median follow-up for patients was 10 years.

IFN was the first cytoreductive treatment in 20% of patients, while it was hydroxyurea in 40% and other drugs in 12%. The median time to cytoreductive treatment across the cohorts was 1 year. Twenty-eight percent of patients received phlebotomy only. Notably the treatment groups differed with regard to age at diagnosis (50 years, IFN; 58 years, hydroxyurea; 54 years, phlebotomy-only; P <.001), ELN risk score (high-risk: 24%, 56%, and 42%, respectively; P <.001), and cardiovascular risk factors (27%, 26%, and 10%; P = .002).

Among the 262 patients in the low-risk subset, 27% received IFN, 32% received hydroxyurea, and 29% received phlebotomy only; these rates were 11%, 50%, and 27%, respectively, in the 208 patients in the high-risk subset.

Treatment crossover happened in 19% of those who received IFN and 26% of those who had received hydroxyurea. Investigators excluded patients on “other” treatment and noted that 199 patients received IFN at any time for a cumulative duration of 1137 patient-years, while 285 patients were given hydroxyurea at any time for a cumulative duration of 1671 years. To account for the crossover and duration in the examination of PPVMF and mortality, investigators conducted time on treatment univariable and multivariable analyses.

Additional data from the multivariable analysis showed that longer time on hydroxyurea was not linked with a significantly lower risk of PPVMF or all-cause mortality. Moreover, older age at the time of diagnosis was linked with increased mortality (HR, 1.1; 95% CI, 1.07-1.12; P <.001) and female patients had reduced mortality (HR, 0.54; 95% CI, 0.36-0.83; P = .005).

Four percent of patients experienced transformation to acute myeloid leukemia, and this was noted to occur at a rate of 0.34 per 100 patient-years. However, because this was relatively infrequent, investigators were able to determine significant differences between the treatment groups.

Over a follow-up of 1137 patient-years, 13% of patients who received IFN ended up discontinuing treatment because of toxicity vs 16% of those who received hydroxyurea over 1671 patient-years of follow-up. The most frequently effects that occurred with IFN included musculoskeletal and constitutional symptoms; those who received hydroxyurea most commonly experienced hematologic, gastrointestinal, as well as skin and soft tissue effects.

“This study demonstrates, for the first time, that initial treatment with IFN of low-risk PV is associated with significantly higher MFS when compared with phlebotomy only or hydroxyurea [log-rank P = .0011],” the authors concluded. “High-risk PV patients treated initially with IFN [n = 22], a minority, had a higher OS compared to hydroxyurea or phlebotomy only [log-rank P = .016]. The results of the ITT analysis support initial treatment with IFN over the standard of care, phlebotomy only, for low-risk patients, and over the standard of care, hydroxyurea, for high-risk patients.”

Reference

1. Abu-Zeinah G, Krichevsky S, Cruz T, et al. Interferon-alpha for treating polycythemia vera yields improved myelofibrosis-free and overall survival. Leukemia. Published online March 2, 2021. doi:10.1038/s41375-021-01183-8