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Chronic myeloproliferative neoplasms

From leeches to interferon: should cytoreduction be prescribed for all patients with polycythemia vera?

Leukemia volume 34, pages 2837–2839 (2020)Cite this article

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Polycythemia vera (PV) is a dangerous disease. Patients with PV may suffer on the short term of devastating vascular events, and on the long term of transformation of their hematologic malignancy in myelofibrosis, myelodysplastic syndrome, or acute myeloid leukemia [1,2,3]. The first step in approaching an individual patient with PV is to identify the potential risk to develop major thrombotic or hemorrhagic complications [4]. Currently, patients are defined to be at low risk by age <60 years and the absence of previous thrombosis but this distinction is becoming weak since low-risk patients, despite being at lower risk in comparison to patients aged >60 and/with prior thrombosis, still exhibit an annual rate of major thrombotic episodes of 2% [5, 6]. This estimate is 2–3-fold higher than the risk of thrombosis observed in the general population, thus all PV patients can indeed be considered at high thrombotic risk when compared to healthy persons [7]. One may argue whether the conservative approach based on phlebotomy and aspirin only is adequate in low-risk PV [8], also considering that a cytoreductive therapy like hydroxyurea may reduce the incidence of thrombosis and the evolution to myelofibrosis compared to phlebotomy alone [9]. In addition, chronic phlebotomy is associated with iron deficiency, significant social and professional burden for young patients [10, 11], and this strategy has already been shown that many patients do not accept to continue on the long term [12]. More importantly, intermittent phlebotomy result in fluctuations in the hematocrit level, when it has been shown that continuously maintening the hematocrit below 45% was associated with lower risk of thrombosis [13]. Nonetheless, experts discourage the use of hydroxyurea in clinical practice in low-risk patients since the supposed leukemogenic risk associated with this drug, although largely uncertain, might outweigh the possible antithrombotic benefits [1, 4, 8, 14]. However, there is now accumulating new evidence from clinical trials showing that Interferon (IFN)-α, used in various formulations and dosages accomplishes in high-risk PV a high rate of complete hematological response, improvement of quality of life and remarkable rates of molecular responses without increasing the risk of leukemia or solid tumors (particularly cutaneous) development [15,16,17,18,19,20,21]. Ropeginterferon alpha-2b, a novel preparation of interferon with an improved pharmacologic profile and a longer elimination half-life, was recently approved by the European Medicines Agency for PV, based on phase-II and III studies in high-risk patients [22, 23]. An overall hematologic response was achieved in more than 80% of patients, and the drug showed good tolerability and importantly, evidence of molecular response. In addition, low rates of thrombosis were observed after 4 years of follow-up in the phase 3 study confirming the efficacy of ropeginterferon to reduce the vascular risk in high-risk patients [24]. Altogether, we believe that it is time to question the management of so-called “low-risk” PV patients and challenge the current phlebotomy only strategy with early treatment with interferon-alpha.

Ropeginterferon alpha-2b (Ropeginterferon) was recently tested in low-risk PV, and results of a pre-planned interim analysis were presented at the EHA 2020 annual meeting (EHA25 virtual, Abstract LB2602). In a large-scale, multicentre, prospective, investigator-driven randomized clinical trial, called the Low-PV study (NCT030030025), the efficacy of phlebotomy plus low-dose aspirin (conventional arm) was compared with Ropeginterferon (experimental arm) administered on top of conventional treatment, in patients strictly defined at low-risk of vascular complications. The primary endpoint of the study was to compare the proportion of patients maintaining the median hematocrit values <45% during 12 months in the absence of progressive disease.

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Authors and Affiliations

  1. AP-HP, Hôpital Saint-Louis, Centre d’investigations Cliniques, Paris, France

    Jean-Jacques Kiladjian

  2. Université de Paris, U1131 Inserm, IRSL, F-75010, Paris, France

    Jean-Jacques Kiladjian

  3. Foundation of Clinical Research-FROM, Ospedale Papa Giovanni XXIII, Bergamo, Italy

    Tiziano Barbui

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Correspondence to Tiziano Barbui.

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JJK served in advisory boards for Novartis, AOP Orphan, BMS. TB served in advisory boards for Novartis, AOP Orphan, Italfarmaco.

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Kiladjian, JJ., Barbui, T. From leeches to interferon: should cytoreduction be prescribed for all patients with polycythemia vera?. Leukemia 34, 2837–2839 (2020). https://doi.org/10.1038/s41375-020-0984-9

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