Distinct efficacy of pegylated-interferon α2a and α2b during treatment of essential thrombocythemia

Abstract

To the Editor, Interferon-a is an effective therapy in essential thrombocythemia (ET), allowing physicians to limit the use of hydroxycarbamide [1, 2]. Pegylation improves its efficiency by increasing the molecule’s bioavailability [3]. No differences in the activity of the two therapeutic pegylatedinterferon molecules (a2a and a2b) have been reported in hematological conditions. A 48-year-old asymptomatic woman presented in 2007 with isolated thrombocytosis (605 9 10/L). Appropriate tests excluded inflammatory syndrome and iron deficiency; JAK2 V617F mutation was absent. Bone marrow biopsy confirmed the diagnosis of ET. Pegylated-interferon (PEGIFN) a2a and aspirin were introduced as first line therapy after 2 years because of increasing thrombocytosis ([ 1100 9 10/L). On introduction of PEG-IFN a2a, the white blood cell (WBC) count was 7.86 9 10/L, hemoglobin (Hb) was 14.3 g/dL, and the platelet count was 1134 9 10/L. The initial dose of PEG-IFN a2a was 90 lg/week, increased at day 15 to 135 lg/week, and at day 45 to 180 lg/week because of persistence of thrombocytosis (1020 9 10/L). It remained ineffective after 3 months, leading to switch for PEG-IFN a2b (initial dose 150 lg/week), with remarkable efficacy. At day 0 of the modification, WBC count was 6.11 9 10/L, Hb level was 14.1 g/dL and platelet count 1068 9 10/L. After 1 month, the platelet count fell to 568 9 10/L, and this improvement was maintained over time. The tolerance was good except for asthenia, leading to taper the dose to 100 lg/ week at 9 months, and then to 100 lg every 2 weeks. After 2 years of follow-up, the platelet count remains below 400 9 10/L (Fig. 1). Some studies have evaluated PEG-IFN a2a and a2b in ET. The median time to PEG-IFN efficacy was around 6 weeks, with a similar response time for either IFN-a2a or IFN a2b [1, 2]. Our case raises the question of whether IFN-a2a or -a2b may have distinct efficacy in the treatment of hematological malignancies. If all the 14 type I subtypes of IFN bind to interferon a/b receptor (IFNAR), it has been shown that they have proper binding affinities [4]. Thus, they vary in their ability to induce downstream signaling events among cellular subsets, with differential activation of IFN-stimulated genes (ISG) and biological responses. This may explain the distinct antiviral properties of these IFN-a2 subsets in chronic HCV infection [5]. In ET, it may be the case that binding of IFN-a2b to megakaryocytes may induce a different antiproliferative ISG-spectrum than that of IFN-a2a, leading to SOCS-1 transcription and inhibition of the TPO-signaling in the malignant clone [6]. The bioactivity of the two PEG-interferons may also differ due to pegylation modalities [3]. PEG-IFN a2b has a 12 kDa PEG chain attached via an unstable urethane bond that is hydrolyzed after injection, releasing native IFN-a2b. In contrast, PEG-IFN a2a has a 40-kDa covalently attached PEG and circulates as an intact molecule. This may result in different binding capacities to IFNAR, as native released interferon-a2b acts as a natural molecule, whereas the stable PEG molecule of PEG-interferon a2a interacts with other surface molecules [3]. N. Noel J.-M. Michot C. Goujard O. Lambotte (&) AP-HP, Service de Medecine Interne, Hopital Bicetre, 78, rue du General Leclerc, 94275 Le Kremlin Bicetre CEDEX, France e-mail: olivier.lambotte@bct.aphp.fr