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Moving Towards a New Era in the Management of Chronic Immune Thrombocytopenia Hans Wadenvik, Bob Olsson

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Moving Towards a New Era in the Management of Chronic Immune Thrombocytopenia Hans Wadenvik, Bob Olsson Moving towards a new era in the management of chronic immune thrombocytopenia Hans Wadenvik, Bob Olsson To cite this version: Hans Wadenvik, Bob Olsson. Moving towards a new era in the management of chronic immune thrombocytopenia. Annals of Hematology, Springer Verlag, 2010, 89 (s1), pp.87-93. 10.1007/s00277- 009-0873-9. hal-00535111 HAL Id: hal-00535111 https://hal.archives-ouvertes.fr/hal-00535111 Submitted on 11 Nov 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Ann Hematol (2010) 89 (Suppl 1):S87–S93 DOI 10.1007/s00277-009-0873-9 CHRONIC ITP Moving towards a new era in the management of chronic immune thrombocytopenia Hans Wadenvik & Bob Olsson Received: 12 October 2009 /Accepted: 23 November 2009 /Published online: 26 March 2010 # Springer-Verlag 2010 Abstract Immune thrombocytopenia (ITP) is an organ- monitored patients to remain well controlled, with good specific autoimmune disease in which a low concentration tolerability for prolonged periods. of plasma thrombopoietin (TPO) contributes to the throm- bocytopenia. Functional thrombopoietin deficiency in Keywords Thrombopoietin mimetics . Romiplostim . response to thrombocytopenia is central to the pathophys- Eltrombopag . Chronic immune thrombocytopenia iology of chronic ITP. Decreased platelet production in ITP patients has been described only in recent years, however. Following the development of TPO-mimetics, it has Introduction become clear that the augmentation of thrombopoiesis is a key therapeutic target. TPO mimetics are novel effective Chronic immune thrombocytopenia (ITP) is an acquired treatments providing durable platelet responses in ITP. Two platelet-specific autoimmune disease characterised by low agents have reached clinical practice, the ‘peptibody’ platelet counts, which can lead to life-threatening bleeding. In romiplostim (Nplate®) approved for treatment of thrombo- ITP, anti-platelet antibodies accelerate the destruction of cytopenia in patients with chronic ITP in Europe, Canada, platelets. In addition, bone marrow platelet production can Australia and the USA and the non-peptide TPO mimetic, be impaired [1–4], and cytotoxic T lymphocytes have been eltrombopag (Promacta®), approved in the USA. This shown to lyse platelets in vitro and in vivo [5–7]. Although review summarises the background to the development of the thrombocytopenia in ITP can be profound, in the these agents and presents an update on data from majority of adult patients, signs of bleeding are typically randomised phase III trials and open-label studies. These mild to moderate. However, persistently low platelet counts novel drugs provide a noteworthy treatment option for (<20 × 109/L) can contribute to a risk of serious bleeding, patients with chronic ITP, in whom thrombocytopenia and such as gastrointestinal and intracranial haemorrhages [8– bleeding risk have not been controlled by standard treat- 10]. When managing chronic ITP in adults, the ultimate goal ments. The first candidates for treatment in clinical practice is to maintain the platelet count at a haemostatically safe are undoubtedly refractory patients with lack of response to level to prevent bleeding with the least possible intervention other therapies or at continued risk for bleeding despite and, therefore, low treatment-related toxicity [11]. treatment. Appropriate inclusion of TPO mimetics into the Treatment remains challenging in many adult patients treatment paradigm will most likely have a positive impact who relapse after therapy with corticosteroids and/or on the long-term outcome of ITP and allow carefully intravenous immunoglobulins and may ultimately require splenectomy [12–14]. Approximately a third of adult patients relapse after splenectomy [15]. While current : H. Wadenvik (*) B. Olsson treatment options for refractory patients post-splenectomy Hematology Section, Department of Internal Medicine, now include immunomodulatory/immunosuppressive Sahlgrenska University Hospital, agents, e.g. intermittent immunoglobulins (IVIg), cortico- SE-413 45 Gothenburg, Sweden e-mail: [email protected] steroids, azathioprin, cyclophosphamide, mofetil mycophe- e-mail: [email protected] nolate, vinca alkaloids and the B cell depleting agent S88 Ann Hematol (2010) 89 (Suppl 1):S87–S93 rituximab, these generally generate low long-term response Romiplostim rates and significant toxicity [16–19]. Progress in uncovering an impaired bone marrow The romiplostim ‘peptibody’, administered subcutaneously, response to low platelet count in chronic ITP has made consists of two covalently linked carrier-Fc domains, each the augmentation of platelet production a key therapeutic attached to a polypeptide containing two c-mpl-activating target [20], with the result that novel effective treatments sequences [38, 40]. Lack of sequence homology to providing high durable response rates in patients with endogenous TPO is clinically relevant as this reduces the chronic ITP are now approved. risk of development of cross-reacting anti-TPO antibodies that can compromise treatment efficacy. Early studies in healthy adults showed that single injections of romiplostim Thrombopoietin induced a dose-dependent increase in platelet count, with no serious adverse events [40, 42]. Platelet numbers peaked The term thrombopoietin (TPO) was first used in 1958 to at 12–16 days, returning to baseline at 28 days [40]. Platelet describe the humoral regulator of platelet production. response in adults with ITP and low platelet counts were Doubts surrounding its existence remained until the first reported in a dose-finding assessment of romiplostim molecule was cloned [21–23]. TPO, the ligand for the c- given as two injections separated by a 15-day interval [43]. mpl proto-oncogene, is mainly expressed in liver and A randomised, double-blind, placebo-controlled phase I/ kidney [21, 22, 24] and has been shown to influence all II US study investigating romiplostim in patients with ITP aspects of megakaryocyte development and platelet pro- led to the establishment of individualised dosing based on duction [25]. Animal model data suggest a feedback platelet counts [44]. The phase II study population was 21 mechanism whereby circulating platelet mass and mega- highly refractory adult ITP patients. Patients were rando- karyocyte mass are inversely related to TPO levels [26, 27]. mised 4:1 to receive weekly doses of romiplostim (1, 3 or Several studies showed that circulating TPO is selectively 6 μg/kg) or placebo, for 6 weeks, with follow-up (FU) up to cleared by platelets through receptor-mediated endocytosis day78. No dose adjustments were allowed, although doses and destruction [28–32]. Paradoxically, TPO levels appear were withheld when platelet count was >350 × 109/L. The normal or only slightly elevated in ITP. These patients primary objectives were to evaluate safety and to identify a uniformly display normal megakaryocyte numbers in bone weekly dose that would give a platelet count within the marrow biopsies, further supporting plasma TPO level target range of 50–450 × 109/L and that was at least twice regulation by circulating platelets and bone marrow mega- the baseline count. Platelet targets were reached or karyocytes [33]. exceeded in 12 of 16 patients assigned to receive Early studies with pegylated and recombinant TPO in romiplostim (1 or 3 μg/kg). Rates of adverse events were the late 1990s demonstrated platelet response in cancer similar across treatment arms, and no neutralising anti- patients with chemotherapy-induced thrombocytopenia [34, bodies against romiplostim or endogenous TPO were 35]. However, clinical evaluation of early TPO analogues, detected. Transient post-treatment worsening of thrombo- i.e. pegylated recombinant TPO, was halted because anti- cytopenia was observed in four patients. bodies were formed that cross reacted with endogenous Two double-blinded phase III trials, carried out at 35 TPO, causing secondary and long-lasting thrombocytopenia sites in the USA and Europe, have investigated 6-month and bleeding [36]. This setback stimulated research for treatment with romiplostim [45]. The trials were of identical second-generation c-mpl agonists including peptide and design, except for splenectomy status. Both studies enrolled non-peptide agonists [37–41]. adults with previously treated ITP with a mean platelet count of <30 × 109/L. Patients were randomised to romiplostim or placebo (2:1). Weekly romiplostim was TPO mimetics given for 24 weeks. Follow-up was 12 weeks. Patients were allowed to enter an extension study after 4 weeks of follow- The search for second-generation TPO analogues has up, or once platelet count fell below 50 × 109/L. The focussed on agents capable of binding to the TPO receptor starting dose was 1 µg/kg with subsequent dosing adjusted as strongly as TPO, without having cross-reactive immu- to achieve and maintain a target platelet count of 50– nogenicity against native TPO. 200 × 109/L. The maximum allowed dose was 15 μg/kg. Two agents have reached clinical practice, the ‘pepti- Patients
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