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(ITP)—Focus on Thrombopoietin Receptor Agonists

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(ITP)—Focus on Thrombopoietin Receptor Agonists 21 Review Article Page 1 of 21 The treatment of immune thrombocytopenia (ITP)—focus on thrombopoietin receptor agonists David J. Kuter Hematology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Correspondence to: Professor David J. Kuter, MD, DPhil. Hematology Division, Massachusetts General Hospital, Ste. 118, Room 110, Zero Emerson Place, Boston, MA 02114, USA. Email: [email protected]. Abstract: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction along with reduced platelet production. All treatments attempt either to reduce the rate of platelet production or increase the rate of platelet production. There is no known cure but most patients attain a hemostatic platelet count. New treatment guidelines have supported a shift from corticosteroids and splenectomy to newer medical treatments that mitigate the thrombocytopenia and avoid splenectomy. The thrombopoietin receptor agonists (TPO-RA), romiplostim, eltrombopag, and avatrombopag, have markedly altered the treatment of ITP. Response rates of 80–90% are routinely obtained and responses are usually maintained with continued therapy. Data shows that TPO-RA are just as effective in early ITP as in chronic ITP and current guidelines encourage their use as early as 3 months into the disease course, sometimes even earlier. TPO-RA do not need to be continued forever; about a third of patients in the first year and about another third after two years have a remission. Whether TPO-RA affect the ITP pathophysiology and directly cause remission remains unclear. This review provides a personal overview of the diagnosis and treatment of ITP with a focus on the mechanism of action of TPO-RA, their place in the treatment algorithm, unique aspects of their clinical use, adverse effects, and options should they fail. Keywords: Immune thrombocytopenia (ITP); thrombopoietin; rituximab; fostamatinib; splenectomy Received: 17 January 2021; Accepted: 24 February 2021; Published: 31 March 2021. doi: 10.21037/aob-21-23 View this article at: http://dx.doi.org/10.21037/aob-21-23 Introduction Although 18% of patients with platelet counts under 10,000/μL are asymptomatic (5), bleeding is the main risk in While thrombocytopenia is a common consultation for patients with ITP. Patients with ITP often tolerate a degree the hematologist, immune thrombocytopenia (ITP) of thrombocytopenia which in other situations will result still remains a reasonably uncommon explanation. ITP in major bleeding. This probably reflects the young, large, has been defined as an isolated platelet count less than hyperfunctional platelets which is reflected in the normal 100,000/μL with no other explanation (1). It affects 2–4 bleeding time seen in ITP patients (6). per 100,000 individuals annually with an overall prevalence While bleeding remains the main concern in patients of about 10/100,000 individuals (2,3). It is probably much with ITP, two other clinical aspects of ITP warrant more common than we realize in that many patients with attention. The first is that many patients with ITP have modest thrombocytopenia of 50,000–100,000/μL often go a reduced health-related quality of life (HRQoL). While unreported and certainly many individuals with platelet this is often hard to assess and quantify, there is a clear counts between 100,000/μL and the standard normal of relationship between thrombocytopenia and fatigue (7,8). 150,000/μL have some autoimmune pathogenesis despite Although the underlying cause remains unclear, it has been the finding that only 6.9% (95% CI: 4.0–12.0%) progress suggested that circulating cytokines may be involved (9). to ITP (4). Treatment of ITP improves the patient’s HRQoL including © Annals of Blood. All rights reserved. Ann Blood 2021;6:7 | http://dx.doi.org/10.21037/aob-21-23 Page 2 of 21 Annals of Blood, 2021 fatigue with thrombopoietin receptor agonists (TPO-RA) (IC) Group Report (23) in this review. In reference to probably having a greater magnitude of effect (7,10). The these guidelines, it is important to note two things. The second important aspect is that ITP is also a prothrombotic first is that guidelines are not mandates for therapy but as disorder, like all other disorders of increased platelet described by the WHO are “intended to assist providers turnover (11-14). In a well-designed Danish registry study, and recipients of healthcare and other stakeholders to 391 chronic ITP patients were compared with a matched make informed decisions. A recommendation provides reference cohort of 3,128 patients without ITP (13). Overall information about what policymakers, healthcare providers rates of venous thromboembolism were 5.32 (95% CI: or patients should do” (26). The second is that despite 2.86–9.89) per 1,000 patient years for ITP patients versus the claim to be “evidence-based”, they are almost entirely 2.04 (95% CI: 1.45–2.87) per 1,000 years for the controls, expert opinion. For example, all 11 adult recommendations a 2.65 (95% CI: 1.27–5.50) fold increase; thromboses of the ASH Guidelines are “very low certainty of the occurred even at very low platelet counts. Sarpatwari (14) evidence” and only 2 recommendations were “strong” compared 1,070 ITP patients with 4,280 patients without (patients with platelet counts over 30,000/μL rarely ITP (matched for age, gender, primary care practice) in a require therapy, corticosteroids should not be used more UK General Practice Research Database and found that than 6 weeks). There are simply not enough randomized after a median of 47.6 months (range, 3.0–192.5 months) of controlled trials comparing head-to-head different follow-up ITP patients had adjusted hazard ratios of 1.58 treatment algorithms for ITP. (95% CI: 1.01–2.48), 1.37 (95% CI: 0.94–2.00), and 1.41 The purpose of this review is to help understand the (95% CI: 1.04–1.91) for venous, arterial, and combined diagnosis and treatment of adult ITP recognizing the (arterial and venous) thromboembolic events, respectively, limitations of these guidelines and available clinical data. compared with controls. The event rates increased as the In so doing, I will assess the available evidence and explain platelet count decreased. The pathophysiology of the how I apply it in my clinical practice in over 2,000 adult thrombosis remains unclear. ITP patients. In using the personal pronoun, it should be The clinical course of ITP is often variable but a staging recognized that some of what I relate below is my own scheme for the disease has been created wherein the first personal clinical practice which may not be fully “evidence- 3 months are considered newly diagnosed ITP, months ≥3– based”. 12 are considered persistent ITP and after 12 months the disease is considered chronic ITP (1). This staging scheme The pathophysiology of ITP is convenient for disease classification and may have some relationship to the underlying pathophysiology. In general, The pathophysiology of ITP has undergone much adult ITP patients have a very low rate of spontaneous investigation in recent decades and is a disease of both remission without therapy estimated to be between 0.9% (15) increased platelet destruction as well as a disease of and 10.3% (9/87) (16) whereas patients in the newly inappropriately low platelet production. The historical diagnosed and persistent phase may have a remission rate studies of Harrington (27) and others (28-31) showed that with therapy of up to 32% (17). Recent data also show the infusion of plasma or blood products from patients that epitope spreading may be occurring as the disease with ITP caused a decline in platelet counts in healthy progresses (18). There remains much interest as to whether recipients with eventual identification that antiplatelet more aggressive therapy with rituximab (19), recombinant antibodies played a major role in this disorder (28,32,33). thrombopoietin (20) or mycophenolate (MMF) (21) in the Indeed, modern methods detected antiplatelet antibody acute and persistent phase might mitigate the emergence of on the surface of 280 (69%) of 360 ITP patient platelet more chronic disease. samples. Multiple antibodies against multiple antigens were With the introduction of TPO–RA, rituximab and common: of these 280, 145 (52%) had antibodies against all fostamatinib, therapeutic options for treating ITP have 3 major platelet antigens, GPIIb/IIIa, GPIb/IX, and GPIa/ evolved from our prior standard care of corticosteroids IIa; few had antibodies only against GPIb/IX (3.9%) or and splenectomy. These have culminated in a number of GPIa/IIa (0%) (Figure 1). new guidelines for treating ITP (22-25). In particular, I Other studies have shown that platelet production is will rely upon the recent American Society of Hematology inhibited to various degrees in patients with ITP. Platelet (ASH) Guidelines (22) and the International Consensus kinetic studies have shown a normal or reduced rate of © Annals of Blood. All rights reserved. Ann Blood 2021;6:7 | http://dx.doi.org/10.21037/aob-21-23 Annals of Blood, 2021 Page 3 of 21 A Anti-GPIa/IIa N=0 Anti-GPIb/IX N=0 N=11 N=145 B N=0 N=76 Anti-GPIIb/IIIa N=48 C Figure 1 Antiplatelet antibody testing in ITP patients. In 260 ITP patients, 360 assays were performed. In 80 patients (53 in clinical remission; 27 with active disease) all antibody tests were negative (18). platelet production from megakaryocytes (34,35). Indeed, the plasma from 12 of 18 ITP patients inhibited in vitro D megakaryocyte growth by 26–95% (36). T cells may play a role directly in attacking platelets or megakaryocytes and alterations in T regulatory lymphocytes may also open a window for loss of immune tolerance (37). Megakaryocytes in the bone marrow have been shown to undergo apoptosis (38).
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