Thrombopoietin: too much or too little

Abstract

The basis of treatment for immune thrombocytopenia (ITP) has conventionally relied on non-specific immune suppression designed to reduce platelet destruction. As a consequence, at least half of the morbidity and mortality in the condition is related to infection secondary to treatment and alternate treatments are desirable. It has been shown that ITP is not purely due platelet destruction and in a significant proportion platelet production is suboptimal. Further interest developed with the discovery that the recombinant thrombopoietins (TPOs) could enhance platelet production in a variety of thrombocytopenic states. With the development of the second generation of TPOs that had no sequence homology to endogenous TPO, studies confirmed clinical effect. Two agents, romiplostim and eltrombopag, are now licensed and their place in the treatment is being evaluated. Platelet responses are seen in a much greater percentage than in other second-line studies, and these are maintained while the drugs continue to be administered. Both are well tolerated with no significant adverse effects over placebo and have an effect both pre- and post-splenectomy. An interesting initial observation has been that the platelet response is associated with an improved quality of life in many patients when compared with conventional management. Clinical trials are also being conducted in patients with thrombocytopenia relating to liver disease, HCV infection, myelodyplasia, and post-chemotherapy.

Keywords:

• Immune thrombocytopenia
• Relapsed and refractory ITP
• Thrombopoietin receptor agonists

Introduction

Primary immune thrombocytopenia (ITP) is an autoimmune disorder typified by a platelet count below the normal range (<100×10⁹/l). Clinical manifestations are related to the severity of thrombocytopenia and include purpura and bleeding episodes. In the past, ‘acute ITP’ described a self-limited form of disease (e.g. secondary to viral illness) and ‘chronic ITP’ thrombocytopenia lasting for more than 6 months. In the absence of reliable predictive clinical or laboratory parameters of disease duration, the term ‘newly diagnosed ITP’ is now adopted for all cases at diagnosis. The term ‘persistent ITP,’ was introduced for patients with disease between 3 and 12 months from diagnosis. This category includes patients not achieving remission or maintaining their response after stopping treatment. The term ‘chronic ITP’ is used for patients with ITP lasting for more than 12 months.

The natural history of ITP is variable and unpredictable. For patients who are in otherwise good health treatment is not required, if the platelet count is close to or above 20×10⁹/l. The mortality rate is <1%, and the morbidity associated with treatment can be worse than the disease. Thus, platelet count and risk for bleeding events should be considered together before treatment is initiated.

ITP is associated with a reduced platelet life span, due to the binding of autoantibodies to platelets with subsequent increased clearance by the reticuloendothelial system, usually in the spleen. Traditionally, most ITP therapies have attempted to reduce antibody production with immunosuppressive agents (e.g. corticosteroids, rituximab, cyclosporine, mycophenolate mofitile), blockade of macrophage Fc receptors [e.g. anti-D immunoglobulin (Ig), intravenous Ig (IVIg), danazol], or removal of the spleen (the primary site of platelet clearance).1,2

Recently, it has become clear that most ITP patients also have inappropriately low platelet production.3 Antiplatelet antibodies4,5 and possibly cytotoxic lymphocytes6 suppress bone marrow megakaryocytes function with reduced platelet production. Inappropriately low platelet production is seen in up to 70% of patients with chronic ITP.4 In these patients, it has been considered that there is a relative deficiency of thrombopoietin (TPO) and that the administration of exogenous TPO may stimulate increased platelet production and may have a place in the treatment pathway.

Traditional Management of ITP

Two-thirds of patients with ITP experience some increase in platelets after receiving corticosteroids, IVIg, or Rh_o(D) IVIg (anti-D Ig) but many relapse. Patients who fail to respond or who relapse face the options of undergoing treatment with second-line drug therapy or splenectomy; however, there is no clear evidence base to support the best approach. In some patients identifying and treating Helicobacter pylori infection which may be all that is necessary. Splenectomy has been shown to provide long-term efficacy, but this is still only successful in around 60%. Second-line drug therapies include high-dose dexamethasone or methylprednisolone; high-dose IVIg or anti-D Ig, vinca alkaloids, and danazol, the immunosuppressants cyclophosphamide, azathioprine, and cyclosporine or mycophenolate mofetil, and the anti-CD20 monoclonal antibody rituximab.5

TPO Receptor Agonists

Megakaryopoiesis and platelet production are governed by signalling through the Mpl receptor and its ligand, TPO, which has a pivotal role in platelet production. Two recombinant TPO molecules were developed, recombinant human TPO and pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMgDF). However, early trials were halted in 1998 with reports that patients receiving PEG-rHuMgDF (which has significant sequence homology with endogenous TPO) developed severe thrombocytopenia stemming from antibodies against PEG-rHuMgDF that cross-reacted with endogenous TPO, neutralizing its biologic activity.

Despite these concerns, the success of these first-generation growth factors in stimulating platelet production led to the development of a second-generation with no sequence homology with native TPO. Clinical trials with these, the TPO peptide mimetic AMG 531 (Nplate or Romiplostim, Amgen, Thousand Oaks, CA, USA) and the non-peptide mimetic eltrombopag (Revolade or Promacta, GlaxoSmithKline, Research Triangle Park, NC, USA) resulted in dose-dependent increases in platelets in healthy subjects and in significant increases in platelets in patients with chronic ITP.6

The extensive clinical studies have shown that platelet responses are seen in approximately 80%, a much greater percentage than in other second-line studies and the response is maintained, while the drugs continue to be administered. They are almost as effective in splenectomized patients as in the non-splenectomized ones.7 Recent phase III studies have confirmed the efficacy and safety following long-term usage of both of the currently available products.7^–9 The licenses for these agents vary throughout the world. In some (USA and Canada) the license covers pre-splenectomy use, whereas in Europe this is only covered for patients in whom the surgery is contraindicated. Although in the UK, the National Institute of Healthcare and Clinical Excellence have sanctioned the use on romiplostim in patients who are refractory to second-line treatment or who require excessive continuing treatment irrespective of splenectomy status.

The overall treatment-related serious adverse event rate was low in all studies at less than 10% and are usually little different from those seen in the placebo/standard of care comparative arms.10 The treatment populations tend to be elderly and deaths have been recorded in the studies; however, in the majority these were not felt related to study drug. In the small number where it was, pre-existing cardiovascular risk factors where present. Deaths were seen in both arms. In those receiving the TPOs, there appears to be no apparent relationship between patient death and either the duration of time on study or the platelet counts immediately prior to death.

There appears to be no increased incidence of thrombotic events in patients who achieve normal platelet counts compared with those receiving placebo; however, thrombotic events have been reported in patients with other risk factors of cardiovascular disease and a recent report has shown an increased of venous and arterial thrombo-embolism in any patient with ITP, suggesting that ITP is a pro-thrombotic condition.11

Most events bleeding events were mild to moderate in severity and did not increase in severity with time on study. Bleeding in the TPO treated arms was generally seen in those who failed to respond and the incidence of severe bleeding was decreased significantly in the treatment arm compared with standard of care/placebo arm. In a recently reported study the duration-adjusted incidence of bleeding events seen with romiplostim in the comparison to standard of care was 3·56 events per 100 patient-weeks in the treated arm compared with 5·02 events per 100 patient-weeks in those receiving standard of care.11

The formation of autoantibodies that were seen in the studies with the first generation of TPOs were not an issue with the second-generation TPOs. Increases in marrow reticulin have been reported, but this appears to be a reversible phenomenon and is not associated with formation of collagen fibrosis. The incidence of increase in marrow reticulin is unclear but where studied is less than 10% and is likely to be higher in patients treated with high doses, which should therefore be used with caution. These agents therefore appear to be well tolerated.

The clinical studies have shown that with prolonged exposure efficacy is maintained with romiplostim for over 5 years and for eltrombopag for over 3 years. Continuous treatment with stable dosing is associated with a steady platelet count, a low rate of bleeding, and a low rate of need for rescue treatments for ITP. It is effective in both non-splenectomized and splenectomized patients. Treatment is associated with a known rate of adverse events which are clinically mild, with no new class of adverse events being seen in the past several years. Prolonged platelet response off treatment is not expected but has been reported in some cases.12 It is clear that this class of agents will have a major role to play in the treatment of thrombocytopenia; however, the exact place needs to be determined by carefully designed clinical studies.

While there is general agreement over treatment of the newly presenting adult with ITP, there are few evidence-based studies that direct therapy in the relapsed and refractory patient. There is an understanding that the patient should be treated for their clinical state rather than their platelet count but not what second-line treatment should be used and in what order. In order to develop a rational approach an international group produced a consensus report on investigation and management giving (where possible) evidence-based advice on treatment pathways.2 It is hoped that by following such an approach treatment in the future can be audited and authoritative guidelines developed so that the place of newer agents, such as the TPO receptor agonists, can be understood and incorporated into routine clinical use.