Thrombopoietin receptor agonists in the treatment of immune thrombocytopenia: A clinician's perspective
Authors: Marco Ruggeri
Journal: American Journal of Hematology (2012)

The introduction of two thrombopoietin-receptor (TPO) agonists (romiplostim and eltrombopag) in the treatment of immune thrombocytopenia (ITP) may represent a major improvement. Registrative [1-4] and extension studies [5, 6] showed that these agents are able to produce a sustained increase of platelet counts, a reduced use of concomitant ITP-specific therapies, and a global reduction of bleeding episodes with a general improvement of the quality of life (QoL). The use of TPO-R agonists has been incorporated in the most recent ITP guidelines [7, 8] as second-line therapy. However, a recent meta-analysis by the Cochrane Collaboration [9] has challenged the efficacy of TPO-R agonists, underlining the lack of evidence of a significant, positive effect in comparison with placebo, in terms of mortality rate and reduction of major hemorrhages. My approach in patients with ITP varies depending on the different phases of the disease and takes into account the individual response to previous treatments. My major concern, besides the efficacy, is the safety of treatment, particularly when new agents are used. In newly diagnosed patients (within 3 months from diagnosis), my aim is to quickly increase the platelet count and to stop or reduce the risk of bleeding. Curative attempts with rituximab [10] or intravenous Ig [11] or high dose dexamethasone [12] failed to show consistent results. TPO-R agonists are not valuable in this setting, since it takes from 10 to 15 days to see any effect on platelet count, and they are devoid of any curative potential. A short course of corticosteroids remains the standard approach. Patients failing corticosteroids enter the persistent phase of the disease (3–12 months from diagnosis) [13]. Determining which approach is the best treatment in this phase is the subject of ongoing debate among experts. When patients still require treatment after 12 months, they formally enter the chronic phase of ITP and spontaneous improvement or remission is unexpected. Thus, my principal aim is to offer a chance of cure. Currently, splenectomy is the only treatment with a curative potential. Sustained, complete responses are obtained in almost 60% of patients and a significant improvement is observed in other 15–20%, with an acceptable safety profile [14, 15, Vianelli et al., submitted]. Compared to splenectomy, rituximab efficacy is much less evident. Although about 50–60% of patients initially respond [16], not more than 20% maintain their response after 5 years [17]. Moreover, there are safety concerns. The use of TPO-R agonists as an alternative to splenectomy is not advisable since these agents require indefinite administration and strict monitoring. European Medicines Agency marketing authorization, which limited the use of TPO-R agonists to patients with ITP refractory to splenectomy, or when surgery is contraindicated, is in keeping with this policy. However, individual patients may require a different approach. For instance, what is the best treatment in a patient with diabetes or severe osteoporosis and persistent ITP in whom corticosteroids are contraindicated? Should we prefer immunosuppressive treatments, which are usually burdened with significant toxicity? In these situations, TPO-R agonists could really be an effective and safe alternative to bridge our patients to splenectomy. Unfortunately, this is an off-label indication. In patient's refractory to or with contraindication to splenectomy, despite the negative conclusions of the Cochrane Collaboration [9], TPO-R agonists are my preferred option. Indeed, I remain concerned with the significant toxicity and limited efficacy of immunosuppressive agents [13] and of rituximab. Although I may concede that there is no clear evidence that TPO-R agonists significantly reduce major bleedings, their ability to consistently increase the platelet count and to reduce global bleeding rate with QoL improvement makes these agents a valuable choice. When patients also fail TPO-R agonists or experience an untoward side effect, rituximab or other immunosuppressive treatments remain an option. The long-term safety of TPO-R agonists is still not fully understood, and the Cochrane Collaboration statement indicating that the rate of adverse effects of TPO-R agonists is similar to that of placebo or standard of care should be tempered with more information. Certainly, more data are needed and postmarketing surveillance and monitoring by regulatory agencies is required. Furthermore, the spectrum of patients enrolled in registrative trials only partially overlaps with that of patients encountered in real practice. For example, in a recent French compassionate–use program with romiplostim, 19/72 (25%) patients would not have been eligible, as they met exclusion criteria for comorbidities (cardiac and renal diseases, history of cancer, etc.) [18]. If TPO-R agonists increase, the thrombotic risk remains unproven and further studies are required. In conclusion, the Cochrane Collaboration revision failed to change my attitude toward TPO-R agonists. Nevertheless, there is certainly ample room for major improvement in the use of these agents, and future studies should be planned to answer some of the issues raised. More meaningful clinical outcomes, including bleeding manifestations and QoL, should complement the surrogate platelet count-based endpoints so far adopted in clinical trials. It is also to be recommended that future studies fully incorporate the proposal of the International Working Group (IWG) on ITP regarding standardization of terminology, definitions, andoutcome criteria. A more standardized, ITP-specific bleeding assessment tool is also desirable and will soon be proposed by the IWG.