Page 307 - Haematologica March 2020

Eltrombopag in inherited thrombocytopenias
bleeding: however, even patients who do not have spon- taneous hemorrhages often require platelet transfusions prior to surgery or other invasive procedures because their platelet count is below the safe threshold for the specific procedure.1-5 Platelet transfusions have several drawbacks, as they expose patients to the risk of acute reactions, transmission of infectious diseases, and alloimmunization with consequent refractoriness to subsequent platelet transfusions.3,6,7 The last is a particularly critical event in these patients with lifelong thrombocytopenia. Moreover, the availability of platelet units is conditioned by the scarceness of blood donors. Less commonly, some patients with inherited thrombocytopenias have frequent episodes of spontaneous bleeding that affect their quality of life, expose them to the risk of major hemorrhages, and may require frequent hospitalization and/or transfusions. In these subjects, obtaining an enduring increase of platelet count sufficient to stably abolish or reduce spon- taneous hemorrhages would be a major achievement.
Thrombopoietin-receptor agonists (TPO-RA) are target- ed agents that can stimulate megakaryopoiesis and platelet production through the activation of the thrombopoietin receptor, MPL. These drugs are currently approved for the treatment of a few forms of acquired thrombocytopenia.8 Although the hypothesis that TPO-RA can increase platelet count also in patients with inherited thrombocy- topenias is appealing, the evidence on this topic is very scarce, mainly because of the difficulties in carrying out clinical trials in these orphan diseases. In fact, only one prospective study has been conducted so far: moreover, this study enrolled patients affected with only one of the many forms of inherited thrombocytopenia. In this trial, a short course of the oral TPO-RA eltrombopag was given to 12 patients with thrombocytopenia deriving from muta- tions in MYH9 (i.e., MYH9-related disease, MYH9-RD): 11 patients showed an increase of platelet count.9 Based on these results, there are anecdotal reports of short-term eltrombopag treatment to prepare MYH9-RD patients for major surgery.10-12 The remaining available clinical informa- tion on the effects of TPO-RA in inherited thrombocytope- nias derives from single case reports13-17 and the retrospec- tive investigation of one small case series.18
Here we report the results of the second prospective clinical trial on the use of TPO-RA in genetic thrombocy- topenias. We investigated the efficacy of eltrombopag in increasing platelet count in patients affected by different forms of inherited thrombocytopenia. Patients received short-term eltrombopag to test whether this treatment can raise platelet count up to safe levels for major surgery. Moreover, in those patients with clinically significant spontaneous bleeding, we also investigated whether pro- longed administration of eltrombopag could induce a per- sistent remission of the spontaneous hemorrhages.
Methods
Patients
Patients were enrolled at five Italian centers (Online Supplementary Table S1). The study protocol was approved by the institutional review boards of all centers. Patients or their legal guardians signed written informed consent to participation in the study, which was conducted according to the Declaration of Helsinki. Inclusion and exclusion criteria for this trial are detailed in the Online Supplementary Methods.
Study design
This was a phase II, open-label, dose-escalation trial. The study consisted of two parts.
The main aim of part 1 was to test whether, and in which forms of inherited thrombocytopenia, a short-term course of eltrom- bopag is effective in increasing platelet count above the safe threshold for all types of surgery (100x109/L).4,5 All patients eligible for the study entered part 1. Patients received eltrombopag 50 mg/day for 3 weeks. Patients who obtained a platelet count >100 x109/L by day 21 stopped treatment (as they had achieved the pri- mary endpoint). In the other cases, patients received eltrombopag 75 mg/day for 3 additional weeks.
The main aim of part 2 of the study was to test the efficacy of long-term eltrombopag in achieving an enduring remission of bleeding symptoms in patients with clinically significant sponta- neous hemorrhages. Criteria for entering part 2 were the follow- ing: patients with spontaneous bleeding at baseline grade ≥2 according to the World Health Organization (WHO) bleeding scale, who completed part 1 without severe side effects and obtained a reduction of bleeding symptoms at the end of part 1. Part 2 consisted of 16 weeks of treatment. Patients were started on eltrombopag 25 mg/day and then re-evaluated every 4 weeks: the eltrombopag dose was adjusted based on bleeding tendency and platelet count according to the schedule reported in Online Supplementary Figure S1.
Endpoints and outcome measures
The primary endpoint of part 1 was the achievement of a platelet count >100x109/L, i.e., a safe level for all types of surgery according to current guidelines.4,5 Major response was defined as the achievement of the primary endpoint. Minor response was defined as the achievement of a platelet count at least two-fold higher than baseline without reaching the criteria for major response.
The primary endpoint of part 2 was the stable reduction of spontaneous bleeding manifestations according to the WHO bleeding scale during the last 2 weeks of treatment. A major response was defined as a complete remission of hemorrhages. A minor response was defined as a reduction of bleeding according to the WHO bleeding scale without reaching the criteria for a major response.
Secondary endpoints included safety and tolerability of the treatments; dosages of eltrombopag required to achieve the pri- mary endpoints; and improvement of health-related quality of life (HR-QoL) with long-term eltrombopag administration (part 2 only).
Exploratory endpoints included the effects of treatment on serum thrombopoietin levels and on platelet function investigated by light transmission aggregometry and/or flow cytometry.
Investigation of patients
Studies performed to investigate patients at baseline and at each subsequent visit are detailed in the Online Supplementary Methods.
Statistical analysis
The statistical analysis was performed as described in the Online Supplementary Methods.
Results
Study population
Twenty-four patients were enrolled between April 2015 and May 2017. They consisted of nine patients with MYH9-RD; nine with ANKRD26-related thrombocytope-
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