High dose romiplostim as a rescue therapy for adults with severe bleeding and refractory immune thrombocytopenia
Authors: Mathilde Roumier, Sébastien Le Burel, Sylvain Audia, Adrien Chauchet, Marie Gousseff, Mohammed Hamidou, François Liferman, Guillaume Moulis, Bertrand Lioger, Lionel Galicier, Mickael Ebbo, Jonathan London, Solène Poutrel, Louis Terriou, Virginie Zarrouk, Marc Michel, Bertrand Godeau, Matthieu Mahevas
Journal: American Journal of Hematology (2020)

To the Editor: Life-threatening bleeding is a rare event in immune thrombocytopenia (ITP) and intracranial hemorrhage (ICH) occurs in less than 1% but is associated with a mortality rate of 44% in adults.1 Even if no controlled study has been conducted in patients with life-threatening bleeding, high-dose corticosteroids, IVIg and platelet transfusions are widely used. In an emergency with uncontrolled bleeding, starting high dose of TPO-RAs can be considered to rapidly increase the platelet count to a level where the risk of severe bleeding is minimized.2 Such off-label strategy has not been systematically evaluated. To evaluate the safety of this "rescue therapy" we carried out a multicenter retrospective cohort study of ITP patients treated with maximal dose of romiplostim for bleeding emergency from 2017 to 2019 in centers belonging to French national network for adult ITP. We included patients who fulfilled the following criteria:(a) Platelet count <30 × 109/L; (b) Severe bleeding manifestations defined as a score ˃ 8 according to the bleeding score previously reported by our group which takes into account cutaneous, mucosal and visceral bleeding3; (c) No response to corticosteroids and IVIg; (d) Rescue therapy with maximal dose of romiplostim (ie, 10 μg/kg body weight). Response (R) and Complete response (CR) were defined according to standardized international criteria.2 We included 30 patients (15 men) with ITP and severe bleeding manifestations (Table S1, Figure S1). The median age was 65 years [range 18-77]. Twenty-seven patients had newly diagnosed ITP and three chronic ITP. All patients had severe bleeding symptoms, characterized by skin and mucosal bleedings. The median bleeding score was 20 [range 8-33], including intracranial hemorrhage (n = 9), visceral hemorrhage — metrorrhagia, macroscopic hematuria, gastrointestinal or peritoneal bleeding (n = 16) (some patients had several manifestations). Twelve patients had received red blood cell transfusions because of severe anemia related to bleeding. The median platelet count was 2 × 109/L [range 0-10] at the time of severe bleeding. All 30 patients had received corticosteroids and IVIg treatment [median dose 2 g/kg.bw, range 1-4] as first-line therapy, and had failed to achieve any response. Twenty patients (67%) received platelet transfusions. Twenty-six patients had received intravenous vinca alkaloid (VA), in median 8 days (range 3-36) after initial bleeding symptoms: either concomitantly (ie,:1-3 days to romiplostim administration) in 20 cases; or 4-14 days before in six cases (8 mg vinblastine, n = 24 and 1 mg/m2 vincristine n = 2). Four patients did not receive VA including two patients who had a contra-indication to VA. Eight patients had received one or two other concomitant therapies. Romiplostim was started at a median of 9 days [range 3-40] after the first bleeding episode. At that time, bleeding symptoms were severe (bleeding score > 83), and for all but two patients, the platelet count was ≤20 × 109/L. These two patients received repeated platelet transfusions because of cerebral bleeding, with platelet counts 63 and 47 × 109/L, respectively. All patients received a starting dose of romiplostim at 10 μg/kg.bw/week from the first injection (n = 26), or from the second administration after a first attenuated dose of 5-8 μg/kg.bw (n = 4). During the first month of follow-up, the median peak platelet count among responders was 531 × 109/L [range 70-3840]; for 16 patients, the platelet count was >500 × 109/L and for nine it was >1000 × 109/L. Patients with a platelet count >1000 × 109/L received empirically low-dose aspirin. Three serious adverse events were noted. One 52-year-old woman who was bed-ridden because of a muscular hematoma, experienced deep-vein thrombosis with an asymptomatic pulmonary embolism 13 days after IVIg treatment and 5 days after the first romiplostim injection; the platelet count was 629 × 109/L at the time of thrombosis. One 70-year-old woman was diagnosed with ischemic stroke in the left parietal and right temporal lobes 13 days after IVIg administration and 10 days after the first romiplostim injection; at that time. Her platelet count was then in normal range (239 × 109/L). No predisposing condition for arterial thrombo-embolic events was found. Lastly, one 67-year-old patient who presented with cerebellar hemorrhage when diagnosed with ITP, died of cerebellar oedema 1 month after initial surgical treatment with external ventricular drains which had to be replaced several times because of infection or occlusion. At that time, cerebellar hemorrhage was stable and complete response was achieved 3 weeks before. We then evaluated response in the 20 patients who received romiplostim and concomitant VA treatment (VA + ROMI group) and compared to an historical cohort of 22 subjects with severe bleeding with absence of response to steroids and IVIg and who received VA without romiplostim (VA group) from 2008 to 2014. The two groups were not closely similar since patients in the VA + ROMI group had more severe bleeding manifestations, with a higher bleeding score (18 [range 8-33] vs 10 [range 8-28]), more ICH (30% vs 5%) and visceral hemorrhage (58% vs 36%) (Table 1). The day of VA administration was considered the starting point for evaluation. During the 14 days period of analysis, steroids were maintained at stable dose in all patients. Additional treatments administered are detailed in Table S1. At day 7 after VA +/− ROMI initiation, there was no significant difference in terms of response between the two groups (VA + ROMI: 70% vs VA: 48%, P = .15), but complete response was significantly higher in the group of patients who received VA + ROMI compared to those who received VA alone [60% vs 29%, P < .05]. Between day 7 and day 14, 13 patients (65%) received a second administration of ROMI in the VA + ROMI group; and 6 (30%) and 9 (41%) patients received a second administration of VA, respectively in the VA + ROMI and in the VA group. At day 14, both response and complete response were significantly higher in the VA + ROMI group compared to VA group [R: 80% vs 43%, P < .05; and CR: 70 vs 17%, P < .0001] (Figure 1). In the group receiving VA alone, one patient died at day 5 from uncontrolled bleeding and hemorrhagic shock, four experienced severe adverse events (agranulocytosis, n = 2, and urinary tract infection, n = 2). No thrombotic event was observed. Our work raises safety concerns, as major thrombotic events (TEs) occurred in two patients out of 30. It is noteworthy that in the present series, the platelet count was >500 × 109/L at time of thrombosis in one patient but <250 × 109/L in the other. This is in line with previous observations showing that thrombosis with TPO-RAs occurred independently from the platelet count4, 5 and may result from platelet activation. We cannot rule out a deleterious pro-thrombotic synergistic effect with other treatments, especially with IVIg which can itself promote TEs when other risk factors are present.6 Thrombocytosis with a platelet count over 1000 × 109/L was observed in a third of the patients, none of whom experienced a symptomatic thrombotic event. However, all were empirically treated with low dose aspirin. Our study strongly suggests that romiplostim given at a maximal dose is effective for treating patients with refractory ITP in emergency bleeding situations. Patients included in this study had life-threatening hemorrhage despite first-line therapy with corticosteroids + IVIg and with platelet transfusion in about two thirds of patients. Failure to respond to this first-line rescue therapy has been found to be associated with the risk of intracranial hemorrhage which occurred in 32% of our patients. Regarding the initial response, most patients received concomitant therapies that may have interfered with the interpretation of platelet response. In particular, vinca alkaloids were used in most patients, with an expected time to initial response that is similar to that of romiplostim.4 To minimize the risk of an interpretation bias, we focused our efficacy analysis on those patients who received romiplostim and VA concomitantly and compared their outcome to an historical group of patients who were treated only with VA in the same situation. We found a significantly higher overall response rate at day 14 in the ROMI + VA group and a significantly higher CR rate at days 7 and 14. The use of romiplostim rather than eltrombopag was preferred firstly because the subcutaneous route of administration was more suitable for critically ill patients with life-threatening bleeding, especially in the intensive care unit, and secondly because the range of dose of romiplostim [1-10 μg/kg/week] is higher than that of eltrombopag [25-75 mg daily]. However, there is no reason to speculate that eltrombopag at 75 mg/day would not also have been effective. The use of a lower dose of romiplostim (ie, 5 μg/kg) could potentially decrease the risk of thrombocytosis but also the efficacy rate. The main limitation of this study is the retrospective design and potential bias of analysis. In conclusion, this study shows that the use of romiplostim at maximal dosage as rescue therapy for ITP patients with severe bleeding not responding to standard rescue therapy is feasible and effective. The risk of thrombo-embolic events and the risk over benefit ratio should however be carefully assessed. Therefore, we suggest that this strategy should be restricted to life-threatening situations while awaiting more robust safety data. MMa received research grants from GSK, and meeting attendance grants from GSK and Amgen. GM received research grants form CSL Behring, Novartis, Grifols, and meeting attendance grants from Amgen and Novartis. LG participated to educational boards for GSK. BG received research grant from Amgen, and B.G. served as an expert for Amgen, Novartis, LFB and Roche. ME has participated in advisory boards for Amgen, Grifols, GSK and Novartis. M.Ma designed the study and initiated this work; B.G., M.M., M.R and S.LB wrote the report; all authors made substantial contributions to acquisition of data, revised the article critically and gave final approval of the manuscript to be submitted. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1 Patient flow chart. Table S1 Initial characteristics of ITP patients receiving romiplostim as rescue therapy at the maximal dosage (ie, 10 μg/kg.bw/week). Bleeding score was graded by an ITP specific bleeding scale by Khellaf et al. 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