Eltrombopag in adult patients with immune thrombocytopenia in the real‐world in France, including off‐label use before 6 months of disease duration: The multicenter, prospective <scp>ELEXTRA</scp> study
Authors: Guillaume Moulis, Johanne Germain, Manuela Rueter, Margaux Lafaurie, Myriam Aroichane, Thibault Comont, Matthieu Mahévas, Jean‐François Viallard, Stéphane Chèze, Mikaël Ebbo, Sylvain Audia, Soraya Leclerc‐Teffahi, Agnès Sommet, Odile Beyne‐Rauzy, Marc Michel, Bertrand Godeau, Maryse Lapeyre‐Mestre
Journal: American Journal of Hematology (2021)

Immune thrombocytopenia (ITP) is a rare autoimmune disease responsible for platelet destruction, impaired platelet production, and resulting in spontaneous bleeding.1 First-line treatment is based on corticosteroids. Intravenous immunoglobulin (IVIg) is added in case of serious bleeding.2, 3 In 60%–70% of adult patients, ITP becomes persistent (lasting >3 months) and chronic (>12 months).4 In such cases, second-line treatments are indicated, including rituximab, splenectomy, immunossupressants, thrombopoietin receptor agonists (TPO-RAs), and recently fostamatinib.2, 3 The two first TPO-RAs, romiplostim and eltrombopag, have been marketed in USA and Europe in 2008–2010. Eltrombopag binds to the transmembrane domain of the thrombopoietin receptor, inducing proliferation and differentiation of megakaryocytes. In randomized controlled trials, eltrombopag had a high efficacy rate, with the achievement of sustained response in >80% of patients. Safety signals were hepatitis, thromboembolism, and reversible myelofibrosis.5 Eltrombopag was initially marketed for adult patients with chronic ITP, refractory or contraindicated to splenectomy. In the late 2010s, the indication was extended to patients aged ≥1 year, with ITP lasting ≥6 months, and refractory to at least one other treatment (e.g., corticosteroids, IVIg). In Europe, the use of eltrombopag before 6 months of disease duration is off-label, while it has been labeled in the USA in patients with persistent ITP (duration >3 months) in February 2021. Indeed, guidelines suggest that TPO-RAs, including eltrombopag, could be used early in the disease course as second-line treatment.2, 3 Real-world data about eltrombopag use, effectiveness, and safety are scarce. They are based on retrospective series, with study periods ending before the publication of guidelines recommending TPO-RAs as second-line treatments early in the disease course (File S1). Therefore, real-world data about eltrombopag effectiveness and safety are needed, particularly in patients treated off-label before 6 months of ITP duration. The study population consisted of all adult patients with incident ITP prospectively included and followed in the CARMEN-France registry from June 2013 to December 2019 who were exposed to eltrombopag during the disease course. Information about this registry is indicated in File S1. The Follow-up ended on December 31, 2019. Exposure to eltrombopag was assessed describing the time from ITP diagnosis to first exposure to eltrombopag and the duration of first exposure to eltrombopag. Patients' characteristics were described, including previous lines of treatments. Concomitant treatment was defined by ongoing treatment at the time of eltrombopag initiation, IVIg in the previous month or rituximab in the previous 6 months. Responses were assessed in the subgroup of patients with a platelet count <30 × 109/L. Overall response was defined by achievement of platelet count ≥30 × 109/L, complete response by platelet count ≥100 × 109/L, partial response by platelet count between 30–100 × 109/L, and no response by platelet count <30 × 109/L. We also described the time from eltrombopag initiation to overall response and complete response achievement; and the number of patients with no bleeding during exposure to eltrombopag. In the whole population, the withdrawal of concomitant treatment present at eltrombopag initiation was described (except rituximab). The frequencies of eltrombopag withdrawal were also described. The reasons of eltrombopag withdrawal were retrospectively assessed. Safety outcomes were the occurrence of adverse drug reactions (ADRs) during eltrombopag exposure, which were collected by investigators. Causality was then assessed by two investigators (G. Moulis. and M. Lafaurie) according to the World Health Organization causality assessment scale.6 All ADRs with a causality score at least as "possible" were described. All outcomes were measured for the first exposure to eltrombopag. Detailed statistical analyses are presented in File S1. Out of 799 adult patients with incident ITP included in the CARMEN-France registry during the study period, 156 (19.6%) had been exposed to eltrombopag, including 95 (60.9%) before 6 months of ITP duration. Patients' characteristics are detailed in Table 1 (Table S1 for secondary ITP). In the whole cohort, eltrombopag was mostly used as second-line and third-line treatment (33.3% and 35.9%, respectively) with a median time from ITP diagnosis to eltrombopag initiation of 3.3 months. Patients' characteristics were similar between patients who initiated eltrombopag <6 months of ITP duration and those who initiated eltrombopag ≥6 months of ITP duration, except a higher frequency of patients with comorbidities of the Charlson's comorbidity index in the first group (46.2% vs. 27.9%) (Table 1). Effectiveness outcomes among the patients with a platelet count <30 × 109/L at eltrombopag initiation (n = 75) are presented in Table S2. Overall response was achieved in 86.7% of patients and complete response in 70.7%. These rates were similar between groups of disease duration, with a slightly higher rate of complete response rate in the <6 months group (Table S2). The median time to overall response was 8 days, and the median time to complete response was 19 days. The rates of overall response and complete response were similar by groups of age, sex, Charlson's comorbidity index, and number of previous lines of treatments (Table S3). During exposure to eltrombopag, 111 (71.2%) patients had no bleeding (74.7% and 65.6% in the groups with a disease duration <6 months and ≥6 months at eltrombopag initiation, respectively). Out of 126 patients with concomitant treatment at eltrombopag initiation, 77 (60.1%) had the concomitant treatment permanently withdrawn during eltrombopag exposure (58.0% in the group with a disease duration <6 months at eltrombopag initiation). In total, 91 (58.3%) patients stopped eltrombopag with a median duration of exposure of 1.8 months. The most frequent reasons were the absence or loss of response (34.1%), ADRs (24.2%) and sustained complete response (18.7%) (Table S4). The median duration of exposure to eltrombopag in the patients who stopped eltrombopag due to sustained response was 164 days. Thirty-eight ADRs scored at least "possible" were reported in 35 patients (22.4%) (Table S5). Thromboembolism occurred in eight patients (Table S6). In this French real-world prospective study of eltrombopag use in adult patients with ITP, the population was more severe than the general ITP population with 84.2% having experienced bleeding before eltrombopag initiation.6 In clinical practice in France, eltrombopag was mostly used off-label before 6 months of ITP duration (60.9%) and as second- and third-line treatment, as suggested by recent guidelines.2, 3 No patient was splenectomized before eltrombopag, in contrast with the first retrospective series in the real-world (File S1). The Charlson's comorbidity index score was higher in patients exposed to eltrombopag in the first 6 months of ITP. We can hypothesize that this higher number of comorbidities resulted in an earlier prescription of eltrombopag instead of immunosuppressive drugs (higher risk of bleeding or of infection reflected a higher Charlson's index score). The rates of response/complete response achievement, overall and without bleeding, as well as the time to response/complete response were similar to that observed in clinical trials and previous retrospective real-world series.5 These rates must be taken with caution in real-world analysis, since concomitant treatment was frequently used either as acute rescue therapy until eltrombopag achieves effectiveness (i.e., corticosteroids or IVIg), or as exposure to previous second-line treatment with delayed effectiveness such as rituximab. In addition, 60.1% of the patients had definitively withdrawn a concomitant treatment during eltrombopag exposure, which is an additional strong outcome to assess real-world effectiveness. The fact that the rates of overall response and complete response were quite similar by subgroups of age, sex, Charlson's comorbidity index groups, previous lines of treatments, as well as by subgroups of disease duration is an important finding, arguing for the same effectiveness of TPO-RAs in patients in early phase of the disease.5 Among the 156 patients, 58.3% stopped eltrombopag. Among them, the reason was sustained response for 18.7%, corresponding to previous retrospective reports (Supporting Information S1). The rate and pattern of ADRs observed in the ELEXTRA study are also in accordance with previous real-world retrospective studies.5 Importantly, 8 (5.1%) patients experienced venous thrombosis, including 7 (4.5%) deep vein thrombosis and/or pulmonary embolism. The mechanisms inducing a higher rate of thrombosis (about 5 per 100 patient-years) in patients with ITP treated with TPO-RAs are unknown.5 Of note, 6 of the 8 venous thromboses occurred in patients with a disease duration <6 months. This high incidence rate of thrombosis during the early phase of the disease must be taken with caution due to the low number of events. Almost all patients had other risk factors for thrombosis. No arterial event attributable to eltrombopag was reported in this study. This may be due to a causality assessment disfavoring eltrombopag in older, comorbid patients with a high prevalence of cardiovascular risk factors except age and sex. Myelofibrosis was not systematically searched in this real-world study but no ADR of central cytopenia was observed. The limitations of this study are the inclusion of patients from mostly referral centers (except in the Midi-Pyrénées region) that may limit the representativeness of the population with more severe patients and an earlier use of eltrombopag in comparison with the entire population of ITP patients treated with eltrombopag in France. Only 75 patients (48.1%) had a platelet count <30 × 109/L at eltrombopag initiation, allowing the measurement of response achievement. The presence of concomitant treatment makes the assessment of the true role of eltrombopag in response/complete response achievement difficult. In conclusion, eltrombopag was used early in the ITP course in the French real-world practice. Effectiveness and safety profile identified in clinical trials and previous retrospective real-world series were confirmed, even in the subgroup of disease duration <6 months. The ELEXTRA was funded by Novartis SAS. The CARMEN-France registry is sponsored by Toulouse University Hospital and also received grants from CSL Behring, Amgen, Grifols, Novartis, the French Society of Internal Medicine and French referral centers for autoimmune cytopenias. See Conflict of interest statement for the role of the funder. This study was granted by Novartis SAS. The design of the ELEXTRA study, protocol, and statistical analyses plan were made by GM, MA, and SLT. Novartis SAS had no access to data and no role in analysis, interpretation of results and manuscript writing. The present manuscript has been sent to Novartis SAS representatives before submission, with no substantial modification requested from the authors. GM received meeting attendance grants from Amgen and Novartis, is coordinator of research studies granted by Amgen, CSL Behring, Novartis and Grifols. He participated in educational sessions funded by Amgen and Novartis, and to boards for Amgen, Novartis and Sobi. TC received honoraria and/or research or educational support from AbbVie, AstraZeneca, Bristol Myers Squibb (Celgene), Novartis and Takeda. SC is investigator of research studies granted by Bioverativ, Novartis, Protalex, Rigel and participated to boards for Novartis and Sobi. ME received meeting attendance grants from Novartis, Octapharma and Sobi, and participated to educational sessions for Amgen, Grifols, Novartis and to boards for Grifols and Novartis. MMi participated to educational sessions and boards for Amgen, Argenx, Novartis, Sobi, and UCB. BG participated to educational sessions and boards Amgen, Grifols, Novartis, Roche and Sobi. All other authors declare having no conflict of interest. File S1. The ELEXTRA study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.