Real-world effectiveness and safety of fostamatinib in difficult-to-treat patients: Results of a three-year registry in France.

Abstract Background: Fostamatinib, a spleen tyrosine kinase inhibitor, has been marketed in France for the management of adult chronic immune thrombocytopenia (ITP) in October 2021. French health authority recommended the use fostamatinib in case of failure or contraindication to eltrombopag, romiplostim (the two thrombopoietin receptor agonists – TPO-RAs – available in France), rituximab and splenectomy, even if every hematologist or internist is allowed to prescribe the drug. The French national health authority also requested a prospective three-year registry to include and follow as many treated patients as possible to provide real-world evidence. We herein present the results of this registry, assessing the use, the effectiveness and the safety of fostamatinib in adult patients with ITP in the real world in France after three years of availability of the drug. Methods: The source of study population was the French fostamatinib registry, appended to the CARMEN-France registry of the French referral network for autoimmune cytopenias, that prospectively includes adult patients with a new diagnosis of ITP in 50 centers. Adult patients were included in the fostamatinib registry 1) if they were previously included in the CARMEN-France registry and initiated fostamatinib or 2) if they were not already in the registry but initiated fostamatinib. In that latter case, a retrospective assessment of ITP history was recorded. Patients who initiated fostamatinib between October 2021 and October 2024 were selected for the present analysis. We described the patients' characteristics, response rate on treatment (defined by an ongoing exposure to fostamatinib and a platelet count ≥30 x 109/L with no rescue in the previous 4 weeks) at M3, M6, M12 and M24, bleeding during fostamatinib, drug discontinuations, adverse drug reactions (ADRs, judged related to fostamatinib by the investigators), and other events of interest, i.e. thrombosis, infection, fracture, cancer and death. Results: During the study period, 164 patients were included in the registry, corresponding to 44.3% of exposed patients in the whole of France, as determined by the national dispensing database. Median age was 59 years and 55.5% were women. Thirty-eight percent had ≥1 comorbidity according to the Charlson Comorbidity Index and 29.7% had chronic arterial hypertension. The median lowest platelet count before fostamatinib was 11 x 109/L and 84.1% patients had experienced bleeding. Thirty patients had secondary ITP. The median ITP duration was 7.2 years and 146 (89.0%) patients had chronic ITP. The median number of previous exposures to ITP treatments was 6 (min-max: 1-13). Seventy-height percent of patients had been exposed to eltrombopag, 74.4% to romiplostim, 86.0% to rituximab, 48.8% to mycopenolate or azathioprine, and 28.0% were splenectomized. A concomitant exposure to another ITP treatment at fostamatinib initiation was present in 65.2% of patients. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Combination treatment (mostly with TPO-RA) was observed in >60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpoint was respectively 27.0%, 44.6%, 55.9% and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding during the exposure to fostamatinib, none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%) patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%), transaminitis (n=7) and neutropenia (n=4). Seven (4.3%) thrombosis and 40 infections (including 12 serious) in 25 (15.2%) patients were reported mostly in patients with known risk factors. One fracture was reported (in an 87-year-old woman exposed to corticosteroids), two cancers (1 lymphoma and 1 adenocarcinoma considered not related to fostamatinib because diagnosed within the weeks following the exposure), and 5 deaths (47 to 82 year-old patients 3 related to infection, 1 to myocardial infarction, 1 of unknown cause). Conclusion: Fostamatinib was used in previously very heavily treated patients, with response rates of 44.0% at M3 and of 20.0% at M24. Combination therapy with TPO-RA is an option to consider in this population. No new safety signal was observed.