LAUSR

Early iron chelation therapy is fundamental in the treatment of b-thalassemia major (b-TM) to avoid the adverse effects of chronic transfusional iron overload. Deferiprone (DFP) was the first oral iron chelator, but remains second line due to safety concerns. Superior efficacy in reducing cardiac iron, especially in combination with deferoxamine (DFO), has been shown. Its favourable cost-effectiveness and its off-patent status make it economically interesting both for developed and developing countries. Utilization in children is still limited since studies in pediatric patients are scarce. The independent consortium Deferiprone Evaluation in Paediatrics (DEEP), born within the context of the TEDDY Network and funded by the EU Commission, investigates safety and efficacy of DFP. The DEEP-3 study investigated the long-term safety of DFP therapy alone and in combination with DFO. DEEP-3 was a multi-center, retroand prospective, non-interventional cohort study which was conducted in 16 hospitals in six Mediterranean countries between November 2012 and April 2016: Albania (1), Cyprus (1), Egypt (1), Greece (1), Italy (11) and Tunisia (1). Endpoints were the nature and incidence of serious and non-serious adverse drug reactions (ADR) to DFP, and potential risk factors for ADRs and DFP withdrawals. Inclusion criteria were: diagnosis of β-TM and transfusional iron overload, start of DFP at age one month to less than 18 years, and at least one dose of DFP. Patients were excluded if previous medical records could not be obtained or were incomplete. Start of observation was the initiation of DFP therapy. Follow up ended when the patient either completed the study (e.g., turned 18 years of age or end of study) or permanently withdrew from DFP for any reason (e.g., adverse reaction). The study was approved by all local ethics committees. For prospective data collection, parents or guardians provided written informed consent. The investigators were asked to report the following adverse events (AE): hospitalization, fever of unknown origin, thrombocytopenia (platelet count <150x10/L), neutropenia (neutrophil count 0.5-1.5x10/L), agranulocytosis (neutrophil count <0.5x10/L), increased transaminases, arthropathies, neurological symptoms, hearing impairments, cardiac symptoms, endocrine dysfunctions, renal dysfunctions, weight gain >5% of baseline, gastrointestinal disorders, cutaneous reactions, death, or any other clinically important events. An independent safety committee evaluated causality, severity and seriousness of each AE. Disagreements were solved by consensus. Only AEs deemed at least possibly related to DFP by the committee and with positive investigator-reported causality were considered to be an ADR to DFP. Additional information on the methods can be found in the Online Supplementary File. Two hundred and ninety-seven patients were enrolled and observed from March 1994 to October 2015, with 717.4 person-years (PY) of follow up (Table 1). Median patient age at start of DFP therapy was 8.5 years (range 0.6-17.6 years). One patient died from non-DFP-related vomitus aspiration and severe convulsions. Median follow up per patient was 1.7 years (IQR 0.8-3.5) and ranged from two days to 15.2 years. Further details are outlined in Online Supplementary Table S2. Most patients received DFP monotherapy (68.3%). Simultaneous therapy with DFO was predominate at Cyprus, Greek and Italian sites (Online Supplementary Table S3). A total of 491 AEs including 158 serious AEs in 183 patients underwent the causality assessment (see full list in Online Supplementary Table S4). After assessment, 172 AE episodes in 104 patients were considered to be DFP related