Exposure to Corticoid-Sparing Treatments in Adult Primary Immune Thrombocytopenia before the Chronic Phase in the Era of Thrombopoietin Receptor Agonists in France. a Nationwide Population-Based Study

Objectives:The aim of this study was to describe the exposure to corticoid-sparing treatments (CST) in adult primary immune thrombocytopenia (ITP) patients during the year before the chronic phase at a nationwide level in the era of thrombopoietin-receptor agonists (TPO-RAs).

Methods:Study population was the 2009-2011 cohort of the French Adult Immune Thrombocytopenia: a French pHarmacoepidemiological study (FAITH, n°ENCEPP/SDPP/4574). The FAITH cohort is the cohort of all incident persistent or chronic adult primary ITP patients treated in France, built through the nationwide French health insurance database, named SNIIRAM. It collects prospectively all data regarding hospitalizations, disabling diseases, drug and procedure reimbursements. They are linkable with demographic data. On the 2009-2011 SNIIRAM data, ITP patients were identified with hospital and disabling disease diagnosis codes (D69.3 code of the International Classification of diseases, version-10). The date of diagnosis was refined thanks to out-hospital drug exposures. Secondary ITPs were excluded thanks to diagnosis codes of diseases associated to ITP, searched in the year before and the semester after the diagnosis. We restricted to incident patients, excluding those with a diagnosis during the first semester of the study, and then to patients followed at least 12 months and with at least one exposure to CST during the year after the diagnosis.

Exposure to CST was searched through out-hospital dispensing, and during hospital stays for splenectomy, rituximab and polyvalent intravenous immunoglobulins (IVIg). A single dispensing defined exposure, except for IVIg (3 monthly dispensing were mandatory to differentiate IVIg used as CST from acute exposure to treat a serious bleeding). We described the percentage of patients exposed to the distinct CST at least once during the year after ITP diagnosis and detailed the lines of therapy. We compared the patients aged <65 years and those ≥65 years.

Results:Out of 2334 adult incident primary ITPs, 1556 were persistent or chronic. Among them, 443 patients were followed at least one year after ITP diagnosis and were exposed to at least one CST during this period. Mean age was 52.7 ± 20.8 years and 59.1% of the patients were females. Patients aged ≥65 years had more frequently mucosal or internal bleeding at ITP onset, and had a higher Charlson’s comorbidity score. Mean time from diagnosis to CST was 3.5 months.

CSTs used in >10% of the patients at any time during the year after ITP diagnosis were, by decreasing frequency: rituximab (57.8%), splenectomy (22.1%), TPO-RAs (16.8%), IVIg (15.0%), danazol (14.4%) and dapsone (10.8%). Hydroxychloroquine was used in 6.5% of the patients and immunosupressant (azathioprine, mycophenolate or ciclosporin) in 5.9%. The CST the most frequently used was rituximab in both age groups. Splenectomy was more frequently used in patients aged less than 65 years (25.2% versus 16.4%, p=0.03). In contrast, TPO-RAs and dapsone were more frequently used in patients aged over 65 years (respectively, 24.8% versus 12.8%, p=0.01, and 17.6% versus 7.2%, p=0.0008).

The mean number of lines of therapy after corticosteroids was 1.5 (extremes: 1-6) and was not different between the two age groups.

As regards CSTs used in second line after corticosteroids, rituximab was the most used (45.4%), followed by IVIg (12.0%), splenectomy (11.3%), danazol (10.1%), dapsone (7.9%) and TPO-RAs (6.3%). There were discrepancies according to the age groups: 11.8% of the patients aged ≥65 years had been exposed to TPO-RAs as second-line compared with 3.5% of younger patients (p=0.0006). Similarly, dapsone was more frequently used as second-line treatment in older patients (13.8% versus 5.2%, p=0.0003), while splenectomy was more frequently used in patients aged <65 years (13.8% versus 6.5%, p=0.02). When detailing the successive lines of therapy, the use of rituximab decreased, while the use of splenectomy and TPO-RA increased in both age groups.

Conclusions: Rituximab was the leading CST used as second and third line of therapy in adult primary ITP before the chronic phase in France, whatever the age group. TPO-RAs have modified treatment strategy of persistent primary ITP as soon as they have been marketed. They were mainly used in accordance with their labeling (after two lines of treatment including corticosteroids).