Safety and Efficacy Of Rituximab In adult’s Immune Thrombocytopenia (ITP) : Results After One-Year Of Follow-Up In 252 Patients From The Prospective French ITP-Ritux Registry
Authors: Khellaf Mehdi , Fain Olivier , Terriou Louis , Viallard Jean-François , Cheze Stéphane , Françoise roudot-Thoraval , Hamidou Mohamed , Slama Borhane , Audia Sylvain , Schleinitz Nicolas , Cliquennois Manuel , le Guenno Guillaume , Bonmati Caroline , Teillet France , Lambotte Olivier , Maigne Gwenola , Galicier Lionel , Hot Arnaud , Lefrere Francois , Adoue Daniel , Bordessoule Dominique , Delbrel Xavier , Bouscary Didier , Cahn Jean-Yves , Ghali Alaa , Verrot Denis , Delmer Alain , Jego Patrick , Magnant Julie , Buchdahl Anne-Laure , Royer Bruno , Rosenstingl Sophie , Durand Jean-Marc , Bierling Philippe , Michel Marc , Godeau Bertrand 
Published: October 2019

Introduction
Adults with ITP usually respond to corticosteroids but typically relapse after discontinuation. Rituximab is thought to be an effective off-label second-line treatment but only few prospective data exist about its long-term efficacy and its long-term safety is a matter of concern. The tolerance and particularly the risk of severe infection is a crucial factor for assessing the risk/benefit ratio of this treatment in ITP. Three years ago, we opened a non-interventional prospective registry in France to investigate the safety (primary outcome) and the efficacy of rituximab in off-trials adults with ITP (ClinicalTrials.Gov: NC1101295). Two hundred and fifty two patients were included on a two-year period. A follow-up duration of five-year is planned. We report here the first results after one year of follow-up.

Methods
The ITP-Ritux registry was set up by the French reference center of adult’s immune cytopenias. Thirty one centers participated to the study. Consecutive patients diagnosed with primary ITP according to the international guidelines (Rodeghiero et al, Blood 2009) who were treated with rituximab were included. Patients with a secondary ITP and those who were previously treated with rituximab were excluded. Response to treatment was assessed according to international guidelines: complete response (CR) was defined by platelet count ³100x109/L and response (R) by a platelet count between 30 and 100x109/L with at least a doubling of the pre-treatment count. The prospective and sequential monitoring of rituximab efficacy and safety was made by using of a standardized electronic case report form. Study nurses visited each center regularly to update the clinical and biological data on the enrolled patients.

Results
Between July 2010 and July 2012, 252 patients (64% of females) with a mean age of 51±21 (16-97) years were enrolled. The median duration of ITP was 1.3 (0-56) years with 44 patients (17%) with a newly diagnosed ITP, 61 (24%) with persistent ITP and 147 (58%) with chronic ITP at time of rituximab treatment. The median platelet counts at time of ITP diagnosis and rituximab first infusion were respectively 18x109/L (1-100) and 17x109/L (1-186). Patients received a median of 2 treatment lines (range 0-7) before rituximab and 25 (10%) were splenectomized. The standard regimen of 375 mg/m2 weekly rituximab infusions for 4 weeks was administered to 179 patients whereas 73 patients (29%) received a fixed dose of 1000 mg on day 1 and day 15. At time of the present analysis, the median follow-up was 18 months and the one-year response was available in 209 patients. A one-year overall response was observed in 90/209 (43%) patients including a CR in 28% and a R in 15%. Nineteen patients who failed to respond to rituximab were splenectomized during the year following rituximab infusions. Sixty eight adverse events occurred in 47 patients (19%). Rituximab infusions have to be stopped in only 3 patients for severe hypotension, dyspnoea with laryngeal discomfort and reversible serum sickness respectively. Three other patients developed severe adverse event related to rituximab requiring admission in hospital including 1 episode of profound neutropenia while 6 episodes of infections occurred in 2 patients. Seven patients (2.7%) have died during follow-up, 52 to 385 days after rituximab infusions. All patients who died but one aged of 18 were 68 to 98-year old. Only one death could be potentially related to rituximab (enterococcus faecium pulmonary infection), 2 deaths were of unknown origin, other causes were: suicide (n=1), multiple myeloma (n=1) and fatal haemorrhage related to ITP (n=2). We did not observe any episode of progressive multifocal encephalopathy or any other case of opportunistic infection.
Discussion and conclusion
Our preliminary results based on the first large non-interventional prospective registry of ITP-adults treated with rituximab in the “real life” confirm that this treatment leads overall to 40% of response after one year of follow-up. Safety of rituximab at 1 year appears to be good since severe infections were uncommon and no opportunistic infections were observed. The ongoing monitoring and upcoming analysis with a planned follow-up up to 5-years will provide more data on long-term safety.

Disclosures:
No relevant conflicts of interest to declare.