Efficacy and Safety of Rituximab in Common Variable Immunodeficiency-Associated Immune Cytopenias: a Retrospective Analysis of 10 Cases.

Patients with common variable immunodeficiency (CVI) are at higher risk of developing autoimmune disease and especially auto-immune cytopenias. The management of immune thrombocytopenia (ITP) and autoimmune haemolytic anemia (AHA) in the setting of CVI is often challenging as usual treatments (i.e corticosteroids, immunosuppressive agents and splenectomy) significantly increase the intrinsic risk of severe infections. While the use of rituximab has shown efficacy in both primary ITP and AHA, its use has been only anecdotally reported in patients with CVI. In order to better assess efficacy and the safety profile of rituximab in adults with CVI-associated ITP and/or AHA, we performed a retrospective study throughout the French network of adult's primary immune deficiencies and the national referral center for adult's immune cytopenias.

To be included, all patients had to have a definite diagnosis of CVI according to standard criteria (Conley ME et al. Clin Immunol. 1999; 93:190-197) with a history of secondary (CVI-associated) ITP and/or AIHA treated with rituximab. Patients treated with rituximab before the age of 18, or in whom the hypogammaglobulinemia was assessed only after rituximab were excluded. To assess treatment efficacy, the following criteria were used: for AHA, a complete response (CR) was defined by a hemoglobin (Hb) level ≥ 12 g/dL in the absence of transfusion and without persistent features of hemolysis, and partial response (PR) by a Hb ≥10 g/dl with an increase of at least 2g from baseline and persistent hemolysis. For ITP, CR was defined by a normal platelet count (i.e > 150 × 10⁹/L) and PR by a platelet count > 50×10⁹/L with at least a twofold increase of the pre-treatment count.

The data from 10 patients (6 women, mean age 44 years ±16) fulfilling the inclusion criteria were analyzed. The patients were given rituximab for either chronic severe ITP (n=5), refractory AHA (n=2) or Evans' syndrome (n=3). The mean ITP and/or AHA duration at time of first rituximab infusion was 23 months; patients received on average 1.4 treatment-lines prior to rituximab, all of them got corticosteroids and 5/10 (50%) had undergone splenectomy. Rituximab was administered at 4 weekly doses of 375mg/m2 in 9 patients and at 1000 mg on day 1 and 15 in a single patient. One month after the first rituximab infusion, the overall response rate was 90% (7 CR and 2 PR). A single patient with ITP syndrome did not respond to rituximab and subsequently achieved a PR on romiplostim. At time of analysis, after a mean follow-up of 18 ±14 months after rituximab, only 1 patient among the 8 initial responders had a relapse. This patient who was treated for an AHA failed to respond to a second course of rituximab and eventually achieved a CR after splenectomy. Only 2 patients were still on low dose of corticosteroids (i.e prednisone 5 mg/day) at time of analysis. The overall safety was good as no cases of severe infections were observed after rituximab except 1 case of aseptic meningitis which occurred one week after the first rituximab infusion in a patient with Evans' and resolved under broad-spectrum iv antibiotics. During the follow-up period after rituximab administration, 8 out of the 10 patients were on substitutive immunoglobulin therapy. At time of analysis, 1 patient had died 2 years after being treated with rituximab from an unrelated cause (hemorrhage after a lobectomy for bronchectasis).

Based on these preliminary data, rituximab appears to be a safe and effective option for the management of chronic severe immune cytopenias in patients with an underlying CVI. This treatment should therefore be considered as a possible alternative to splenectomy and immunosuppressive drugs in this subgroup of patients at high risk of infections. The mechanisms of action of rituximab in this setting remain to be determined.

Off Label Use: Rituximab as a treatment of CVI-associated immune cytopenias.