A Multi-Centre, Single-Arm, Open-Label Study Evaluating the Safety and Efficacy of Fixed Dose Rituximab in Patients with Refractory, Relapsing or Chronic Idiopathic Thrombocytopenic Purpura (R-ITP1000 Study) and Exploring Rituximab Response with the FcGammaR3A Polymorphisms

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count and mucocutaneous bleeding. Approximately 25–30% of adult patients with acute ITP develop chronicity; 30% of chronic ITP patients become refractory to corticosteroids and require additional therapy. As B-cells play an important pathophysiological role in autoimmune disease, rituximab, a chimeric anti-CD20 monoclonal antibody which depletes CD20⁺ B-cells has been used in chronic ITP. A dosing regimen based on lymphoma therapy (375 mg/m² weekly × 4) has shown efficacy (∼38% Overall Response Rate-ORR) in adults in this context. Whether this schedule is optimal in autoimmune disease, in which the burden of pathological B-cells is low, is unknown. In this study we explored an abbreviated rituximab schedule, consistent with the approved rheumatoid arthritis dosing. We also explored inherited polymorphisms in FcGammaR3A (FCGR3A) as it has been shown to correlate with response to rituximab.

The primary objective of this study was to determine the ORR, at week 8, among adults (≥ 18 years) with chronic or relapsing ITP (platelet count > 10 × 10⁹/L and ≤ 50 × 10⁹/L) according to the ASH guidelines, who received rituximab 1000 mg intravenous (IV) on days 1 and 15. A laboratory sub-study investigated the relationship between the FCGR3A-V/F158 polymorphisms and response to rituximab.

Patients received planned doses of rituximab and were followed-up for a minimum of 12 weeks. Assessments and procedures at mandatory follow-up visits occurring on weeks 8, 12, 26, 39 and 52 included physical examination, vital signs, FBC and serum chemistry. ORR was defined as the proportion of patients achieving a Complete Response (CR, platelet count > 150×10⁹/L) or Partial Response (PR, > 50 × 10⁹/L) at weeks 8 and 12 with 2 consecutive measurements, confirmed at least 2 weeks apart. Simon's 2-stage design was used to determine if the ORR was more likely to be ≤ 38% or ≥ 50%. At least 50 out of 108 responders (46%) were required to conclude, with 95% confidence and 80% power, that the ORR was likely to be ≥ 50%. FCGR3A-V/F158 genotyping was performed using allele specific polymerase chain reaction (PCR) techniques previously described (Koene HR, et al. Blood 1997;90:1109–1111). Distribution of polymorphisms was correlated according to response rate, as pre-defined in the study protocol and the frequencies compared using the standard chi-squared test for independence via contingency table analysis.

Out of the 124 patients recruited, 2 did not receive study medication and 14 did not have a platelet count ≤ 50 × 10⁹/L within 7 days of first rituximab dose and were excluded from analysis. At week 8, the confirmed ORR was 44% (47/108 patients); 9% and 34% of whom achieved CR and PR respectively. At week 12, 9 patients had a missing platelet count value and therefore response rate data was available for 99 patients; ORR=46% (45/99). Treatment was well tolerated with no safety signals reported. Genotyping data was available for 87 patients. Correlations between FCGR3A-V/F158 polymorphisms and response to rituximab showed that 32% (16/50) non-responders [minor or no response] and 19% (7/37) responders [CR or PR] were homozygous for the FCGR3A-F/F158 genotype; p=0.21.

The ORR is comparable with published studies using a more frequent rituximab schedule. Although not statistically significant, non-responders were more likely to be homozygous for the FCGR3A-F/F158 genotype than responders. Further investigations are warranted to determine whether the same response can be achieved with single/lower dosing rituximab, if longer/ more intense dosing might improve ORR and if maintenance rituximab may improve durability of responses.

Thurley:ROche Products Australia: Employment.