Elsevier

The Lancet

Volume 385, Issue 9978, 25 April–1 May 2015, Pages 1653-1661
The Lancet

Articles
Rituximab as second-line treatment for adult immune thrombocytopenia (the RITP trial): a multicentre, randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(14)61495-1Get rights and content

Summary

Background

Immune thrombocytopenia is characterised by immune-mediated destruction and suboptimum production of platelets. Despite the absence of supporting evidence, rituximab is frequently used off-label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy-sparing treatment in patients who were previously treated with corticosteroids.

Methods

In this multicentre, randomised, double-masked, placebo-controlled trial, we enrolled corticosteroid unresponsive adult patients (aged ≥18 years) with primary immune thrombocytopenia and a platelet count of less than 30 × 109 platelets per L. Patients were randomly assigned (1:1) to four weekly infusions of 375 mg/m2 rituximab or placebo. Concurrent treatment with corticosteroids only was allowed during the study. The primary endpoint was rate of treatment failure within 78 weeks—a composite of splenectomy or meeting criteria for splenectomy after week 12 if splenectomy was not done, assessed in all patients who received at least one dose of study treatment. Secondary endpoints were response rates, relapse rates, and duration of response. Efficacy endpoints were assessed with the Kaplan-Meier method. Safety endpoints were assessed in all patients who received at least one dose. This trial is registered with ClinicalTrials.gov, number NCT00344149.

Findings

Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients. 32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan-Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio [HR] 0·89, 95% CI 0·55–1·45; p=0·65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p=0·15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p=0·12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p=0·01) but not complete response (76 vs 49 weeks; p=0·19). Rates of bleeding were similar in the two groups (21 [38%] in the rituximab group vs 27 [50%] in the placebo group; p=0·08) as were rates of infection (22 [40%] vs 13 [24%]; p=0·09).

Interpretation

Despite no reduction in the rate of long-term treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab.

Funding

South-East Regional Health Authority and Østfold Hospital, Norway; Roche, France; and Roche, Norway.

Introduction

Immune thrombocytopenia is caused by immune-mediated platelet destruction and impaired platelet production, causing thrombocytopenia and occasionally bleeding.1 The main goals of treatment are: first, to achieve sustained, haemostatic platelet counts to minimise the risk of bleeding; and second, to cure the patient if possible—both aims should be achieved with the fewest possible toxic effects.2, 3 Corticosteroids are the main first-line treatment for immune thrombocytopenia in adults, yielding initial response rates of 70–90%;2, 3 however, because of relapses during dose tapering or after corticosteroid discontinuation, sustained responses are reduced and occur between 30% and 80% of the time.2, 4, 5, 6 Patients who do not achieve a sustained response to corticosteroids usually need second-line treatment. Splenectomy is still recommended as the standard second-line therapy in patients with chronic immune thrombocytopenia.3 Splenectomy is an invasive procedure associated with perioperative and postoperative complications,7, 8 with no means to predict the patient's response to the procedure.9 Because of the availability of medical alternatives2 and increasing evidence of late remissions, whether spontaneous or with continuing treatment,5, 10 physicians have become more reluctant to do a splenectomy and patients are less willing to undergo splenectomy.9, 11

Of the many available second-line alternatives,2 the anti-CD20 antibody rituximab and approved thrombopoietin receptor agonists are widely used.9 Rituximab has been shown to provide initial response rates of about 60%;12 however, sustained responses lasting for more than 2 years occur in substantially fewer than 60% of patients.13, 14 Whether the administration of rituximab to patients who did not respond to corticosteroid treatment would render splenectomy or other therapeutic options superfluous is unknown. This trial aimed to assess the long-term efficacy of rituximab as a splenectomy sparing option in corticosteroid-exposed adult patients with immune thrombocytopenia.

Section snippets

Study design and patients

In this double-masked, placebo-controlled trial, we enrolled adult patients with immune thrombocytopenia10 in 14 centres in Norway, Tunisia, and France. The eligibility criteria for inclusion in the study were unsplenectomised patients with primary immune thrombocytopenia with a platelet count of less than 30 × 109 platelets per L (or 30–50 × 109 platelets per L if a higher platelet count was deemed necessary because of bleeding or concomitant anti-platelet therapy); patients who did not

Results

Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients (figure 1, table 1). Of 112 randomly assigned patients, three patients did not receive the allocated treatment and were not included in the full analysis set. Two patients in the placebo group were lost to follow-up.

Table 2 summarises the number of patients who responded to treatment and serious safety outcomes. The Kaplan-Meier estimates of cumulative incidence of overall response at 78 weeks were 81% in the rituximab group and

Discussion

To our knowledge, this trial is the first randomised placebo-controlled study to assess long-term efficacy of rituximab as a second-line treatment for immune thrombocytopenia in adults (panel). The study shows that provision of rituximab to patients not achieving a sustained response to corticosteroids does not significantly reduce the rate of treatment failure compared with placebo.

The aim of the study was to establish whether the use of rituximab would ultimately render splenectomy

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