The authors concluded that the totality of the evidence on efficacy of rituximab for treatment of steroid-refractory cGVHD demonstrated that skin was the most responsive organ. The authors' conclusions represented the evidence presented. However, given the limited search and inclusion of small and uncontrolled studies, the reliability of the authors' conclusion is uncertain.

To evaluate the effectiveness of rituximab in steroid-refractory chronic graft-versus-host disease (cGVHD).

PubMed was searched with no search limits. Search terms were reported. References from relevant retrieved articles were scanned for additional studies. Experts in the field were contacted for additional studies and unpublished data.

Eligible for inclusion in the review were prospective studies (any number of patients) and retrospective studies (at least five patients) that evaluated the efficacy of rituximab in steroid refractory cGVHD.

Reported outcomes of interest included mortality, overall response rate, organ-specific response rate (skin, mucosa (oral), liver, gastrointestinal, lung and other organs), reduction/discontinuation of immunosuppressive therapies and treatment-related morbidity and mortality. In most studies organ-specific criteria were used to assess response. Dose of rituximab was the same in most studies (375mg/m² at weekly intervals for four weeks). Median age of patients varied between studies (35 years to 60 years).

Four reviewers selected studies for inclusion in the review. Any disagreements were resolved by consensus.

Two reviewers independently assessed study quality. The criteria used to assess study quality were not explicitly stated, but it appeared that sampling procedure, sample size and a priori setting of hypotheses were assessed.

Two reviewers independently extracted data on the proportion of patients who experienced each outcome.

Proportions were transformed into a quantity according to the Freeman-Tukey variant of arcsine square root transformed proportion. A pooled proportion

overall response rate (ORR) with 95% confidence intervals (CI) was calculated as the back transform of the weighted mean of the transformed proportions using a random-effects model. Sensitivity analyses were planned, but not conducted due to insufficient numbers of studies. Statistical heterogeneity was assessed using the I² statistic. Publication bias was assessed using the Begg's and Egger funnel plot.

Seven studies were included in the review: three non-controlled prospective studies and four retrospective studies that included one case series (n=111 patients). Sample sizes ranged from three to 38. The authors stated that sampling procedures were unclear in all three prospective studies and as a consequence selection or ascertainment bias could not be ruled out. The authors also stated that it was unclear whether the analyses of retrospective studies were based on a prior hypotheses or on post hoc observations. There was no evidence of publication bias.

The pooled proportion of mortality was 15.8 % (95% CI 8.3% to 25.3%; seven studies, 111 patients).

Pooled proportion ORRs for other outcomes were: cGVHD 66% (95% CI 57% to 74%; six studies, 108 patients); skin cGVHD 60%, (95% CI 41% to 78%; six studies, 67 patients) with evidence of statistically significant heterogeneity (I²=60%); mucosa (oral) cGVHD 36% (95% CI 12% to 65%; five studies, 46 patients); liver cGVHD 29% (95% CI 12% to 51%; six studies, 34 patients); gastrointestinal cGVHD 31% (95% CI 7% to 62%; four studies, 12 patients); and lung cGVHD 30% (95% CI 11% to 53%; three studies, 14 patients).

Ranges of response were reported for ocular cGVHD (13% to 38%) and musculoskeletal cGVHD (75% to 100%).

Median glucocorticoid steroid reduction was reported for two studies (86% and 75%).

Side effects of rituximab therapy included: infusion reactions (5% to 11%); infectious complications that included sepsis (3% to 33%); pneumonia (8% to 33%); viral conjunctivitis (5%); diarrhoea (14%); and herpes zoster reactivation (33%).

The totality of the evidence on efficacy of rituximab for treating steroid-refractory cGVHD demonstrated that skin was the most responsive organ. Response to rituximab appeared less pronounced in other organs.

The review addressed a clear research question and was supported by adequate inclusion criteria. The search strategy was limited to one database, handsearching and contact with experts in the field, so relevant studies may have been missed. The authors stated that study quality was assessed and although the criteria were not explicitly stated, the authors' discussions of the methodological limitations of the included studies appeared appropriate. Adequate details of primary studies were provided. Synthesis methods were appropriate. Review processes were carried with sufficient attempts to minimise reviewer error and bias. The authors' conclusions represented the evidence presented. However, given the limited search and inclusion of small and uncontrolled studies, the reliability of the authors' conclusion is uncertain.

Practice: The authors did not state any implications for practice.

Research: The authors stated that there was a need for well-designed adequately powered prospective studies to determine the efficacy of rituximab for treatment of patients with steroid refractory cGVHD. Future trials should evaluate response rates at different times in the course of cGVHD to provide a better understanding of the pathophysiologic evolution of cGVHD over time and should use quality of life assessment tools.

None stated.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.