title: Efficacy and safety of rituximab in auto-immune hemolytic anemia: A meta-analysis of 21 studies.
abstract: OBJECTIVE
  This study aims to evaluate the response to rituximab (RTX) treatment in auto-immune hemolytic anemia (AIHA) patients.
  
  
  METHODS
  Studies were selected from MEDLINE up to March 2014. Two investigators independently extracted data on study design, patient characteristics, clinical features (AIHA type, disease duration, previous treatments), dose-schedule of rituximab, duration of treatment follow-up, and toxicities. Pooled overall response rate (ORR) and complete response (CR) rates were evaluated to determine RTX efficacy and toxicity by calculating the weighted mean proportion with fixed or random-effects models in case of heterogeneity (p<0.1 or I(2)>50%).
  
  
  RESULTS
  Twenty-one studies encompassing 409 patients were included in the meta-analysis. The characteristics of the entire analyzed cohort reported were as follows: mean male proportion: 43%, mean age: 50 years, splenectomized patients range: 0-50%. Warm AIHA, primary AIHA and adults were mostly represented. With the random-effect model, the overall response rate (ORR) was 73% (95% CI 64-81%, 20 studies encompassing 402 patients). CR rate was 37% (95% CI 26-49%, 20 studies including 397 patients). The ORRs were close to 70% for warm AIHA (79%, 95% CI 60-90%, 11 studies, 154 patients), primary AIHA (67%, 95% CI 49-81%, 10 studies, 161 patients), and secondary AIHA (72%, 95% CI 60-82%, 8 studies, 66 patients). The ORR was 57% (95% CI 47-66%, 6 studies, 109 patients) for cold agglutinin disease (CAD). The CR rate was 42% (95% CI 27-58%, 11 studies, 154 patients) for warm AHAI, 32% (95% CI 17-51%, 11 studies, 176 patients) for primary AIHA, 46% (95% CI 30-62%, 9 studies, 87 patients) for secondary AIHA and only 21% (95% CI 6-51%, 7 studies, 118 patients) for CAD. Definitive response rates were evaluated during follow-up. CR rate was the highest within 2 to 4 months after RTX (13 studies, 203 patients, CR=70% [57-80%]). As for toxicities, 38 adverse events in 364 patients were noted (14% (95% CI 9-21%)). Sixteen events were infusion-linked side effects, mostly chills and fever, whereas twenty-two were severe. Only one opportunistic Pneumocystis jiroveci pneumonia was reported. Seventeen patients out of 364 (4.6%) died during follow-up. In univariate mixed-effect meta-regressions, ORR and CR were significantly associated with warm AIHA (p=0.002) and mean age (p<0.001), and marginally associated with disease type (p=0.06 and 0.005, respectively).
  
  
  CONCLUSIONS
  Rituximab seems to be a safe and effective therapy for AIHA in this meta-analysis of observational studies. The authors suggest that it could be used at an earlier point in therapy, before more toxic immunosuppressive drugs, or in place of splenectomy in some cases.
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Quitterie
authors.initials: Q
authors.lastname: Reynaud
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France; UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Claude Bernard University Lyon 1, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Durieu
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Dutertre
authors.affiliation: Anesthesiology and Critical Care Department, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Ledochowski
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Durupt
authors.affiliation: Department of Hematology, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Michallet
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Vital-Durand
authors.affiliation: Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Claude Bernard University Lyon 1, France; UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Claude Bernard University Lyon 1, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Lega
mesh_terms: D000328:Adult; D000744:Anemia, Hemolytic, Autoimmune / Q000188:drug therapy* / Q000453:epidemiology / Q000601:surgery; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D006801:Humans; D064887:Observational Studies as Topic; D000069283:Rituximab; D013156:Splenectomy
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab
keywords: Autoimmune hemolytic anemia; Cold agglutinin disease; Complete response; Overall response rate; Rituximab; Warm autoimmune hemolytic anemia