Donald M. Arnold, MD, MSc; Francesco Dentali, MD; Mark A. Crowther, MD, MSc; Ralph M. Meyer, MD; Richard J. Cook, PhD; Christopher Sigouin, MSc; Graeme A. Fraser, MD; Wendy Lim, MD, MSc; John G. Kelton, MD
Acknowledgments: The authors thank the staff of the McMaster Transfusion Research Program for their administrative assistance with this research.
Grant Support: Dr. Arnold is a research fellow of the Canadian Institutes for Health Research and Canadian Blood Services; Dr. Crowther is a Career Investigator of the Heart and Stroke Foundation of Ontario; Dr. Cook is a Canada Research Chair; Dr. Fraser is a research fellow of The Terry Fox Foundation through an award from the National Cancer Institute of Canada; Dr. Lim is the recipient of the ISTH Clinical Research Fellowship.
Potential Financial Conflicts of Interest: Consultancies: R.M. Meyer (Hoffmann-LaRoche, Canada); Honoraria: R.M. Meyer (Hoffmann-LaRoche, Canada); Grants received: D.M. Arnold (Hoffmann-LaRoche, Canada); Grants pending: D.M. Arnold (Roche Canada).
Corresponding Author: Donald M. Arnold, MD, McMaster University Health Sciences Center, Room 3N-43, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada; e-mail, email@example.com.
Current Author Addresses: Dr. Arnold and Mr. Sigouin: McMaster University Health Sciences Center, Room 3N-43, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
Dr. Dentali: Department of Clinical Medicine, Insubria University, Viale Borri 57, Varese, Italy 21100.
Dr. Crowther and Dr. Lim: St. Joseph’s Hospital, 50 Charlton Avenue East, Room L-208, Hamilton, Ontario L8N 4A6, Canada.
Dr. Meyer: Clinical Trials Division, Cancer Research Institute, Queen’s University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada.
Dr. Cook: University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
Dr. Fraser: Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada.
Arnold D., Dentali F., Crowther M., Meyer R., Cook R., Sigouin C., Fraser G., Lim W., Kelton J.; Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura. Ann Intern Med. 2007;146:25-33. doi: 10.7326/0003-4819-146-1-200701020-00006
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Published: Ann Intern Med. 2007;146(1):25-33.
Rituximab, a monoclonal anti-CD20 antibody, is increasingly used to treat idiopathic thrombocytopenic purpura (ITP).
To systematically review the literature on the efficacy and safety of rituximab for the treatment of adults with ITP.
MEDLINE, EMBASE, the Cochrane Library, abstracts from the American Societies of Hematology and Clinical Oncology annual meetings, and bibliographies of relevant articles and reviews were searched in duplicate until April 2006.
Descriptive and comparative studies in any language that met predefined inclusion criteria were eligible. Efficacy analysis was restricted to studies enrolling 5 or more patients.
Platelet count response, toxicities, dose, previous treatments, baseline platelet count, duration of ITP, study design, and sources of funding were extracted in duplicate.
We identified 19 eligible reports on efficacy (313 patients) and 29 on safety (306 patients). Weighted means for complete response (platelet countÂ > 150Â Ã—Â 109 cells/L) and overall response (platelet countÂ > 50Â Ã—Â 109 cells/L) with rituximab were 43.6% (95% CI, 29.5% to 57.7%) and 62.5% (CI, 52.6% to 72.5%), respectively. Responses lasted from 2 to 48 months. Nearly all patients had received corticosteroids, and 53.8% had undergone splenectomy. Nine patients (2.9%) died.
There were no controlled studies, and no studies met all criteria for study quality. Reported deaths could not necessarily be attributed to rituximab. Overall, the number of rituximab-treated patients with ITP reported in the literature is small.
Rituximab resulted in an overall platelet count response in 62.5% of adults with ITP. However, this finding derives from uncontrolled studies that also reported significant toxicities, including death in 2.9% of cases. These data suggest that providers should avoid indiscriminate use of rituximab and that randomized, controlled trials of rituximab for ITP are urgently needed.
Francisco Javier PeÃ±alver
FUNDACION HOSPITAL ALCORCON
January 30, 2007
Rituximab for ITP patients: inclusion of the largest series reportes could modify conclusions
We have read with the utmost interest the systematic review about the use of rituximab for ITP by Arnold et al. (1). In this paper the authors mention a study by our group (2), but exclude it from metaanalysis, claiming "these are not original data". We cannot agree with this statement, for our report certainly compiles original data, only reported in abstract form before (3). We consider it fulfils sufficient criteria for inclusion in the metaanalysis. Ours is a retrospective multicentric study to asses the therapeutic efficacy and toxicity of rituximab in 89 patients with chronic ITP, unresponsive to several treatments. Our series is the largest reported to date on the use of rituximab in chronic ITP. It specifies the follow-up period, during which no patients were lost. In our series achieving a complete response was the only factor predicting a long -held response. Response was worse in patients with longer duration of disease and heavily treated, but our results indicate rituximab can induce good responses even in these patients and can be a good second line therapeutic option. Rituximab induced rapid responses, most in the first week after the fist dose (40% of responders) and just one dose could be enough in some cases.
Probably our results would not significantly modify the response rates reported by Arnold, although significance and power of the analysis would improve, our series being the largest to date. However, conclusions regarding toxicity might change notably. In our series toxicity was mild. Immediate side effects were two episodes of fever during infusion and transitory rash (two cases). We had no deaths although our patients had longer duration of ITP and were heavily treated. Almost 60% of all mild infusional effects reported in Arnold's report correspond to the high rate found in the largest prospective study (4), that can be explained by not administering steroids before rituximab. In the metaanalysis 9 deaths were reported, although probably only one is really drug-related (fatal hepatic failure); this rate is similar to ITP-related mortality in large retrospective cohort studies, but it is higher than that of the same drug in the therapy of malignant lymphoma. We think the mortality rate is probably overestimated, as the authors recognize. In short, we consider Rituximab a therapeutic alternative for selected ITP patients, useful in refractory and heavily treated cases, with little associated toxicity. Controlled, randomized studies must be conducted to validate these results.
1.-Arnold DM et al. Ann Intern Med. 2007; 146:25-33
2.-PeÃ±alver FJ et al. Ann Hematol. 2006;86:400-4
3.-Cabrera JR et al Blood (abstract). 2004; 104: 2074
4.-Cooper N et al. Br J Hematol. 2004; 125:232-9
Donald M. Arnold
February 19, 2007
Systematic review of rituximab in ITP: Scrutinizing primary reports
We appreciate the comments from Penalver and colleagues about our systematic review of rituximab in ITP(1). Our inclusion criteria for primary reports in this review had to be fairly liberal as most reports were case series or cohort studies, reflecting, perhaps surprisingly, the paucity of methodologically rigorous trials in this field. Nevertheless, we established a priori that care must be taken to avoid redundant publications, since many were published in abstract form only and some were follow-up reports of preliminary studies.
The report by Penlaver and colleagues gave us reason to pause(2). In fact, the authors were kind enough to share their raw data with us for further contemplation. True, their report of 89 patients with ITP treated with rituximab was the largest of any published series, and indeed, patient follow up was complete. However, this report described the results of a questionnaire sent to 43 different centers in Spain. Our principle reservation about the paper was that we could not be sure that the patients contributing to the data had not been reported elsewhere (i.e. their originality). Moreover, survey data is particularly prone to recall and reporting bias, and measures to safeguard against these methodological pitfalls were not described in the paper. As Penalver and colleagues surmised, the inclusion of their report in our systematic review does not change the estimated overall response to rituxumab significantly: 62.0% (instead of 62.5%); but it does tighten somewhat the confidence intervals: 53.0 "“ 71.0% (instead of 52.6 "“ 72.5%).
The principles of any systematic review require careful scrutiny of primary reports so that the results are comprehensible and free of bias. This is especially true of systematic reviews of observational data(3). We were strict about our inclusion criteria even if it was at the expense of a report as large as Penalver's.
We agree that rituximab is a promising therapy for patients with ITP and its use is becoming widespread in countries where the drug is unregulated. However, without properly controlled trials, we are putting patients' safety at risk for a benefit that is as of yet undetermined.
(1) Arnold DM, Dentali F, Crowther MA, Meyer RM, Cook RJ, Sigouin C et al. Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura. Ann Intern Med 2007; 146(1):25-33.
(2) Penalver FJ, Jimenez-Yuste V, Almagro M, Alvarez-Larran A, Rodriguez L, Casado M et al. Rituximab in the management of chronic immune thrombocytopenic purpura: an effective and safe therapeutic alternative in refractory patients. Ann Hematol 2006; 85(6):400-406.
(3) Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283(15):2008-2012.
D.M. Arnold has received a grant from Hoffman-LaRoche limited for the conduct of a clinical trial of rituximab in ITP.
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Hematology/Oncology, Platelet Disorders, Coagulopathies.
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