Original Title: Guide usage optimal: usage optimal des Immunoglobuline en hématologie

Authors' objectives: Non-specific human immunoglobulins (Igs) are stable products derived from human plasma. Their cost is high, their supply variable, and their use in Quebec has been steadily increasing for many years, particularly in hematological indications. Additionally, there is concern on the part of Québec’s Comité consultatif national de médecine transfusionnelle (CCNMT), which has called attention to the lack of recommendations regarding the use of Igs in most of the hematological indications. At the CCNMT’s suggestion, the Ministère de la Santé et des Services sociaux (MSSS) therefore asked the Institut national d'excellence en santé et en services sociaux (INESSS) to develop clinical recommendations regarding the use of Igs in hematology in the form of an optimal usage guide (OUG). On completion of this project, INESSS had developed clinical recommendations for the optimal use of intravenous Igs (IVIgs) in 25 hematological indications.

Authors' results and conclusions: RESULTS: The results of primary studies and systematic reviews of primary studies permit the conclusion, with a level of evidence deemed moderate or high, that IVIgs therapy is efficacious in 4 indications: allogeneic hematopoietic stem cell transplantation, hypogammaglobulinemia secondary to a hematologic cancer, acute immune thrombocytopenia in children and acute immune thrombocytopenia in adults. IVIgs are approved by Health Canada for these indications, which are conditions for which IVIgs therapy is recommended in all the selected CPGs. The results of the systematic reviews indicate, with a level of evidence deemed low, that IVIgs therapy is efficacious in 5 indications. Thus, the CPG recommendations and the experiential data concur and permit recommending IVIgs as first-line treatment in 1 indication, acute immune thrombocytopenia during pregnancy, and as second-line treatment in 3 indications, namely, chronic immune thrombocytopenia in children, chronic immune thrombocytopenia in adults and infection-induced immune thrombocytopenia (HIV, HCV). In 1 indication, the presence of coagulation factor inhibitors (von Willebrand syndrome acquired as a result of monoclonal gammopathy of undetermined significance [MGUS]), the experiential data indicate that a recommendation should not be made and that this indication should not be included in the OUG, given that cases of acquired von Willebrand syndrome are extremely rare. The results of the systematic reviews indicate, with a level of evidence deemed low or moderate, that there is no significant difference in efficacy between IVIgs therapy combined with treatment of recognized efficacy and the latter used alone in 7 indications. Thus, the CPG recommendations and the experiential data concur and permit recommending IVIgs as second-line treatment in 3 indications, namely, hemolytic disease of the newborn or fetus, autoimmune hemolytic anemia (AIHA) and Evans syndrome, and not recommending it in 4 indications, namely, aplastic anemia, hemophagocytic syndrome, hemolytic-uremic syndrome (HUS) and thrombocytopenic thrombotic purpura (TTP). However, based on the experiential data, the use of IVIgs may be considered in the presence of a precipitating factor in cases of hemophagocytic syndrome and in the presence of an anti-factor H in HUS. The scientific safety data indicate that most of the transfusion reactions that occur after IVIgs administration are not serious. However, different serious reactions, which are usually rare, have been reported in the scientific literature or to Québec’s hemovigilance system. Two of these, thromboembolic reaction and hemolytic reaction, have been the subject of studies and communications on the part of Health Canada and the FDA in recent years. Lastly, the results of the systematic reviews permit the conclusion, with a level of evidence deemed low to moderate, that subcutaneous Igs (SCIgs) are efficacious in 2 indications: allogeneic hematopoietic stem cell transplantation and hypogammaglobulinemia secondary to a hematologic cancer. CONCLUSIONS: Evidence on the efficacy of IVIgs was available for a minority of the indications. Based on the scientific data reviewed, most of the indications (20 out of 25) were associated with a level of evidence deemed low or insufficient. This can be explained mainly by the fact that these indications are rare and that it is therefore difficult to put together RCTs with a sufficient number of participants. Thus, for these 20 indications, CPG recommendations and the opinions of the advisory committee’s experts carried more weight than for the other indications when developing the clinical recommendations. Given that the available data concern almost exclusively IVIgs and that the administration of SCIgs in hematology concerns only 2 of the 25 indications selected, INESSS has developed an OUG specifically for IVIgs. Mention is nonetheless made of SCIgs.

Authors' methods: For the purposes of the MSSS's request, INESSS adopted a collaborative approach called "knowledge mobilization”. This approach consists in analyzing and triangulating scientific and contextual data and experiential knowledge. (Scientific data) To assess the efficacy and safety of Igs in children and adults with one of the 25 hematological indications selected, we conducted systematic reviews of several bibliographic databases from the date of their creation to February 2019 to identify all the primary studies and systematic reviews, with or without meta-analysis, published on the subject. The official product monographs for Health Canada-approved Igs, Health Canada and the U.S. Food and Drug Administration (FDA) advisories, and a report on transfusion accidents and incidents published by the Institut national de santé publique du Québec (INSPQ) were consulted to complete the research regarding safety. To document the conditions of use of Igs, we conducted a systematic literature review to identify guidance documents, clinical practice guidelines (CPGs) and any other items containing clinical recommendations published between January 2009 and February 2019. The grey literature and the official product monographs for Health Canada-approved Igs were consulted to complete the research on the conditions of use of Igs. Items were selected according to predefined exclusion and inclusion criteria, and the quality of these items was assessed using the appropriate tools. These steps were carried out independently by two reviewers. The data were then extracted by one reviewer and validated by another. The results were presented in tables and summarized in the form of an analytical narrative synthesis. The main efficacy results reported in the selected studies were presented as brief statements of scientific evidence, and an overall level of scientific evidence was assigned to each statement of evidence according to a four-level scale (high, moderate, low, insufficient). To determine the main characteristics of the 25 indications of interest, we explored the scientific literature, the CPGs and the website Orphanet. (Contextual data and experiential knowledge) The number of patients treated and the quantity (expressed in grams) of Igs administered in Québec in 2016 and 2017 were documented from a report on the use of IVIgs prepared by the INSPQ using information extracted from the TraceLine™ system database. Health Canada’s website was consulted to determine the approval status of IVIgs and subcutaneous immunoglobulins (SCIgs). The recommendations were developed in collaboration with the advisory committee. In general, information on the contextual and experiential data was presented in narrative form and summarized in tables. (Process for developing recommendations) Triangulating the scientific and contextual data and experiential knowledge enabled us to structure the arguments leading to the development of recommendations. Only those for which there was a consensus among the experts were selected. The 25 indications of interest were classified into 4 usage categories: IVIgs recommended, IVIgs are possible treatment options, IVIgs not recommended, and insufficient data.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/guide-dusage-optimal-des-immunoglobulines-en-hematologie.html

Year Published: 2020

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/guide-dusage-optimal-des-immunoglobulines-en-hematologie.html

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: INESSS