Clozapine rechallenge or continuation despite neutropenia or agranulocytosis using colony-stimulating factor: A systematic review

Objectives: Rechallenge/continuation of clozapine in association with colony-stimulating factors (CSFs) following neutropenia/agranulocytosis has been reported, but many questions remain unanswered about efficacy and safety. This systematic review aims to assess the efficacy and safety of rechallenging/continuing clozapine in patients following neutropenia/agranulocytosis using CSFs. Methods: MEDLINE, Embase, PsycInfo, and Web of Science databases were searched from inception date to July 31, 2022. Articles screening and data extraction were realized independently by two reviewers, according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 systematic review guidance. Included articles had to report on at least one case where clozapine was rechallenged/continued using CSFs despite previous neutropenia/agranulocytosis. Results: Eight hundred forty articles were retrieved; 34 articles met the inclusion criteria, totaling 59 individual cases. Clozapine was successfully rechallenged/continued in 76% of patients for an average follow-up period of 1.9 years. There was a trend toward better efficacy reported in case reports/series, compared with consecutive case series (overall success rates of 84% and 60%, respectively, p-value = 0.065). Two administration strategies were identified, "as-needed" and prophylactic, both yielding similar success rates (81% and 80%, respectively). Only mild and transient adverse events were documented. Conclusions: Although limited by the relatively small number of published cases, factors such as time of onset to first neutropenia and severity of the episode did not seem to impact the outcome of a subsequent clozapine rechallenge using CSFs. While the efficacy of this strategy remains to be further adequately evaluated in more rigorous study designs, its long-term innocuity warrants considering its use more proactively in the management of clozapine hematological adverse events as to maintain this treatment for as many individuals as possible.