Efficacy and safety of fostamatinib in refractory immune thrombocytopenia: a meta-analysis from randomized controlled trials

Background Immune thrombocytopenia (ITP) is an immune-mediated disease that results in low platelet counts. Despite appropriate treatment, many patients continue to experience refractory disease. Fostamatinib, an oral spleen tyrosine kinase (SYK) inhibitor, has emerged as a promising option for refractory ITP. Objective This meta-analysis aims to evaluate the efficacy and safety of fostamatinib compared to conventional therapy in adults aged ≥ 18 years with refractory ITP. Materials and methods Literature search was conducted in PubMed, Scopus, Embase, and clinicaltrials.gov databases from inception to March 31, 2024. Randomized controlled trials (RCTs) assessing the safety and efficacy of fostamatinib in adults with refractory ITP were included. Data extraction, risk of bias assessment, and statistical analysis were performed following PRISMA guideline. Results A total of 495 articles were screened, with three RCTs meeting the inclusion criteria. Fostamatinib therapy demonstrated superior efficacy in achieving stable platelet response by week 24 (ORR 0.80; 95%CI 0.72–0.88), platelet count ≥ 50,000/µL at weeks 12 (ORR 0.80; 95%CI 0.72–0.90) and week 24 (ORR 0.82; 95%CI 0.72–0.90). Additionally, fostamatinib improves platelet counts in subjects with a baseline count of < 15,000/µL. The Number Needed to Treat (NNT) was calculated as 10. Adverse effects include diarrhea (RR 2.32; 95%CI 1.11–4.84), hypertension (RR 2.33; 95%CI 1.00-5.43), and abnormal liver function tests (RR 4.18; 95% CI 1.00-17.48). Interestingly, the occurrences of nausea (RR 1.77; 95% CI 0.33–9.67) and rash (RR 2.28; 95% CI 0.50-10.29) did not achieve statistical significance. Conclusion This meta-analysis provides robust evidence supporting the efficacy of fostamatinib in improving platelet counts and achieving therapeutic goals in adults with refractory ITP. However, fostamatinib’s safety profile warrants consideration due to higher rates of diarrhea, hypertension, and abnormal liver function tests. Supplementary Information The online version contains supplementary material available at 10.1007/s00277-024-05824-7.


Risk of Bias assessment
The RoB assessment covers five domains, each of which was evaluated based on the criteria outlined in the tool.
1.Randomization Process: All studies provided detailed information about the allocation sequences, which were stratified random.Two studies balanced patients with prior splenectomy and the degree of thrombocytopenia, while one study stratified by baseline platelet count (< or ≥15 000/μl).Conflict arose in the allocation concealment part; while one author (J.J) rated all studies as "No information," the other authors (S.T. and N.B) pointed that in the context of a large trial run by an experienced clinical trials unit, responding with "Probably yes" rather than "No information" is more reasonable.Our judgment differed from a previous meta-analysis, which rated it as some concern due to no information.No baseline differences between treatment arms were observed.We rated low risk in this domain.

2.Deviation from Intended Interventions:
We assessed this domain as low risk, as all studies employed double-blind designs, ensuring that participants and physicians were unaware of their assigned interventions during the trial.Additionally, the primary outcome measure, platelet count evaluation, was conducted consistently across all studies, aligning with the intended intervention protocols.
3.Missing Outcome Data: Our assessment of this domain resulted in a low-risk rating, as all data relevant to the outcomes of interest were available for analysis.There were no instances of missing outcome data reported in the included studies, minimizing the risk of bias associated with incomplete outcome reporting.

4.Measurement of the Outcome (detection bias):
We rated this domain as low risk because the measurement of outcomes was consistent and comparable between treatment groups across all included studies.The outcome measures were well-defined and standardized, facilitating accurate assessment and interpretation of treatment effects.
5.Selection of the Reported Result (reporting bias): Our evaluation of this domain yielded a lowrisk rating as the data analysis was conducted according to pre -specified analysis plans established before the randomization process.This approach minimizes the risk of selective reporting bias and enhances the transparency and reliability of the reported results.

Item in data extraction form
OUTCOMES• Stable platelet response (n; by Week 24)• Platelet response (n; at Week 12)• Platelet response (n; at Week 24)• Frequency and Severity of Bleeding According to the ITP Give the total number of included studies and participants and summarise relevant characteristics of studies.YesSynthesis of results8 Present results for main outcomes, preferably indicating the number of included studies and participants for each.If meta-analysis was done, report the summary estimate and confidence/credible interval.If comparing groups, indicate the direction of the effect (i.e. which group is favoured).Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect.Present results of all investigations of possible causes of heterogeneity among study results.n/a20dPresent results of all sensitivity analyses conducted to assess the robustness of the synthesized results.n/aReportingbiases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.