Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis

Abstract

Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time to response, and improves exacerbation rates at the expense of increased relapse and bleeding risk.

Graphical abstract

Figure 1.

PRISMA flow diagram of study selection for systematic review. ASH, American Society of Hematology; EH, European Hematology Association.

Figure 2.

Summary of primary efficacy and safety outcomes across eligible trials. We present the outcomes reported in each individual trial as well as meta-analysis according to study design. Control refers to SOC alone without caplacizumab (refer to supplemental Table 2C “Details of treatments received”). Event rates refer to the number of patients with the event of interest. Below the pooled estimate of the risk difference, we present the same finding as the difference in absolute risk of the outcome among patients treated with caplacizumab plus SOC (compared with those treated with SOC alone) per 1000 patients treated with caplacizumab. Df, degrees of freedom; SD, standard deviation.