Caplacizumab in Immune-Mediated Acquired Thrombotic Thrombocytopenic Purpura: A Systematic Literature Review and Meta-Analyses of Clinical Trials and Observational Studies

Introduction Caplacizumab (CPLZ) is approved for treating adults with immune-mediated acquired thrombotic thrombocytopenic purpura (iTTP) in conjunction with plasma exchange (PEX) and immunosuppression (IS). The safety and efficacy of CPLZ in iTTP have been assessed in clinical trials (CTs) and observational studies. A systematic literature review of this evidence body followed by meta-analyses (MAs) was conducted to assess the outcomes of CPLZ+PEX+IS (CPLZ cohort) alone or in comparison with PEX+IS (control), with or without rituximab, in treating iTTP. Methods Conforming with Cochrane, PRISMA, and NICE guidelines, databases (Embase, PubMed, and Cochrane) were searched up to June 9, 2023, supplemented by grey literature searches. Relevant randomized controlled trials (RCTs), non-RCTs, and observational studies of CPLZ in adult patients with iTTP were included. The feasibility of conducting MAs was based on heterogeneity between studies on clinical aspects (treatment used, baseline characteristics, and CPLZ initiation timing), study type (RCT/observational and comparative/single cohort), and outcome definitions (assessment start date, PEX in days [d]/sessions, and mean/median measures). Frontline CPLZ administration within 72 h of PEX initiation (per ISTH guidelines and FDA and EMA labels) was emphasized, and cohorts with known delayed CPLZ initiation (>72 h) were excluded. New definitions of exacerbation and relapse were used to enhance treatment comparability and clinical relevance. While the old criteria (Scully et al., 2017) defined exacerbation/relapse as a recurrence within or beyond 30 d post-PEX cessation, the new criteria (Cuker et al. 2021) also included anti-von Willebrand factor therapy (CPLZ) cessation. The MAs were conducted for time to platelet count normalization, exacerbation, relapse, hospital stay, PEX duration, mortality, and bleeding events. The mean difference (MD) was calculated for continuous endpoints and the risk ratio (RR) for binary endpoints. The number needed to treat (NNT) was estimated for binary endpoints to aid results' interpretation. Pooled estimates were derived using standard frequentist MA methods, employing fixed and random effects models. Results A total of 35 publications reporting 23 studies (2 RCTs, 2 non-RCTs, 9 comparative cohort studies, and 10 single-cohort studies) were identified. Sample sizes varied from 5 to 113 (1,286 treated episodes) in CPLZ cohorts and 12 to 216 (871 treated episodes) in controls. The feasibility assessment showed clinical heterogeneity across studies, leading to estimates from the random effects models being preferred. The MAs showed that CPLZ significantly shortened the median time to platelet normalization vs control (MD [95% CI]: -3.77 d [-5.86; -1.68]) by 51% (3.59 vs 7.36 d for CPLZ vs control). The mortality rates significantly favored CPLZ vs control (RR [95% CI]: 0.44 [0.21; 0.92]) with an NNT of 25 patients. CPLZ significantly reduced the duration of hospital stay (MD [95% CI]: -5.34 d [-7.09; -3.58]) by 30% (12.31 vs 17.65 d) and PEX duration (MD [95% CI]: -4.51 d [-5.87; -3.15]) by 41% (6.41 vs 10.92 d) vs control. CPLZ significantly lowered exacerbations rates (RR [95% CI]: 0.41 [0.22; 0.76]) with an NNT of 5 patients. CPLZ was associated with an increased risk of bleeding events vs control (RR [95% CI]: 1.40 [1.08; 1.80]). However, when specifically assessing major bleeding events, the difference was not statistically significant (RR [95% CI]: 2.11 [0.62; 7.22]). Thus, CPLZ increased the risk of minor and manageable events. The 1-year assessment after an iTTP episode showed relapse rates not significantly differing between cohorts (RR [95% CI]: 0.98 [0.35; 2.74]). The MAs for the single-cohort studies were aligned with the comparative cohort findings. Conclusions When compared to PEX+IS, CPLZ+PEX+IS consistently showed an improved efficacy, decreased mortality, and reduced healthcare resource utilization in CTs and observational studies involving patients with iTTP. The use of the new criteria in iTTP enhanced clinical relevance and resulted in significantly reduced exacerbation in CPLZ cohort and similar 1-year relapse in both cohorts. Adherence to the treatment guidelines and comprehensive analysis across varied study types constituted the strengths of the study, while clinical heterogeneity and small sample sizes remain potential limitations.