A meta-analysis of immunosuppressive and Pharmacological therapies in aplastic anaemia with and without Indigenous equine antithymocyte globulin (eATG)

Abstract Aplastic anaemia (AA) is a rare bone marrow failure disorder with a notably higher incidence in Asian populations, including India. Due to limited access to bone marrow transplantation (BMT) in resource-limited settings, immunosuppressive therapy (IST) remains the mainstay of treatment. However, the optimal combination of available IST regimens in low-resource environments remains uncertain. Therefore, we performed a meta-analysis to evaluate the effectiveness and safety of various immunosuppressive strategies—particularly equine antithymocyte globulin (eATG) combined with cyclosporine A (CSA), with or without eltrombopag (EPAG), as well as CSA and anabolic steroids-based monotherapies, for the treatment of AA in Indian patients. Fifty-nine studies (49 single-arm, 10 multi-arm) from PubMed, Google Scholar, and Indian Society of Haematology & Blood Transfusion (ISHBT) conference proceedings from December 1995 to December 2024 were included. The primary outcomes comprised overall response rates (ORRs) at 3, 6, and 12 months. Secondary outcomes included 5-year overall survival (OS), event-free survival (EFS), and treatment-related adverse events (TRAEs). Pooled estimates were calculated using a random-effects model, and heterogeneity was assessed with I² statistics. Meta-regression was used to explore sources of variability, and sensitivity analyses assessed the robustness of the pooled outcomes. Response rates (RR) varied significantly across treatment modalities and time points. In single-arm analysis, monotherapy with CSA or anabolic steroids showed limited efficacy, with pooled ORRs at 3 months of 26.9% and 19.77%, respectively. In contrast, dual therapy with eATG plus CSA substantially improved outcomes, achieving ORRs of 45.4% at 3 months and 62.99% at 6 months. A comparable trend was observed with THYMOGAM (an Indigenous eATG) plus CSA, with ORRs of 44.7% and 59.6% at the same intervals. The most pronounced benefit was noted with triple therapy regimens. The combination of eATG + CSA + EPAG yielded the highest ORRs—63.1% at 3 months, 80.7% at 6 months, and sustained 79.4% at 12 months. THYMOGAM-based triple therapy also performed well, maintaining an ORR of approximately 52% at 3 months. At 12 months, most combination therapies showed stable or slightly reduced responses, whereas monotherapy results remained poor or unchanged. A comparative analysis of double-arm studies further revealed differences in treatment efficacy. The RRs between THYMOGAM + CSA and ATGAM + CSA at 3, 6, and 12 months were not statistically significant (OR 0.69, p  = 0.13; OR 0.72, p  = 0.12, and OR 0.67, p  = 0.23, respectively). Similarly, comparative analysis of dual therapy (eATG + CSA) with triple therapy (eATG + CSA + EPAG) at 6 months showed no significant difference in ORRs (OR 0.67, p  = 0.50). In survival analysis, the eATG + CSA and THYMOGAM + CSA demonstrated 5-year OS rates of 74.90% and 73%, respectively. The 5-year EFS rate for eATG + CSA was 63.5%. Common TRAEs included febrile neutropenia and serum sickness. Mortality rates showed no significant differences among different treatments regimens: eATG + CSA vs. ATGAM + CSA (11.31% vs. 6.24%, p  = 0.15), THYMOGAM + CSA vs. ATGAM + CSA (13.15% vs. 6.24%, p  = 0.17), and eATG + CSA vs. eATG + CSA + anabolic steroids (11.31% vs. 15.03%, p  = 0.41). In conclusion, IST remains an effective frontline approach for AA patients in India, especially where transplant options are limited. Regimens incorporating EPAG offer superior response rates, and THYMOGAM presents a cost-effective yet clinically viable alternative to ATGAM. These insights support more tailored, accessible treatment strategies in resource-constrained settings.