Qualitative assessment of predictors of response to immunosuppressive therapy in aplastic anemia: A systematic literature review Free

Introduction

Aplastic anemia (AA) is a rare hematologic disorder. Recommended treatments include hematopoietic stem cell transplantation or immunosuppressive therapy (IST) with horse antithymocyte globulin and cyclosporine (double therapy) ± eltrombopag (triple therapy). However, recommended criteria for treatment with IST does not reliably predict individual response, and predictive evidence remains limited. The primary objective of this systematic literature review (SLR) was to evaluate response rates with IST. The identified studies were used for a qualitative analysis and summary of clinical, immunological, genetic, and molecular predictors of response to IST in patients with all severities of AA.

Methods

A PRISMA-compliant SLR of English-language records published between 1980-2025 in PubMed and Embase databases was undertaken. Studies reporting response rates with double or triple IST and including data related to any predictor in AA - covering any disease severity and any age group - were included in this qualitative analysis. Dual screening with independent adjudication was performed, supported by a validated AI screening tool (Robot Screener, [Nested Knowledge; NK]) as a second reviewer. Data pertaining to the primary objective were extracted using AI and curated by human reviewers. Information on predictors was obtained via tags using a yes/no format within NK, and categorized as clinical, immunologic, or genetic/molecular for the qualitative analysis.

Results

The search identified 2,335 candidate studies. A total of 89 studies reported IST use for AA; of these, 45 studies reported on predictors of response to IST in AA. Study types comprised of 25 retrospective cohort/observational, 13 prospective cohort, 4 randomized controlled trials (RCT), 2 non-randomized trials, and one case series. The qualitative analysis showed that, across the 45 studies (6,254 patients of all ages), key clinical predictors of improved response rate in AA included younger age and lower-severity AA (definitions varied by study), although children with non-severe AA (per Camitta criteria) had higher relapse rates. Additional predictors were higher baseline absolute reticulocyte count (ARC), absolute lymphocyte count (ALC), and absolute neutrophil count (ANC), in effect, residual hematopoiesis. The presence of PNH clones is the most conflicting predictor. Some studies associate PNH positivity with improved overall survival (N=259, retrospective), while others examine its association with complete response, showing mixed results—ranging from negative predictive value (N=98, pediatric RCT) to positive associations (N=125, prospective, all ages), with some studies finding no association with clinical outcomes (N=51, observational, adults).Two studies found that immunologic markers such as lower CD57+ CD8+ naïve T-cells, higher CD8+ memory stem T-cells, and higher proportions of natural killer cells at baseline and post-treatment were associated with higher response rates. Genetic and molecular findings were heterogeneous: the presence of interferon gamma (IFNG) and transforming growth factor beta 1 (TGFB1) polymorphisms correlated with improved response. Longer telomere length showed improved response in one study (N=92, prospective, all ages), but no association with response in other studies (N=51, observational, adults and N=314, retrospective, pediatric). Sustained elevated thrombopoietin correlated with non-response. Delayed initiation of IST (>6 months from diagnosis) and older age (≥40 years) were associated with worse complete response.

Conclusions

Qualitative analysis of articles identified in this SLR showed age, hematopoietic reserve, and immune cell profiles as potential predictors of response to IST in patients with AA. Furthermore, poorer response with delayed therapy underscores the importance of timely diagnosis and treatment. Despite variability in study designs and limited statistical power, these initial qualitative findings support the potential for a more personalized, targeted approach to the treatment of AA, enabling clinicians to better assess the likelihood of hematologic recovery with IST. This SLR combines all findings to date and adds genetic and molecular predictors to general AA knowledge. Further, more in-depth analyses are planned to elucidate details regarding the identified predictors, drill down on conflicting findings such as those related to PNH clones and explore additional predictors.