Characterizing the Clinical, Humanistic, and Economic Burden of Warm Autoimmune Hemolytic Anemia: A Systematic Literature Review and Evidence Gap Assessment

Introduction

Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disorder characterized by the destruction of red blood cells by autoantibodies. The disorder may be idiopathic or secondary to other conditions. Currently, there are few clinical trials and no treatments specifically FDA-approved for wAIHA, posing challenges in disease management. Data describing the costs, healthcare resource utilization, and patient-reported outcomes associated with wAIHA are sparse. This systematic literature review (SLR) aims to systematically identify and qualitatively summarize published literature reporting on clinical, humanistic, and economic outcomes among patients with wAIHA. To our knowledge, this is the first SLR evaluating these outcomes in wAIHA without restriction to specific treatments.

Methods

Systematic searches for English language studies in MEDLINE, Embase, and Cochrane libraries were conducted in May 2024, supplemented by manual searches of grey literature and abstracts and posters from recent major hematology conferences (2022-2024). Articles published from 2014 to present were evaluated for inclusion. Studies were screened at 2 levels (title/abstract and full text) for relevance using pre-specified criteria by 2 researchers independently, with disagreements adjudicated by a third reviewer. Clinical trials, observational studies, and SLRs/meta-analyses were included. This SLR is registered with PROSPERO (CRD42024569954).

Results

Among 1,041 articles identified, 67 studies with ≥10 subjects reported outcomes of interest relevant to this analysis. Sample sizes varied widely within the included studies, ranging from 12 patients with wAIHA to 1,548 patients with wAIHA. Among the 60 primary studies, 8 were clinical trials, including 3 comparative, of which 2 were Phase 3 (FORWARD and RAIHA). The remaining 5 clinical trials were single-arm. While there are no FDA-approved treatments specifically for wAIHA, treatments evaluated within the set of clinical trials included fostamatinib, rituximab, ibrutinib + rituximab, sovleplenib, parsaclisib, and pulse cyclophosphamide. The remaining 52 primary studies were observational, including 9 prospective studies, 41 retrospective studies, and 2 cross-sectional studies. Half of the studies were based in the US or Europe. Other individual countries that were responsible for more than 1 study included India (5), China (3), Egypt (3), Mexico (3), Thailand (3), Japan (2), and Tunisia (2).

Patient populations and outcomes among the included studies were heterogenous: 42 studies reported survival outcomes, 32 reported transfusions, 30 reported relapse rates, and 26 reported overall response rates. Within these outcomes, definitions of response differed, complicating any potential cross-study comparisons and conclusions. Further, only 11 studies reported duration/durability of response, 4 reported economic outcomes (e.g. costs, healthcare resource utilization), and 2 reported humanistic outcomes (e.g., patient-reported outcomes). Although reported health outcomes varied widely in this heterogenous group of wAIHA studies, substantial unmet need is evidenced by low hemoglobin (Hb) levels and fatigue across the study set.

Conclusions

Our SLR has identified considerable gaps and inconsistencies in the literature, including a lack of economic and humanistic burden studies specific to wAIHA and heterogeneity in the reporting of response outcomes across studies. While wAIHA is a relatively poorly studied disease, available data suggests low Hb levels and associated risks across both clinical trials and real-world study publications, reflecting a high unmet need in this patient population. Patient-reported outcomes, including health-related quality of life measures, should be evaluated with clinical outcomes in future trials and observational studies to facilitate understanding of outcomes that are important to patients.

Piatek:Sanofi: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Argenx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Alpine Immune Science: Research Funding; Zenas BioPharma: Research Funding. Kaufhold:Novartis: Consultancy. Shane:Novartis: Consultancy. Nellesen:Novartis: Consultancy. Paul:Novartis: Current Employment. O'Sullivan:Novartis: Current Employment, Current equity holder in publicly-traded company. Iorga:Novartis: Current Employment. Lee:Novartis: Current Employment, Current holder of stock options in a privately-held company.