Eltrombopag for the Treatment of Fanconi Anemia

National Heart, Lung, And Blood Institute

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Abstract

Overview We report integrated results through August 2025 for the NIH protocol evaluating eltrombopag (EPAG) in human participants with FA and BMF. Recruitment is complete (target n=25), and 21 participants have reached the 6‑month landmark assessment. The mean on‑study treatment exposure among the continuously treated cohort is 24 months (range 6–42 months). Hematological Outcomes Since the 2024 Annual Report, five additional participants have reached the 6-month evaluation. Across the full cohort, marrow responses were observed in 18 of 21 participants (86%), while peripheral blood (PB) improvements in at least one lineage occurred in 15 of 21 (71%). Among the newly evaluable participants, four of five (80%) achieved marrow responses, and all five showed PB improvement at one or more time points. These findings confirm the previously documented high frequency of marrow responses and substantially increase the overall prevalence of PB responses. As in earlier analyses, robust platelet recovery (>50 × 10³/µL) and substantial absolute neutrophil count (ANC) increases were restricted to participants who received dose escalation beyond standard pediatric recommendations, as permitted under an IRB-approved amendment initiated in May 2024. All participants continued into the extended phase of the study. At the most recent assessment, one newly evaluable participant achieved a trilineage peripheral blood (PB) response accompanied by improvement in marrow cellularity from markedly hypocellular to approximately 40%. Another demonstrated substantial erythroid and neutrophil responses alongside a marrow response characterized by the emergence of measurable CD34+ progenitor cells (0.2–0.3%) from a near-absent baseline and a significant reduction in red blood cell transfusion requirements. Two additional participants showed sustained marrow responses accompanied by unilineage erythroid PB improvements. One participant exhibited an erythroid-only PB response without concurrent marrow response, maintaining clinical benefit despite persistent cytopenias. Collectively, these outcomes highlight eltrombopag’s ability to enhance functional hematopoiesis in FA, while underscoring response heterogeneity, especially concerning megakaryocyte lineage recovery. Safety and Clonal Surveillance EPAG has been generally well tolerated. The most frequent adverse event remains iron deficiency attributable to chelation, manageable with supplementation. Two instances of transient transaminitis required temporary holds. Across new evaluations, liver enzyme elevations were mild and did not necessitate permanent discontinuation. Bone marrow examinations showed no dysplasia or blast excess; flow cytometry revealed no paroxysmal nocturnal hemoglobinuria (PNH) clones. Cytogenetics were stable in most cases; in one, an isolated +X mosaicism persisted without myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML)-associated mutations on targeted sequencing, warranting ongoing protocolized surveillance. In the full study history to date, one AML case and one monosomy 7 event have occurred, both attributed to underlying FA risk rather than EPAG exposure. Continued vigilance for clonal evolution remains integral to the study design in light of FA biology. Methods and Datasets Evaluations consist of serial complete blood counts (CBC) including absolute neutrophil count (ANC), comprehensive transfusion requirement tracking, and bone marrow aspirate/biopsy analysis with quantification of cellularity and CD34+ progenitor frequency by flow cytometry. Genomic surveillance comprises conventional cytogenetics, chromosome breakage analysis using diepoxybutane (DEB), and targeted sequencing panels for mutations associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Collectively, these assessments yield integrated longitudinal hematologic, histopathologic, and genomic datasets critical for characterizing response durability, safety, and potential clonal evolution. Conclusions and Next Steps Integrated through August 2025, EPAG demonstrates an overall marrow response in 86% and PB response in 71% of evaluable participants at the 6 month landmark, with dose escalation associated with improved outcomes in most escalated cases. Safety remains acceptable with proactive monitoring. The team will complete data lock, maintain scheduled marrow and molecular surveillance, and finalize a manuscript now in preparation, with publication anticipated in FY2026. These findings support EPAG as a medically tractable strategy to augment hematopoiesis in FA and as a potential bridge to HSCT or to future autologous gene therapy approaches.