Reversible Eltrombopag-Associated Bone Marrow Fibrosis With Hematologic Recovery After Drug Withdrawal in...

Hypoplastic myelodysplastic syndrome (MDS) often overlaps clinically with aplastic anemia and frequently involves clonal hematopoiesis. Thrombopoietin receptor agonists (TPO-RAs), including eltrombopag, are increasingly used to treat cytopenias in hypoplastic marrow failure syndromes; however, their long-term effects on clonal dynamics and marrow fibrosis remain incompletely defined. We report a case of ASXL1- and TET2-mutated hypoplastic MDS, initially managed as aplastic anemia, in which eltrombopag therapy was associated with a biphasic clinical course. Hematologic parameters initially improved with reduced transfusion requirements; however, prolonged exposure was followed by progressive marrow fibrosis (MF-2 to MF-3), worsening cytopenias, and expansion of a minor paroxysmal nocturnal hemoglobinuria (PNH) clone. Serum lactate dehydrogenase levels increased in parallel with fibrosis progression. After eltrombopag discontinuation, the patient achieved transfusion independence within 3 months and substantial regression of marrow fibrosis, accompanied by recovery of marrow cellularity exceeding the pretreatment baseline. Longitudinal molecular analysis demonstrated modest fluctuations in variant allele frequencies without evidence of overt unidirectional clonal progression. The temporal association between fibrosis progression and hematologic deterioration, together with sustained improvement after drug withdrawal, suggests that eltrombopag may have contributed to treatment-associated microenvironmental remodeling that constrained hematopoiesis after an initial stimulatory phase. This case suggests that eltrombopag-associated marrow fibrosis may be reversible even in the presence of clonal hematopoiesis, and that clinical worsening during TPO-RA therapy does not necessarily indicate irreversible clonal evolution. Careful reassessment of marrow morphology, clonal dynamics, and treatment-related niche perturbation may be warranted in patients with hypoplastic MDS who deteriorate during TPO-RA therapy.

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