Romiplostim (AMG 531) and TPO-mimetic antibody approaches for CAMT1: variant-specific considerations for MPL c.305G>C (p.Arg102Pro)

For MPL c.305G>C (p.Arg102Pro), a pathogenic missense variant in the thrombopoietin receptor extracellular domain, the therapeutic relevance of TPO receptor agonists (romiplostim, a peptibody; eltrombopag, a small-molecule) depends critically on the residual receptor function. Romiplostim is an Fc-peptide fusion ("peptibody") that mimics TPO and activates MPL through a binding site partially overlapping with native TPO. If p.Arg102Pro retains sufficient membrane localization and conformational integrity for romiplostim binding, even partial receptor activation could stimulate residual megakaryopoiesis. However, for variants causing complete loss of surface expression, TPO mimetics are ineffective.

MPL (thrombopoietin receptor, c-Mpl) is essential for megakaryocyte differentiation and platelet production. Biallelic MPL loss-of-function variants cause congenital amegakaryocytic thrombocytopenia (CAMT), which progresses to pancytopenia/aplastic anemia as HSCs gradually deplete. Type I CAMT (null variants, complete MPL loss) presents with severe thrombocytopenia at birth and early marrow failure; Type II (hypomorphic variants, partial MPL function) has later onset and milder course. The p.Arg102Pro substitution in the extracellular cytokine receptor homology domain (CRH) likely disrupts local secondary structure but may not completely abolish surface expression. Romiplostim has been used off-label in CAMT case reports with variable success: patients with hypomorphic MPL variants (type II) showed platelet responses, while those with null variants (type I) did not respond (Ballmaier & Germeshausen, Blood 2009; PMID:19005177). Eltrombopag binds the MPL transmembrane domain (a different site from TPO) and has theoretical advantages for variants affecting the extracellular domain while preserving transmembrane/intracellular signaling.

TPO receptor agonists are palliative — they do not correct the underlying genetic defect or prevent the progression to aplastic anemia in type I CAMT. The only curative therapy is allogeneic HSCT. Response to romiplostim/eltrombopag is strictly genotype-dependent: null MPL variants cannot respond regardless of dose. The p.Arg102Pro variant has not been functionally characterized for surface expression or TPO/romiplostim binding capacity, making response prediction uncertain. CAMT is ultra-rare (estimated <100 known patients), so evidence for TPO mimetics comes from individual case reports, not trials. Long-term TPO agonist use raises theoretical concerns about marrow fibrosis and potential for clonal hematopoiesis in a genetically predisposed marrow. Eltrombopag's hepatotoxicity is a concern in pediatric patients requiring chronic therapy.