Thrombopoietin receptor agonists and HSCT for MPL p.Arg102Pro CAMT: current standard and emerging gene therapy

For MPL c.305G>C (p.Arg102Pro), a pathogenic missense variant in the thrombopoietin receptor that impairs TPO-mediated megakaryopoiesis, allogeneic HSCT remains the only curative treatment for congenital amegakaryocytic thrombocytopenia (CAMT). TPO receptor agonists (romiplostim, eltrombopag) — approved for immune thrombocytopenia — are sometimes used as supportive therapy in CAMT, but their efficacy is inherently limited because they act through the defective MPL receptor itself. Arg102 is located in the extracellular domain of MPL and participates in TPO binding; the R102P substitution (classified as CAMT type II) typically allows some residual receptor signaling, resulting in transient platelet recovery in infancy before progressive bone marrow failure. This residual signaling may explain why some CAMT-II patients show partial responses to supraphysiological TPO agonist doses.

CAMT patients with type II MPL mutations (missense variants with residual receptor function, including R102P) generally have a milder early course than type I (null variants) but ultimately progress to pancytopenia and aplastic anemia by age 3-5 years, necessitating HSCT (Ballmaier & Germeshausen, 2009, PMID: 19846852). Allogeneic HSCT achieves >85% overall survival when performed before aplastic transformation with a matched donor. Case reports have documented transient responses to romiplostim (Fc-peptibody TPO mimetic) and eltrombopag (small molecule TPO agonist) in CAMT patients, with temporary platelet increases, though responses are incomplete and unsustained. Ex vivo lentiviral MPL gene therapy in CD34+ HSPCs is in preclinical development — proof-of-concept in Mpl-knockout mice has shown restoration of megakaryopoiesis and platelet production following transplantation of corrected cells.

TPO receptor agonists cannot overcome severe MPL loss-of-function — for type I (null) variants, they are completely ineffective. Even for type II variants like R102P with residual receptor function, agonist responses are partial and temporary, providing at best a bridge to transplant. HSCT carries transplant-related mortality (5-15% with matched donors, higher with mismatched/haploidentical donors), GVHD risk, and long-term complications including infertility and secondary malignancies. Gene therapy (lentiviral MPL correction of autologous HSPCs) remains preclinical with no clinical trials reported. The progressive nature of CAMT — evolving from isolated thrombocytopenia to pancytopenia as HSCs fail — means that the therapeutic window for gene therapy or transplant closes as bone marrow reserve diminishes. Newborn or early infant diagnosis via genetic testing is essential for optimal outcomes.