Pilot Study of Low-Dose Splenic Irradiation and Transplantation in JAK Inhibitor-Refractory Myelofibrosis With Splenomegaly

Splenomegaly is a hallmark feature of myelofibrosis, driven by extramedullary hematopoiesis due to progressive bone marrow fibrosis. Enlarged spleens cause significant symptoms, impair quality of life, and complicate hematopoietic stem cell transplantation (HSCT) by increasing the risk of delayed engraftment, graft failure, and relapse. While Janus kinase (JAK) inhibitors can reduce spleen size, some patients remain refractory or lose response over time. Splenic irradiation has emerged as an alternative strategy, though optimal protocols and safety profiles remain unclear. In this bicentric observational study, we evaluated the safety and efficacy of a standardized low-dose splenic irradiation protocol administered immediately prior to HSCT in patients with myelofibrosis and refractory splenomegaly. We included 11 patients with primary or secondary myelofibrosis who underwent first HSCT from 2020 to 2025. Patients received standardized low-dose splenic irradiation of 3.0 Gy fractionated into three or six daily sessions using volumetric modulated arc therapy (VMAT), administered either shortly before or partially concurrently with the conditioning regimen. We systematically monitored spleen size, hematologic parameters, molecular clearance of driver mutations, donor chimerism, and transplant-related outcomes. Median spleen size before irradiation was 25 cm, which significantly decreased to 22 cm postirradiation (median reduction: 3 cm) and further reduced to 17.7 cm by engraftment (median additional reduction: 4.3 cm). All patients achieved neutrophil engraftment within a median of 12 days and platelet engraftment was achieved by 82% within 14 days. Isolated hyperbilirubinemia occurred transiently in 82% of patients without significant clinical consequences. No occurrences of veno-occlusive disease, thrombotic microangiopathy, or hemorrhagic complications were reported. At days 30 and 100 post-transplant, full donor chimerism was achieved in 91% and 80%, with driver mutation clearance observed in 70% and 80%, respectively. With a median follow-up of 5.5 months, overall survival was 91%, with two cases of early relapse and two instances of acute graft-versus-host disease. Two patients experienced poor graft function, one requiring stem cell boost. Our study demonstrates that low-dose splenic irradiation prior to HSCT is an effective and safe adjunct treatment for managing splenomegaly in myelofibrosis patients. The standardized protocol resulted in substantial spleen size reduction, favorable engraftment kinetics, and acceptable toxicity profiles. These promising outcomes highlight splenic irradiation as a viable, less invasive alternative to splenectomy, warranting further exploration in larger prospective trials to refine protocols and confirm long-term benefits.