An evolving landscape – how changing conditioning regimes can improve myelofibrosis transplant outcomes.

Abstract Introduction Allogeneic stem cell transplantation in myelofibrosis carries significant risks, and outcomes remain suboptimal, with reported 5-year survival rates ranging from 40% to 60%1. Despite these challenges, it remains the only potentially curative option. There is considerable variability and a lack of standardised conditioning regimens across centres both in the UK and worldwide. With increasing referrals to Barts Health NHS Trust for transplant consideration, we reviewed our outcomes to ensure we are providing the highest standard of care. Method We retrospectively reviewed Barts Health NHS transplant data from 2010 to 2025, focusing on changes in outcomes over time, particularly in relation to the introduction of new conditioning regimens. Our analysis included patient demographics, date of diagnosis, date of transplant, conditioning regimen used, prior lines of treatment, cytogenetics, molecular results and donor type. The primary outcome measured was overall survival, secondary was event free survival (graft failure, disease transformation, death). Results 16 patients underwent allogeneic stem cell transplantation during this period. Seven patients received stem cells from matched sibling donors, eight were from volunteer unrelated donors (VUD) and one was a haploidentical donor. 11 were for a diagnosis of primary myelofibrosis, four for secondary myelofibrosis and one was for myelofibrosis transformed to AML. The average age at time of transplant was 55 years with a male predominance, 11 patients out of 16 being male. Of the 16 cases, seven received Fludarabine/Busulphan/Antithymocyte globulin (Flu/Bu/ATG) conditioning (Fludarabine 30mg/m2 day -9 to day -5, Busulphan 3.2mg/kg on day -4 and day -3 and rabbit ATG 2.5mg/kg on day -2 and day -1), seven underwent Fludarabine/Cyclophosphamide (Flu/Cy) conditioning (Fludarabine 25mg/m2 day -6 to day -2 and Cyclophosphamide 1g/m2 on day -3 and day -2), and two received Fludarabine/Melphalan (Flu/Mel) (Fludarabine 25mg/m2 day -6 to day -2 and Melphalan 100mg/m2 on day -2). The haploidentical transplant was conditioned with Fludarabine 30mg/m2 day -6 to day -2, Cyclophosphamide 14.5mg/kg day -6 and day -5 and TBI 200cGy on day -1 with post-transplant Cyclophosphamide. From 2022, all transplants utilised Flu/Bu/ATG conditioning, with only one patient receiving this prior to 2022. Of the seven patients in the Flu/Bu/ATG group two have died (29%) and five are alive (71%), compared to eight deaths (89%) and one alive (11%) in the other group. Five patients had one prior line of therapy, five had two prior lines of therapy and six had more than two prior lines of therapy. Therapies included Ruxolitnib, Momelotinib, splenic irradiation, Hydroxycarbamide, Danazol, Interferon, Cyclophosphamide, Anagrelide, Thalidomide, Panobinostat and Navitoclax. Four patients had abnormal cytogenetics (two in the Flu/Bu/ATG group,two in the other group), nine had normal cytogenetics and three were unknown. These were del(20q), t(8:9), del(13q) and del(5q). 10 patients were JAK2 positive, two CALR positive, one MPL positive, one patient had a JAK2:PCM translocation and one was triple negative, the final patient had a normal molecular screen. Five patients had additional molecular abnormalities (IGH rearrangement, ASXL1, SF3B1, EZH2 and U2AF1). The median overall survival (OS) and event free survival (EFS) for the entire cohort were respectively 42 and 24 months. When stratified by conditioning regimen, the median OS and EFS for patients receiving Flu/Bu/ATG was 80 months (both for OS and EFS), compared to respectively 24 and 6 months for those treated with Flu/Cy or Flu/Mel. Looking at GVHD outcomes, eight patients developed acute GvHD (four from each group), of these four went on to develop chronic GvHD (two from each group). GvHD data was unavailable for one patient. Acute GvHD was the cause of death for three patients (one from the Flu/Bu/ATG group and 2 from the other group) Other causes of death included pneumonia, AML and an acute illness. Four causes of death are unknown. Graft failure occurred in four out of 16 patients (25%). Although limited by a small sample size, these findings indicate that the Flu/Bu/ATG conditioning regimen may be associated with improved outcomes, thereby supporting its adoption as the preferred approach for patients undergoing allogeneic stem cell transplantation for myelofibrosis as per BSH guidelines.2