Effect of pre-allogeneic HCT splenic irradiation on post-transplant engraftment and outcomes in patients with myelofibrosis: A single-center experience

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for myelofibrosis (MF) but carries significant non-relapse mortality (NRM). Splenomegaly in MF patients undergoing allo-HCT is linked to delayed engraftment, poor graft function, and worse overall survival (OS). Strategies to reduce spleen size pre-HCT have been explored. Splenic irradiation (SI) offers a non-invasive approach for rapid spleen size reduction, though data on transplant outcomes are limited. Retrospective studies suggest SI just before HCT may reduce relapse and effectively shrink spleens with acceptable toxicity. Methods: We conducted a single-center observational study on MF patients with splenomegaly undergoing allo-HCT between 2022–2024. SI (100 cGy in 5 fractions) was delivered within 6 weeks pre-HCT. Primary endpoints: engraftment kinetics (including primary engraftment failure), time to neutrophil/platelet engraftment, and transfusion independence. Secondary endpoints: OS, progression-free survival (PFS), relapse, NRM, and rates of acute/chronic GVHD. Kaplan–Meier methods were used for OS/PFS; cumulative incidence functions with competing risks were used for relapse/NRM. Results: Thirteen patients were analyzed. Median age was 63 (range 40–74) years, and 54% were male. Eight (62%) patients had primary MF, 3 (23%) post-essential thrombocytosis, and 2 (17%) post-polycythemia vera. Eleven (94.6%) patients had prior Ruxolitinib therapy, and 10 (76.9%) harbored a JAK2 mutation with a median variant allele frequency of 51% (range 34%–94%). DIPSS risk at transplant was low in 1 (7.7%), intermediate-1 in 8 (61.5%), and intermediate-2 in 4 (30.8%) patients. Median pretransplant spleen size was 22.4 (range 14.5–28) cm. Two patients had a history of thrombosis, including 1 with portal vein thrombosis. The median interval between SI and stem cell infusion was 14 (range 10–43) days. The median HCT-CI score was 2 (range 0–6), and the median KPS was 80% (range 80–100%). Most patients (76.9%) received a HLA-matched unrelated donor transplantation, while 3 (23.1%) received haploidentical donor grafts. All grafts used peripheral blood stem cells. Reduced-intensity conditioning (RIC) was used in 11 (84.6%) patients, while 2 (15.4%) received myeloablative conditioning (MAC). Five (38.5%) patients received total body irradiation (TBI) as part of conditioning, with all receiving a TBI dose of 200 cGy. All patients received post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis. With a median follow-up of 17.1 months, median neutrophil engraftment occurred at 18 (range 14–45) days, platelet engraftment at 30 (range 15–434) days, red blood cell transfusion independence at 35 (range 11–341) days, and platelet transfusion independence at 24 (range 10–312) days. Median hospital stay was 26 (range 14–86) days. Primary engraftment failure occurred in 1 (8.3%) patient. One (7.7%) patient developed veno-occlusive disease. Four (33.3%) patients experienced CMV reactivation, and 3 developed CMV disease requiring systemic therapy. Median post-transplant spleen size was 16.6 (range 12.2–25.2) cm, and 30% of patients achieved >50% spleen size reduction, with a median time of 114 (range 45–212) days, with none having a normal spleen at day 30 post-transplant but 2 (15%) patients having a normal spleen at day 100 post-transplant. At 1 year, OS was 73.3% (95%CI, 51.5–100%), and PFS was 66% (95%CI, 44%–100%). The 1-year cumulative incidence of relapse was 7.6%, while 1-year NRM was 25.7%. Seven (53%) patients developed acute GVHD, with 1 patient experiencing grade III acute GVHD that progressed to sepsis and death at day 248 post-transplant. Two additional deaths occurred (graft failure=1, multiorgan failure=1). Two (15%) patients developed moderate chronic GVHD Conclusion: In this single-center cohort, SI pre-allo-HCT was feasible, tolerated, and associated with promising OS and PFS. Engraftment occurred in >90%, with one case of primary engraftment failure and most achieving transfusion independence within reasonable time frames. SI reduced spleen size in >30%, though acute GVHD was frequent. It remains uncertain whether the incidence and severity of GVHD may be influenced using TBI as part of the conditioning regimen (albeit reduced in intensity) in addition to splenic irradiation. Larger prospective studies are needed to clarify SI's impact on engraftment, transfusion dependence, GVHD, and outcomes in MF patients.