Low-dose splenic irradiation prior to hematopoietic cell transplantation in hypersplenic patients with myelofibrosis

For patients with myelofibrosis undergoing hematopoietic cell transplantation (HCT), splenomegaly can lead to a protracted post-transplant course and is associated with lower survival in some series [1–3]. Splenectomy has been used in some patients prior to HCT, and studies have demonstrated that splenectomy prior to HCT reduced engraftment time (13 versus 20 d [2]). However, at many centers, splenectomy has fallen out of favor due to high complication rates (5% peri-operative mortality and 30–45% peri-operative morbidity [4]) and acceptable engraftment rates with HCT even in patients with significant splenomegaly [5]. Splenic irradiation has a long history in treating myelofibrosis, with low-dose treatment effective in alleviating painful splenomegaly [6,7]. In patients undergoing HCT for chronic myeloid leukemia, splenic irradiation has been used prior to transplant to reduce tumor burden and improve post-transplant kinetics [8], with a randomized study showing a survival benefit to splenic irradiation in a subset of patients [9]. Immunomodulatory drugs, JAK inhibitors, and mTOR inhibitors have also demonstrated efficacy in improving splenomegaly but have not been evaluated in the pre-transplant setting [10]. Starting in 2011, it has been standard practice at our institution to refer myelofibrosis patients with splenomegaly for low-dose splenic irradiation (LDSI) prior to HCT to attempt to reduce spleen size and improve posttransplant count recovery without the morbidity of splenectomy. Herein we report the outcomes of these patients. Medical records were examined after approval was obtained from our institution’s institutional review board. Between 2011 and 2015, eight patients received LDSI prior to HCT for myelofibrosis. Radiographic documentation of spleen size preand post-transplantation was available for seven patients. Spleen length is reported as the maximum cranio-caudal dimension on abdominal ultrasound. Regarding HCT, five patients had HLA matched related donors. All patients underwent reduced intensity conditioning regimens with busulfan plus fludarabine or melphalan. Anti-thymocyte globulin was given to one of five related donor patients and to all three unrelated donor patients. No patient received total body irradiation. Graft versus host disease (GVHD) prophylaxis was evenly split between cyclosporine and tacrolimus: one patient, whose donor was an identical twin, did not require GVHD prophylaxis. Median LDSI prescription dose was 4.5 Gray (range 3.0–6.0 Gray), delivered in 3 fractions (range 3–6 fractions) over 6 d (range 3–9 d). Patients finished treatment a median of 14 d prior to HCT (range 7–24 d). The date of graft infusion was defined as day 0 of transplant. Patients achieved neutrophil and platelet engraftment on the first of three consecutive days with an absolute neutrophil count of 0.5 10/L and an absolute platelet count of 50,000 10/L, respectively. At our institution, patients received red blood cell and platelet transfusions if their hemoglobin level fell below 8 g/dL and their platelet level fell below 30,000 10/L, respectively. Change in spleen length was evaluated by the Wilcoxon rank sum test, with continuity correction for continuous variables. Median age and Karnofsky performance score were 60 years and 80, respectively (Table 1). Median pre-transplant spleen length was 27 cm. All patients had a spleen size greater than 20 cm. Median time after HCT to repeat splenic imaging was 5 months (range 2–8 months). The patient cohort experienced a significant reduction in spleen size (median decrease 10cm (36%), p< . 01). Acute LDSI treatment toxicity was mild (two patients with grade 1 and two patients with grade 2 nausea); no grade 3 toxicities were observed. Median times to neutrophil and platelet engraftment were 13 and 26 d, respectively. At 2 years post-HCT, 75%