Splenic Irradiation and a Reduced-Intensity Conditioning Regimen Prior to Allogeneic Stem-Cell Transplantation for Myelofibrosis

Abstract

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with myelofibrosis (MF). Reduced-intensity conditioning (RIC) regimens have been used to extend this therapy to older and sicker patients. Splenectomy prior to HSCT for MF has been shown to enhance neutrophil engraftment and decrease transfusion requirements, but has a reported operative mortality of 9% or higher. Splenic irradiation (sXRT) has been historically used as a palliative treatment in MF. We present our experience with a RIC regimen incorporating extracorporeal photopheresis (ECP) in combination with either pre-HSCT splenectomy or sXRT. Methods: The Tufts BMT database, the Center for International Bone Marrow Transplantation Registry (CIBMTR) database, and chart review were used to gather data. All patients underwent conditioning consisting of ECP administered on days -6 and -5, pentostatin 4mg/m2by continuous infusion over 48 hours on days -4 and -3, and a total dose of 600 cGy total body irradiation (TBI) administered in 3 fractions on days -2 and -1 (PPT). sXRT, when employed, was given in the week prior to start of PPT (days -6 to -11) with total doses ranging from 300 to 500cGy. Cyclosporine and methotrexate were used for GVHD prophylaxis. Patients surviving a minimum of six months were considered evaluable for response assessment. Complete hematologic response was defined as resolution of clinical signs of MF as well as normalization of peripheral blood counts (Hgb>10gm/dL, ANC>1000/µL, Platelets >100K and all counts below upper limit of normal) and the absence circulating blasts. Histological response could not be assessed due to lack of follow-up bone marrow data. Clinical improvement, stable disease, progressive disease, spleen response were defined using revised IWG-MRT guidelines. Overall survival (OS) was estimated using the Kaplan Meier method from time of stem cell transplant to death. Non-relapse mortality (NRM) was estimated from time of transplant to death, treating death due to MF and relapse as competing risks. Results: Ten patients (7 females, 3 males) with MF underwent allogeneic HSCT with PPT conditioning between February 2001 and December 2012. Median age was 54 years (40-60 years). Median time from diagnosis to transplant was 48 months (6-137 months). MF was primary in 8 and secondary to essential thrombocytosis in 2 patients. According to DIPSS scoring, 1, 2, 5 and 2 patients were low, intermediate-1, intermediate-2 and high risk respectively. Donors were equally distributed between matched related and matched unrelated. Bone marrow was used as the source in all but one patient. Nine patients (90%) had palpable splenomegaly. Six underwent splenectomy of which 1 died of a related complication (sepsis from abscess in the splenic bed). Three received sXRT prior to HSCT with no associated complications. All but one patient (who had a prior splenectomy) engrafted successfully. Median time to engraftment was 18 days (sXRT 18 days, splenectomy 19 days) for neutrophils and 26 days for platelets regardless of splenic therapy. Only 2 patients developed acute grade III-IV GVHD and 1 patient developed extensive chronic GVHD. 4/7 patients with a prior splenectomy were evaluable for disease response. Of these 2 had complete hematologic response, 1 had clinical improvement with eventual relapse, and 1 had progressive disease. Among the 3 patients receiving sXRT, 2 patients had complete hematologic response as well as a spleen response and 1 had stable disease.Three patients were alive at last follow-up. Causes of death included disease relapse (n=2), GVHD (=3) and sepsis (n=2). Cumulative incidence of NRM was 40% at 1 year. Five year OS was estimated at 30%. Discussion: Our data demonstrates that splenic XRT is well tolerated and equivalent to splenectomy in terms of engraftment outcomes and disease response. Survival and GVHD outcomes with PPT conditioning were similar to those reported with other RIC regimens. PPT is a reasonable conditioning regimen for these patients. Further study to optimize timing of HSCT and patient selection to reduce NRM is needed. Disclosures Comenzo: Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Splenic irradiation before allogeneic stem cell transplantation for myelofibrosis

“…Reports on the role of SI prior to ASCT for myelofibrosis are sparse and included small groups of patients or case studies [ 8 , 9 , 16 , 17 ]. Eight patients with MF received median splenic radiation dose of 450 cGy within median of 2 weeks prior to ASCT in Kalman study [ 8 ].…”

“…These results were then confirmed by others. Administration of SI as a part of reduced-intensity conditioning at doses ranging from 300 to 500 cGy in three patients was found to be feasible with acceptable toxicity [ 9 ].…”

“…It was demonstrated in patients transplanted for chronic myeloid leukemia that SI before ASCT did not increase relapse incidence and transplant-related mortality [ 7 ]. There are only few small studies on SI prior to ASCT in MF patients [ 8 , 9 ].…”

Splenectomy in Myelofibrosis: Indications, Efficacy, and Complications

“…The role of splenic irradiation before HSCT in MF patients is not well established and has been investigated in only a few small studies. 13,14 Nonetheless, low-dose splenic irradiation was found to significantly reduce spleen size (median decrease 10 cm, 36%), and was a safe and well-tolerated adjunct to HSCT in 8 hypersplenic patients with MF. 13 In a more recent study, Helbig et al 15 assessed the outcome of pretransplantation splenic irradiation in 44 patients with MF who underwent allogeneic HSCT.…”

Allogeneic Hemopoietic Stem Cell Transplantation for Myelofibrosis: 2021

“…Splenic irradiation (SI) may also be used to reduce the spleen size and related symptoms; there are only few small studies on SI prior to transplant in MF patients ( 22 , 23 ). It was demonstrated that SI alleviates splenic discomfort and reduces spleen size in a majority of MF patients, with a median duration of response of 6 months ( 24 ).…”