Abatacept for GVHD Prophylaxis after Hematopoietic Stem Cell Transplantation (HCT) for Pediatric Sickle Cell Disease (SCD): A Sickle Transplant Alliance for Research (STAR) Trial

Abstract

Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life and premature mortality. Hematopoietic stem cell transplantation (HCT) is curative in SCD. Outcomes are especially good in young children with HLA matched related donors (MRD), where acute and chronic graft versus host disease (GVHD) are uncommon. In adolescent patients with SCD receiving MRD HCT and patients with SCD receiving matched unrelated donor (MUD) HCT, GVHD and resulting morbidity and mortality, remain important barriers. Building on the encouraging preliminary experience with abatacept (CTLA-4Ig) for GVHD prophylaxis in mismatched URD HCT for hematologic malignancies we launched an early phase, multicenter trial (n = 25) through the Sickle Transplant Alliance for Research (STAR) of abatacept in pediatric SCD patients at high risk for GVHD. Patients with severe sickle cell disease are eligible if they are receiving a MRD HCT and either they or their donor are at least 10 years or if they are receiving a MUD HCT. We herein report the preliminary results in the 13 patients enrolled to date. Patients received reduced intensity conditioning (RIC) with distal alemtuzumab, fludarabine, thiotepa and melphalan and marrow grafts. Four doses of abatacept (10 mg/kg/dose IV on days −1, +5, +14, +28) were added to standard GVHD prophylaxis using a tacrolimus and methotrexate. The median age was 12 years (4-21 years). 8 received a MRD HCT and 5 a MUD HCT. All patients engrafted with neutrophils at median of 21 days (17-27), platelets at median of 22 days 14-50) and are surviving free of SCD with median follow up of 8 months (range 1-12). Full donor chimerism was seen in whole blood, myeloid subsets in all, with only 2 patients with mixed T cell chimeras (>65% donor) and remained sustained. Abatacept has been well tolerated. There have been 3 cases of EBV viremia, 2 cases of CMV viremia, 1 case of bacterial sepsis. There have been no cases of PTLD. There has been no acute or chronic GVHD and three patients are now off immune suppression. There has been no cerebral hemorrhage but one patient developed non-infectious encephalopathy of unclear etiology that responded to steroids, withdrawal of calcineurin inhibitor and supportive therapy. The preliminary results in first 13 patients enrolled to our trial suggest that incorporating abatacept into GVHD prophylaxis may be a safe and effective way to improve outcomes in HCT for pediatric SCD.