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

Abstract

Patients with severe sickle cell disease (SCD) experience organ damage, poor quality of life and premature mortality. Hematopoietic cell transplantation (HCT) is curative in SCD. Excellent outcomes have been achieved in young children with HLA matched related donors (MRD), with low rates of acute and chronic graft versus host disease (GVHD). Adolescent patients with SCD receiving MRD HCT and patients with SCD receiving matched unrelated donor (MUD) HCT, remain at highest risk for GVHD and resulting morbidity and mortality. Building on the encouraging experience with abatacept (CTLA-4Ig) for GVHD prophylaxis in URD HCT for hematologic malignancies, we launched an early phase, multicenter trial (n=25) through the Sickle Cell Transplant Advocacy and Research Alliance (STAR) of abatacept in pediatric SCD patients at high risk for GVHD. Patients with severe sickle cell disease were eligible if they were receiving a MRD HCT and either they or their donor were at least 10 years or if they were receiving a MUD HCT. Twenty-five patients have been enrolled to date with 23 patients completing conditioning and HCT. All 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 tacrolimus and methotrexate. Abatacept dosing was extended to eight doses for the last 11 patients (+60, +90, +120, +150). Tacrolimus was tapered at day 180 if no GHVD was present. The median age at HCT was 11 (3-21 years); 13 received a MRD HCT and 10 a MUD HCT. All patients engrafted with neutrophils at a median of 21 days (range 13-26) and platelets at a median of 23 days (13-55). As of 10/1/2019, median follow up is 804 days (range 46 – 1139). The mean myeloid and T-cell chimerisms at one (n=17) and two years (n=10) were 97.9 +/- 4.9 and 94.2 +/- 10.0 and 96.6 +/- 8.9 and 97.5 +/-4.3, respectively. Three evaluable patients at 2 years did not have chimerism studies sent. There have been 4 cases of EBV viremia (1 PTLD) and 6 cases of CMV viremia (1 disease). Grades 3-4 acute GVHD was seen in one patient and chronic/overlap in 5 patients with two patients currently receiving sytemic immune suppression. There has been no cerebral hemorrhages but one patient developed non-infectious encephalopathy of unclear etiology. The overall and sickle cell free survival at 2 years post HCT in evaluable patients (N=13) is 100% and 100%, respectively. The preliminary results in first 23 patients enrolled to date suggest that incorporating abatacept into GVHD prophylaxis is a safe and efficacious approach to improving outcomes in HCT for pediatric SCD.