A Novel Intermediate Alemtuzumab Schedule Optimizes the Incidences of Mixed Chimerism and Acute Gvhd in Patients with HLH and XLP Undergoing Allogeneic HCT

Introduction:  Reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan improves the hematopoietic cell transplant (HCT) outcomes of patients with hemophagocytic lymphohistiocytosis (HLH).  Proximal dosing of alemtuzumab is associated with a high incidence of mixed chimerism (MC) whereas distal dosing is associated with less MC but higher incidences of acute GVHD following initial graft infusion.  We hypothesized that an intermediate alemtuzumab schedule would optimize the incidences of MC and acute GVHD.  Methods:  Twenty-five consecutive transplants were performed in patients with HLH or XLP using a RIC regimen with a novel intermediate alemtuzumab schedule of 1mg/kg beginning on day -14.   The cumulative incidences of MC and acute GVHD were compared to 2 retrospective cohorts of patients with HLH and XLP treated with distal (n=15) or proximal (n=33) alemtuzumab schedules.  All patients received fludarabine 150mg/M2 (1mg/kg if <10kg) divided over days -8 to -4, and melphalan 140mg/M2 (4.7mg/kg if <10kg) on day -3.  Melphalan was reduced by 50% in one infant due to concern for toxicity.  GVHD prophylaxis consisted of methylprednisolone and cyclosporine or tacrolimus in all but 2 patients who received methylprednisolone and MMF.  Three patients additionally received methotrexate.  Results:  The cumulative incidence of MC was less in the intermediate alemtuzumab cohort at 34%, versus 72% in the proximal and 40% in the distal cohorts (p=0.008).  The cumulative incidence of acute GVHD related to initial graft infusion (before MC) was 4% in the intermediate cohort and 0% in the proximal cohort (p=0.26), versus 13% in the distal cohort (p=0.04, proximal versus distal).  There was a trend toward less overall acute GVHD (following graft infusion or following intervention for MC) in the intermediate cohort at 12%, versus 16% and 27% in the proximal and distal cohorts (p=0.55). Conclusion:  This novel 14 day RIC regimen optimizes the incidences of MC and acute GVHD.