The Schedule and Dose of Alemtuzumab Determine the Incidence of Mixed Chimerism in Pediatric Patients Undergoing Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

Introduction: Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan can be associated with high incidences of mixed chimerism (MC). We have previously observed a significant effect of dose and timing of alemtuzumab on incidences of MC in patients with HLH. Here we sought to determine the effects of alemtuzumab schedule and dose on chimerism in a large cohort of patients treated with RIC. Methods: We performed 187 RIC HCT in 186 pediatric patients between 2004 and March, 2012. Fourteen patients were excluded because of regimen alterations due to illness or intolerance (n=13) or malignancy relapse (n=1). All patients received fludarabine 150mg/M2 (1mg/kg if <10kg) divided over days -8 to -4 or -7 to -3, and melphalan 140mg/M2 (4.7mg/kg if <10kg) on day -3 or -2. RIC HCT procedures were divided into 3 groups based upon the timing and dose of alemtuzumab. The distal group received alemtuzumab with a dose escalation schedule of 3mg/10mg/15mg/20mg or 3mg/10mg/10mg/10mg starting on day -23, -22, or -21. The intermediate group received 1mg/kg alemtuzumab divided over 5 days starting on day -14. The proximal group received alemtuzumab beginning on days -12, -11, -9 or -8, with either of the dosing schemas. The distal group was further subdivided based on cumulative alemtuzumab doses of greater or less than 3mg/kg (the median dose/kg). The cumulative incidences (CI) of MC were compared. Results: A 75% CI of MC was observed in the proximal group, versus 32% and 39% of patients treated with the intermediate and distal schemas (p<0.0001). Within the distal group, the CI of MC was 67% in patients who received >3mg/kg and 28% in patients who received <3mg/kg (p=0.008). Conclusion: Proximal dosing of alemtuzumab with relation to graft infusion and higher doses of alemtuzumab significantly increase the incidence of mixed chimerism.