Mixed Chimerism and Graft Loss in Pediatric Recipients of an Alemtuzumab-Based Reduced-Intensity Conditioning Regimen for Nonmalignant Disease

Reduced-intensity conditioning (RIC) regimens are increasingly used to reduce transplant-related mortality (TRM) for pediatric patients (pts) undergoing hematopoietic cell transplantation (HCT) for nonmalignant diseases.  However, these pts are at increased risk for post-transplant mixed donor/recipient chimerism (MC) and/or primary and secondary graft failure (GF).  Intervention with donor lymphocytes (DLI) or second transplants may be necessary, but there is limited information about timing and results of intervention.  We retrospectively evaluated 31 consecutive pediatric recipients of an alemtuzumab-based RIC HCT at the Children’s Hospital of Philadelphia from May 2007 to December 2012 to determine the incidence of MC and GF, and timing of interventions.  All pts received alemtuzumab (Campath) with either fludarabine (150mg/m²)/melphalan (140 mg/m²) (n=30) or fludarabine/busulfan (n=1).  The timing of Campath differed according to disease.  Pts with hematologic disorders and IPEX received Campath beginning day -21 or -22.  Pts with hemophagocytic lymphohistiocytosis (HLH) received proximal (N=8) or intermediate (n=2 ) Campath starting at day -9 or -13, respectively.  Diagnoses included HLH in 10 pts, hemoglobinopathy in 8 pts, primary immunodeficiency in 8 pts, and bone marrow failure in 5 pts.  All grafts were unmanipulated bone marrow from matched sibling donors (45%), matched unrelated donors (52%) or mismatched related donor (3%).  Donor chimerism was evaluated using polymerase chain reaction of microsatellite markers/short tandem repeats at regular intervals post-transplant.  Four pts died of TRM (n=3) or early disease progression (n=1) and were not included in the analysis.  Of the 27 surviving pts, 18 (66.7%) displayed MC (donor chimerism <100%) on at least one occasion, with 12 (44.4%) reaching a nadir MC level <80%.  Two pts with MC≥80% experienced recurrent disease, one with HLH and one with auto-immune syndrome.  Of the 12 pts with nadir MC<80%, 6 received DLI with 2 subsequent GFs.  Of the remaining 6 pts who did not receive DLI, there were also 2 GFs.  The overall incidence of GF/recurrence was 22.2% (6/27). Within the HLH group 7/7 surviving pts developed MC, with 5 (71.4%) reaching a nadir <80%.  Despite DLI/boost in all 5 of these pts, 2 progressed to GF.  The incidence of GF/recurrence in the surviving HLH pts was 42.9% (3/7)  By contrast, in the non-HLH pts, only 11 of 20 (55.0%) surviving pts developed MC with 7 (35.0%) reaching a nadir<80%.  Of these 7 with MC<80%, 2 progressed to GF for an overall incidence of GF/recurrence of disease of 15% (3/20).  In summary, we observed a high incidence of MC and GF in recipients of Campath-based RIC, particularly in HLH pts.  The role for DLI/boost in preventing GF in pts receiving RIC HCT for non-malignant disease who experience low/falling MC requires further study.