Immune Reconstitution Following Reduced Intensity Stem Cell Transplantation for Non-Malignant Disorders in Children

Introduction: Myeloablative stem cell transplants (SCT) for nonmalignant disorders (NMD) are complicated by early and late treatment-related toxicities.  We used a novel reduced intensity conditioning (RIC) regimen with early administration of alemtuzumab to achieve donor engraftment with lower toxicities in NMD.  Delayed immune reconstitution (IR) and severe/fatal late infections have been previously described with RIC using alemtuzumab peri-SCT.  Early administration in our protocol is designed to selectively deplete host immunity with minimal effects on post-transplant IR.  We report the kinetics of IR and infection patterns in the first year post-SCT with this approach.

Methods: HSCT was performed for marrow failure, genetic diseases or immune disorders with alemtuzumab (day -22 to -19; 33 mg if < 10 kg; 48 mg if > 10 kg), fludarabine (day -8 to -4; 150 mg/m2), and melphalan (day -3; 140 mg/m2) followed by infusion of matched related (MRD) or matched unrelated (MUD) marrow/PBSC.  GVHD prophylaxis included a calcineurin inhibitor (6-9 m), short course methotrexate (days 1, 3 and 6) and short course prednisone (28 d).  Stable engraftment (> 20% donor) occurred in 89% of patients.  Lymphocyte numbers, proliferation, and immunoglobulin levels were measured at 3, 6 and 12 m.  We evaluated 35 MRD and 31 MUD recipients with immune studies collected at a minimum of two time periods after SCT and tracked cumulative incidence of bacterial, viral and fungal infections.

Results: Lymphocyte, NK, CD4 and CD8 T cell numbers and immunoglobulin levels normalized by 6 months post SCT in both groups (Table 1).  MUD SCT resulted in slower IR than MRD.  Notably, MUD recipients had lower B cells after 6 months though immunoglobulin levels were normal.  The kinetics of recovery of immune function correlated with incidence of infections, which were highest until day 100 and declined after day 180.

Conclusions: SCT following RIC with early administration of alemtuzumab resulted in successful donor marrow engraftment and rapid IR within 6 months in contrast to previous experience.  Only B cell recovery was noted to be slower in MUD compared to MRD transplants.  This RIC regimen supports early immune recovery with reduced and more localized infectious complications after the first 6 months.  These results provide a context for refining infection surveillance, antibiotic prophylaxis, revaccination and return to normal lifestyle devoid of infectious complications.