Immune Reconstitution and Infection Patterns after Early Alemtuzumab and Reduced Intensity Transplantation for Nonmalignant Disorders in Pediatric Patients

Abstract Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution following immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease (GVHD) prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days -21 to -19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at three time-points (100 days, 6 months and 1-year post-HSCT). NK cell recovery was rapid and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months following RD HSCT and by 1-year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1-year respectively post-HSCT compared to patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 following RD HSCT but took 1-year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups presumably due to comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than prior reports utilizing reduced intensity conditioning with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100 days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort with “early” alemtuzumab compared to regimens administering serotherapy in the peri-transplant period. Patients were susceptible to bacterial infections primarily in the first 100 days irrespective of donor source, and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1-year. Close monitoring and prophylaxis against bacterial infections in the first 100-days post-HSCT is necessary, but is followed by robust immune reconstitution, especially in the T-cell compartment.