Immune Reconstitution After Double Umbilical Cord Blood Transplantation in Adults without In Vivo T Cell Depletion of the Graft.

Abstract 1246

Infusion of two partially matched units can overcome the barrier of cell dose in umbilical cord blood transplantation (UCBT). Besides engraftment, restoration of adaptive immunity remains a major problem resulting in higher transplant-related mortality in UCBT compared to marrow or peripheral blood transplantation. According to reported data, prolonged immunodeficiency in adult recipients of single-unit UCBT is characterized by long-term impairment of thymopoiesis, whereas the impact of double UCBT on immune reconstitution has not been elucidated. We prospectively monitored cellular and humoral immunity in consecutive adult recipients of double UCBT to assess the time frame and pattern of immune reconstitution. From 08/2006 until 07/2010, 27 patients underwent double UCBT at our center. Twenty-two, who fulfilled defined criteria [conditioning without antithymocyte globulin (ATG), sustained donor engraftment, no relapse before day 100], were included in study analysis. Patients received double UCBT for high-risk acute leukemia or lymphoma (AML: 15, ALL: 5, type 2 dendritic cell leukemia: 1, hepatosplenic γδ T-cell lymphoma: 1), at a median age of 37 years (range, 16–59). The conditioning regimen was ablative in 16, and reduced-intensity in 6 cases. The combination of mycophenolate mofetil to calcineurin inhibitor (cyclosporine: 18, or FK506: 4) was used for prevention of acute graft-versus-host disease (GvHD). The majority of units (36/44) were 4/6 matched to recipient at HLA-A, -B, and -DRB1 loci, the remaining being 5/6 matched. Median total nucleated and CD34+ cell doses from both units were 4.36 × 10^7/kg (range, 2.65–6.86) and 1.56 × 10^5/kg (range, 0.6–5.13) at infusion, respectively. Intravenous immune globulin (IVIG) was routinely administered every 2–4 weeks during the first 6 months from transplant. Absolute counts of B, NK, and T lymphocytes as well as serum immunoglobulin levels (prior to infusion of IVIG), were routinely assessed at 1, 2, 3, 6, 9, 12, 15, 18, 24 months, and annually thereafter. Neutrophil engraftment (absolute count >500/μl) was achieved at a median of 19 days (range, 6–52). Twenty patients developed acute GvHD (grade II: 17, grade III-IV: 3). Chronic GvHD occurred in 4 patients, and was extensive in 2. Cytomegalovirus (CMV) infection was detected in 6 out of 16 seropositive recipients (at a median of 58, range 25–116, days after UCBT), and in none of the 6 seronegative. In addition, 5 patients developed HHV-6 infection, and 1 EBV-related lymphoproliferation. Relapse occurred in 4 patients. There were 5 deaths of infection, 3 of GvHD, and 2 of other causes. The absolute counts of T and B cells were extremely low early post transplant, while NK cells recovered from the first month and reached normal values by the second month (median count, 147/μl). The number of CD8+ T cells started to increase from the third month, and exceeded lower normal limit after 6 months (median count, 234/μl). CD4+ T cells remained substantially low (<100/μl) for the first 3 months, increased moderately afterwards, but achieved normal values only at 18 months (median count, 465/μl). CD4+/CD45RA+ naïve T cells were significantly impaired over the first year, but appeared at increasing counts at 18 months (median count, 157/μl) and beyond. CD19+ B cells were severely suppressed for the entire first semester (median count at 3 months, 5/μl), increased to moderate normal counts by 9 months, and showed a marked elevation exceeding normal range between 12 (median count, 985/μl) and 18 months (median count, 1501/μl). Notably, that was consistent with delayed achievement of normal serum IgG levels at 15 months (median, 1130 mg/dl) and normal IgA levels at 24 months (median, 133.5 mg/dl). Our results differ from previously reported data regarding immune reconstitution post UCBT, mainly due to the absence of in vivo T cell depletion in our series. By elimination of ATG from conditioning, we did not observe rapid recovery of B cells in the early post-transplant period. Moreover, B cells remained severely depressed for 6 months, a finding that may be accounted for by the increased incidence of acute GvHD in our series. On the other hand, T cell reconstitution was relatively faster, and a stable rise of naïve CD4+ T cells suggestive of thymopoietic recovery was noted after the first year from transplant. In conclusion, immune reconstitution patterns following UCBT may be divergent depending on the conditioning regimen.