Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis

Abstract

The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

Figure 1

Cumulative Incidence of Neutrophil and Platelet Engraftment.

Figure 2

Cumulative Incidence of Treatment-Related Mortality and Relapse.

Figure 3

Kaplan-Meier Estimates of Progression-Free and Overall Survival

Figure 4

a–e. Immunologic Reconstitution After Transplantation a) Lymphocyte Subsets b) CD4⁺ Lymphocyte Subsets c) CD8⁺ Lymphocyte Subsets d) B lymphocyte and NK Subsets d) Monocyte Subsets. Median values are plotted on a log10 scale and zero values are set equal to one. Error bars extend to the 25^th and 75^th percentiles.