Prognostic Value of IL-7 and SCF Levels on Thymic Reconstitution and Clinical Outcomes after Double Umbilical Cord Transplantation in Adults

Umbilical cord blood transplantation (UCBT) is characterized by delayed immune reconstitution even with the use of double unit UCBT (dUCBT).  Previously we reported that reconstitution of thymopoiesis, as determined by assessment of T-cell receptor excision circles (TRECs), plays a critical role in the clearance of CMV viremia and is associated with improved overall survival in dUCBT recipients. We also determined that recovery of specific T-cell subsets after dUCBT correlates with serum levels of Interleukin 7 (IL-7) and Stem Cell Factor (SCF). Here we investigated whether thymic reconstitution depends on IL-7 and SCF and examined the prognostic role of TRECs, IL-7 and SCF levels in clinical outcomes after dUCBT. Fifty-two patients with hematologic malignancies received dUCBT following either reduced-intensity (fludarabine, melphalan and antithymocyte globulin) or myeloablative conditioning ((fludarabine, cyclophosphamide and TBI). GvHD prophylaxis was tacrolimus in combination with sirolimus or mycophenolate mofetil. The incidence rates of grade II-IV acute GvHD and chronic GvHD were 15.4% and 29% respectively. The 5-year cumulative incidence of relapse, non-relapse mortality (NRM), progression-free survival (PFS) and overall survival (OS) were 43%, 31%, 26%, and 41% respectively. During the first 3 months after dUCBT, TRECs remained undetectable or extremely low but, at 6 months, 69.7% of patients had detectable levels. At one year, TRECs were detectable in 86.6% of patients with a median value of 2404 copies/ug DNA. Serum levels of IL-7 increased 3-fold from baseline by 1 month after dUCBT, remained elevated through the first 3 months, and gradually declined to pre-transplant levels by 1 year. SCF levels peaked at 2 months after dUCBT and gradually declined thereafter. We observed a statistically significant inverse correlation between TRECs and IL-7 (p=0.036) or SCF (p<0.02) serum levels at various time points after dUCBT, suggesting that uptake of these two cytokines by thymocytes may lead to their differentiation into TREC-containing Recent Thymic Emigrants (RTE). In multivariable analysis, higher TREC levels independently correlated with improved OS (p=0.02) and lower NRM (p=0.008). Conversely, higher levels of SCF and IL-7 correlated with lower OS (p=0.005 and p<0.0001). Furthermore, SCF level predicted NRM (p=0.003), whereas serum IL-7 level independently predicted cGvHD (p=0.03). Taken together, our findings suggest that high IL-7 and SCF serum levels are associated with delayed thymic reconstitution and may predict adverse outcomes after dUCBT, including cGvHD, NRM and OS.