Neutrophil Engraftment Timing after Single-Unit Cord Blood Transplantation as a Prognostic Marker of Transplant Outcomes Influenced by GVHD Prophylaxis: A nationwide, retrospective study by the Japanese Society for Transplantation and Cellular Therapy.

Background

Delayed neutrophil recovery after cord blood transplantation (CBT) has been established as an adverse prognostic factor; however, the prognostic impact of early neutrophil engraftment remains unclear.

Objective

To investigate the association between neutrophil engraftment (NE) timing and transplant outcomes after single-unit CBT. STUDY

Design

Using the Japanese nationwide transplant registry, we investigated the association between NE timing and transplant outcomes in 9,049 adult patients undergoing single-unit CBT without anti-thymocyte globulin. The association between NE timing and overall survival (OS) was evaluated using a time-dependent Cox model with restricted cubic splines, followed by analyses of transplant outcomes across NE timing groups defined based on the observed spline association.

Results

NE timing showed a U-shaped, nonlinear association with mortality, with the lowest estimated hazard at approximately day 18. In univariate analyses, intermediate NE (days 15-23) was associated with the most favorable OS, whereas early NE (≤14 days) was associated with inferior OS, higher non-relapse mortality (NRM), and an increased incidence of grade III-IV acute graft-versus-host disease (GVHD). Delayed NE (≥24 days) was associated with inferior OS, increased NRM, and infectious complications. In day-35 landmark analyses, delayed NE remained associated with increased infectious complications after neutrophil recovery, and the overall patterns of OS and NRM were preserved. NE timing correlated with subsequent platelet and erythroid engraftment, suggesting that delayed NE may reflect impaired recovery of other hematopoietic lineages, including lymphocytes, contributing to post-engraftment complications. In multivariable analyses, delayed NE remained independently associated with inferior OS and higher NRM, whereas early NE was not independently associated with these outcomes in the overall cohort. Importantly, excess mortality associated with early NE was not observed in the mycophenolate mofetil-based prophylaxis subgroup, whereas early NE remained independently associated with inferior OS and higher NRM in the methotrexate-based prophylaxis subgroup. These findings suggest that the prognostic significance of early NE may differ according to GVHD prophylaxis.

Conclusions

These results suggest that NE timing after CBT has an optimal range, with both early and delayed engraftment associated with distinct adverse outcomes, supporting its utility as a simple marker for risk stratification after CBT.