Risk Factors for and Impact of Pre‐Engraftment Syndrome on Outcomes Following Single‐Unit Cord Blood Transplantation in Adults

ABSTRACT Pre‐engraftment syndrome (PES) is a unique complication of cord blood transplantation (CBT) whose risk factors and impact on transplant outcomes remain controversial. Using a nationwide database in Japan, we analyzed a total of 3734 patients who underwent single‐unit CBT. PES occurred in 18.3% of patients, and risk factors for PES included a higher hematopoietic cell transplantation‐specific comorbidity index, first transplantation, myeloablative conditioning (MAC), lower total nucleated cell (TNC) dose, and graft‐versus‐host disease (GVHD) prophylaxis regimens excluding tacrolimus with methotrexate. Patients who developed PES had significantly higher incidences of grade II–IV acute GVHD (53.1% vs. 31.3%, p < 0.001) and chronic GVHD (27.2% vs. 21.7%, p = 0.002) compared to those without PES. Landmark analysis with multivariable adjustment revealed that PES was independently associated with increased non‐relapse mortality (NRM, hazard ratio [HR] 1.46; 95% CI 1.22–1.75; p < 0.001), reduced relapse incidence (HR 0.78; 95% CI 0.63–0.96; p = 0.020), and a trend toward inferior overall survival (OS, HR 1.13; 95% CI 0.98–1.30; p = 0.088). Moreover, patients who experienced both PES and acute GVHD had the highest 2‐year NRM (31.7%; 95% CI 26.0%–37.6%) and the lowest 2‐year OS (55.9%; 95% CI 50.0%–62.4%), compared with those who experienced either PES (NRM 20.7%; OS 65.0%) or acute GVHD (NRM 19.5%; OS 62.8%) ( p < 0.001), highlighting the combined effects of these complications. This study, the largest to date on PES, demonstrates its clinical significance as an early complication with lasting effects on transplant outcomes.