Pre-Engraftment Syndrome (PES) Is Frequent in Double Unit Cord Blood Transplantation (dCBT) Recipients and Is Potentiated By the Addition of Haplo-Identical CD34+ Cells

Abstract

Introduction PES is common after dCBT. Manifestations have been described but severity & risk factors are not fully established. Methods We analyzed the incidence, manifestations, severity & risk factors of PES in adult dCBT recipients transplanted 8/2012-12/2017 for hematologic malignancies/ severe aplastic anemia with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. Standard PES therapy was IV methylprednisolone (IV MP) 1 mg/kg/day x 3 days. Results 133 1st allograft dCBT recipients (median 49 years, range 21-65) were analyzed. Patients (pts) most commonly had acute leukemia (n = 98, 74%). The median TNC cell doses were 2.4 × 107/kg/unit (range 1.2-6.0). The median unit-recipient HLA-match was 5/8 (range 3-7); the median unit-unit HLA-match was 4/8 (range 0-8). 71 (53%) pts also received haploidentical CD34+ cells. 96% of pts engrafted with CB. Overall, 98 pts developed non-infectious sustained fevers ≥ 38.5°C consistent with PES for a cumulative incidence of 74% (95%CI: 65-80) by 21 days post-dCBT (Table). The median onset was 10 days (range 6-21) post-dCBT with a median temperature at onset of 38.9°C degrees (range 38-39.8). Nearly all (94, 95%) of PES pts required IV MP therapy. PES associated rash within the 1st 72 hrs only occurred in a minority of pts (incidence 24%; 95%CI: 17-32). Weight gain > 5% from the baseline 24 hrs prior to PES onset (incidence 18%; 95%CI: 12-25) was correlated with the development of hypoxia requiring oxygen (incidence 20%; 95%CI: 14-28). Incidence of PES associated renal impairment (gr 2-3 AKI) was low overall at 2% (95%CI: 0-8). No pt had hypotension. Concurrent bacteremias were treated in 2 pts but clinical manifestations/ therapy response was consistent with PES. Median time to MP therapy was 1 day (range 0-12). Therapy response was rapid (median 1 day, range 1-9). The median MP duration was 3 days (range 3-14). 7/94 (7%) PES pts [7/133, 5% of entire cohort) required ICU care; this correlated with delayed therapy [median MP start 4 days (range 0-5)]. 30 (32%) pts required a 2nd MP course. Addition of haploidentical cells was associated with a higher PES incidence & severity as measured by weight gain & hypoxia (Table). There was no association with age, disease (acute leukemia vs other), dominant unit-recipient or unit-unit HLA-match or total TNC infused dose (split at median). Conclusions PES is common after dCBT. It should be promptly treated with IV MP without waiting for results of infectious work-up as delay can be associated with severe capillary leak syndrome & multi-organ failure. The worse manifestations in haplo-dCBT recipients supports PES being mediated by GVG/ GVH reactions & an associated cytokine storm. This is highly relevant to CBT platforms that involve infusion of multiple donors including 3rd-party products. We are now investigating day -1 tocilizumab 8 mg/kg in dCBT recipients with the aim to abrogate PES & acute GVHD (Politikos et al, ASBMT 2019).