Early Immune Reactions Following Reduced-Intensity Cord Blood Transplantation.
Authors: Kishi Yukiko , Kami Masahiro , Miyakoshi Shigesaburo , Matsumura Tomoko , Taniguchi Shuichi 
Published: October 2019

Background : We have demonstrated the feasibility of reduced-intensity cord blood transplantation (RI-CBT) in adult patients(Miyakoshi et al, Clin Cancer Res, 2004), and have shown the presence of preengraftment immune reactions following RI-CBT.

Methods : We retrospectively investigated clinical features of immune reactions in 57 adult RI-CBT recipients. The preparative regimen comprised fludarabine, melphalan (n=51) or busulfan (n=6), and 4 Gy TBI. GVHD prophylaxis was cyclosporin. When patients with no evidence of infection or adverse effects of medication exhibited features such as fever >38°C, skin eruption, diarrhea, jaundice, or body weight gain >10% of baselines, these findings were defined as immune reactions. Reactions were classified into the following subtypes: those which developed 6 or more days before engraftment were defined as preengraftment immune reactions (PIR), those within 5 days of engraftment were defined as engraftment syndrome (ES), and the others were defined as postengraftment syndrome, which generally corresponded to acute GVHD.

Results : Forty five patients achieved engraftment, on a median day of day 19. Twelve patients who developed documented infection were excluded from the analysis of PIR, 42 of the remaining 45 patients developed PIR on a median of day 9 (range, 5–13), including 6 patients who had never engrafted. Body weight gain, high-grade fevers, and elevated CRP levels were more frequent in PIR than in ES and GVHD. Jaundice was infrequent in PIR (Table). ES developed in 41 of the evaluable 44 patients. Five patients with ES developed central nervous system complication. Twenty-nine of the evaluable 44 patients developed acute GVHD: grade I (n=1), II (n=7), III (n=15), and IV (n=6). Cumulative incidences of relapse and non-relapse mortality (NRM) at day 180 were 15% and 62%, respectively. Relapse-related mortalities were 11% and 0% in patients with and without PIR, respectively (p=0.17). NRM were 77% and 52%, in patients with and without PIR, respectively (p=0.07). Since development of ES was associated with PIR, they could not be separated from each other in evaluation of their effect on relapse and NRM. Development of GVHD was not a significant prognostic factor for relapse or NRM, when PIR was treated as a time-dependent covariate.

Discussion : Three immune reactions occur after RI-CBT. PIR is a novel finding in RI-CBT. It develops even in patients who have never engrafted. When compared to ES and GVHD, the higher levels of CRP and fever in PIR suggest that the inflammation in PIR is intense. Further studies are required to clarify its pathogenesis and prognostic values in RI-CBT.

Clinical characteristics of immune responses following reduced-intensity cord-blood transplantation

Type of immune responses PIR ES GVHD Abbreviations: PIR; preengraftment immune reactions, ES; engraftment syndrome, GVHD; graft-versus-host disease, CR; complete response, PR; partial response, MR; minimal response, NC; nochange Number of patients with immune responses/numer of evaluable patients 42/45 41/44 29/44 Elevation of body temperature ≥38 degree 40 24 34 Skin rash 16 15 21 Diarrhea 19 20 22 T-Bil ≥2.0 mg/dL 10 21 25 Body weight gain >10% of baseline 14 3 5 Central nervous system complications 0 5 0 Serum levels of C-reactive protein (mg/dL) (median, range) 14.1 (0.3–25.6) 4.8 (0.2–23) 7.2 (0.4–46.8) Use of corticosteroid 25 28 25 Response to cortisosteroid (CR/PR/MR/NC) 15/5/1/4 7/3/1/17 15/7/1/2