Engraftment Syndrome (ES) After Reduced-Intensity Stem Cell Transplantation (RIST): ES May Have a Negative Impact on Survival In Standard-Risk Patients
Authors: Maeda Takeshi , Yakushijin Kimikazu , Asakura Yoshitaka , Hiramoto Nobuhiro , Kurosawa Saiko , Kamiyama Yutaro , Fukuhara Suguru , Ueno Niina , Kim Sung-Won , Mori Shin-Ichiro , Tanosaki Ryuji , Heike Yuji , Tobinai Kensei , Takaue Yoichi , Fukuda Takahiro 
Published: October 2019

Abstract
Abstract 2318

Introduction:
ES has been well recognized to increase non-relapse mortality (NRM) in autologous hematopoietic cell transplantation (HCT). However, little information is available on ES in allogeneic HCT, particularly after reduced-intensity conditioning. To determine the incidence, risk factors and outcome of ES after RIST, we retrospectively reviewed the medical records of 285 patients (pts) who underwent RIST at our institution between 1999 and 2007.

Patients and Methods:
After excluding 37 pts who received cord blood transplantation or a second or subsequent allogeneic HCT, and those who experienced primary graft failure, 248 pts (male 153, female 95) with a median age of 55 y (range, 21–68) fulfilled the criteria of this study. The underlying diagnosis included lymphoma (106 pts; 43%), acute myeloid leukemia (59; 24%), myelodysplastic syndrome (51; 21%), and others (32; 13%). Ninety-two pts (37%) had a standard-risk disease such as acute leukemia or lymphoma in CR1, and 156 (63%) had a high-risk disease. The donor and stem cell source were related PBSC in 170 pts (69%), related BM in 8 (3%), and unrelated BM in 70 (28%). All of the pts received reduced-intensity conditioning with a purine analog and a busulfan-based regimen. With the use of G-CSF after HCT, neutrophil engraftment (ANC ≥500/μ l) was achieved at a median of 12 days (range, 5–28). ES was diagnosed when the patient showed at least 2 of the following symptoms within 96 h of neutrophil engraftment: (1) fever (>38.0°C) without an identifiable source of infection, (2) skin rash (>25% of body surface area) that was not due to a drug reaction, (3) weight gain (>2.5% of baseline body weight), and (4) hypoxia (sPO2 <94%) or pulmonary infiltrates.

Results:
Among the 248 pts, 45 (18%) developed ES at a median of 14 days (6-23) after allogeneic HCT. Symptoms consisted of fever (100%), skin rash (53%), weight gain (62%) and hypoxia (33%). The incidence of ES in recipients of unrelated donor grafts was significantly higher than that in recipients of related donor grafts (28% vs 14%, p=0.02), and male pts had a significantly higher incidence of ES than female pts (22% vs 12%, p=0.04). No significant difference in the incidence of ES was observed between groups stratified according to age, stem cell source, TNC or CD34+ cell dose, disease risk, GVHD prophylaxis, and the timing of engraftment. By a multivariate analysis, use of an unrelated donor (HR 2.3, 95%CI 1.3–4.1, p=0.007), pts with lymphoid malignancy (HR 2.0, 95%CI 1.1–3.7, p=0.03) and male pts (HR 2.0, 95%CI 1.0–4.0, p=0.04) were associated with a significantly increased risk of ES. Among the 40 pts who required systemic corticosteroid therapy, 31 (78%) achieved a complete response, and the remaining 9 (23%) responded partially. There was a trend toward a higher incidence of grade III-IV acute GVHD (27% vs 18%, p=0.10) in pts with ES, and the incidence of extensive chronic GVHD (69% vs 62%, p=0.04) was significantly higher in pts with ES. Overall survival (OS) and non-relapse mortality (NRM) were not significantly different between the two groups, after a median follow-up of 53 months (range, 2–108) in surviving patents. A multivariate analysis showed that pts with high-risk disease (NRM, HR 1.9, 95%CI 1.1–3.3, p=0.01; OS, HR 2.5, 95%CI 1.6–3.8, p<0.001) and those with myeloid malignancy (NRM, HR 2.0, 95%CI 1.2–3.4, p=0.01; OS, HR 1.5, 95%CI 1.0–2.2, p=0.03) were associated with an increased risk of NRM and worse OS after allogeneic HCT, whereas the development of ES did not affect NRM or OS. In a subgroup analysis of 92 pts with standard-risk disease, pts with ES had a significantly worse OS (50% vs 76% at 3 y, p=0.03, Figure, left panel) and a higher NRM (49% vs 20% at 3 y, p=0.03) compared to those without ES. In a subgroup analysis of 156 pts with high-risk disease, however, OS (42% vs 46% at 3 y, p=0.76, Figure, right panel) and NRM (48% vs 39% at 3 y, p=0.84) of pts with ES were equivalent to those of pts without ES.

Conclusions:
ES is a rather common complication after RIST, especially in recipients of unrelated donor grafts. Although ES shows an initial good response to corticosteroid therapy, ES may have a negative impact on survival, especially in pts with standard-risk disease, and this effect may be related to the occurrence of GVHD. The development of an optimal treatment for ES may improve the outcome of pts who have received RIST by reducing GVHD-related mortality.

Disclosures:
No relevant conflicts of interest to declare.