Engraftment Syndrome After Allogeneic Hematopoietic Cell Transplantation: Relationship to Acute Gvhd and Impact on Transplant Outcomes

The clinical significance of engraftment syndrome (ES) after allogeneic hematopoietic cell transplantation (HCT) is controversial. In order to validate the criteria for ES as described by Spitzer (Bone Marrow Transplant 2001; 27 :893) and to analyze the relationship of ES to acute GVHD (aGVHD), we performed a retrospective review of the incidence of and risk factors for ES and the impact of ES on transplant outcomes in 250 consecutive allogeneic HCT recipients at the MGH between 2000 and 2010.

After excluding 28 patients with primary graft failure, missing date of engraftment, second or subsequent transplant and syngeneic transplant, 222 patients (128 males, 94 females) with a median age of 53 (range 19–76) yrs were selected for analysis. Underlying diagnoses were AML (32%), NHL/HD (28.8%), MDS (14%) and other (25.2%). 79 patients (35.6%) were in CR, 35 (15.8%) in PR, 65 (29.3%) had refractory disease at the time of transplant, while 43 (19.4%) had either relapsed or progressive disease. Conditioning included either myeloablative (38.3%) or non myeloablative (61.7%) regimens. Donor source was related in 171 (77%) patients (MRD 64.4% vs haploidentical 12.6 %) and unrelated in 51 (23%) patients (MUD 17.6% vs cord blood 5.4%). 71.2% received cyclosporine (CYA) based aGVHD prophylaxis, while 28.8% received non-CYA based prophylaxis. Median time to engraftment was 14 (range 6–65) days.

48 of 222 patients (21.6%) met the criteria for ES. Clinical criteria included fever (97.9%), rash (81.3%), weight gain (72.9 %), pulmonary infiltrates (52.1%), elevated creatinine (27.1%), elevated bilirubin (20.8%), transaminitis (20.8 %), and transient encephalopathy (10.4 %). All criteria occurred significantly more commonly in the ES group (p<0.0001 for all except transient encephalopathy, p=0.04). 33 patients (68.8%) with ES received corticosteroids, while 15 patients (31.2%) received only supportive care. 20 (60.6%) of those who received steroids achieved complete resolution of their ES while 11 (33.3%) achieved partial resolution. 2 patients did not respond. With supportive care only, 11 patients (73.3%) achieved complete resolution, while 4 (26.7%) had partial resolution. Using univariable logistic regression analysis, the incidence of ES was not statistically different between the groups according to age, sex, diagnosis, status of the disease at the time of transplant, type of conditioning regimen or the donor type. CYA based aGVHD prophylaxis was associated with a significantly greater risk of developing ES (OR 3.5, 95%CI 1.41–8.71, p=0.007), while transplants after 2006 were associated with a lower risk of ES (OR 0.31, 95%CI 0.16–0.61, p=0.0007). These results are consistent in multivariable analysis: CYA use was associated with a higher risk of developing ES (OR 6.4, 95%CI 1.19–34.4, p=0.03), and transplants after 2006 with a lower risk (OR=0.33, 95% CI 0.14–0.75, p=0.009).16 patients with ES (33.3%) developed early aGVHD within 4 weeks of engraftment vs none who did not develop ES (p <0.0001). The overall rates of aGVHD (47.9% for ES vs 39.1% for non ES, p= 0.32) and of grade 2–4 aGVHD (29.2% vs 23.6%) were not significantly different between the two groups. The incidence of chronic GVHD was also not significantly different between the two groups (42% vs 35%, p=0.24). Although the overall (OS) and progression-free survival (PFS) were shorter in the ES group, the difference was not significant: 2-yr OS and PFS were 45% vs 60% (p=0.1), 33% vs 39% (p=0.09), respectively; HR 1.51 (95%CI 0.97–2.37, p=0.07) for OS, HR 1.44 (95%CI 0.97–2.13, p=0.07) for PFS in multivariable Cox regression analysis.

The originally reported clinical criteria that were used to establish a diagnosis of ES (21.6% of patients in this series), were validated in this retrospective analysis of a large cohort of allogeneic HCT recipients receiving diverse conditioning regimens and sources of stem cells. Although predictive for early aGVHD, ES occurred independently of GVHD in more than half of the patients. The reason for the higher incidence of ES in CYA treated patients and patients transplanted before 2006 is unclear and warrants further investigation. A suggestion of inferior OS and PFS in patients who developed ES, apparently independent of GVHD, supports the need to explore early therapeutic intervention to prevent or treat ES.

No relevant conflicts of interest to declare.