Redefining Engraftment Syndrome After Post-Transplant Cyclophosphamide Allogeneic Hematopoietic Cell Transplantation: A Novel Classification and Impact on Outcomes

Abstract

Engraftment syndrome (ES) is a non-infectious febrile complication of hematopoietic cell transplantation (HCT), with diagnostic challenges, particularly in the allogeneic setting. The increasing use of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease prophylaxis highlights the need for a re-examination of ES in this contemporary context. To evaluate the incidence and clinical presentation of ES, as well as its impact on transplant outcomes in the era of PTCy-based prophylaxis. We retrospectively analyzed 552 allogeneic HCT patients receiving PTCy, sirolimus, and mycophenolate mofetil across various donor types. To improve ES diagnosis in this setting, we proposed new criteria in which peri-engraftment fevers (PEFs) (d -4 to d +3 before and after myeloid engraftment) were classified as follows: definite ES (PEF meeting Spitzer, Maiolino, or Grant criteria); probable ES (PEF plus ≥1 additional ES sign); and possible ES (PEF without additional signs). Among the 80 patients (14.5%) who developed PEF, 24 (30%) fulfilled criteria for definite ES, 14 (17.5%) for probable ES, and 42 (52.5%) for possible ES. The 30-d cumulative incidence of overall ES was 15% (95% confidence interval [CI], 12 to 18), comprising 4.4% (95% CI, 2.9 to 6.4) for definite ES, 2.6% (95% CI, 1.5 to 4.2) for probable ES, and 7.8% (95% CI, 5.7 to 10) for possible ES. In addition to fever, the most frequently observed ES-related symptoms included diarrhea (n = 18), weight gain (n = 14), skin rash (n = 11), hepatic dysfunction (n = 8), and pulmonary infiltrates (n = 7). Risk factors associated with the development of ES were younger age (defined as <40 yr), underlying lymphoproliferative neoplasms, haploidentical donor transplantation, and a history of prior cytokine release syndrome. Importantly, ES resolved within 48 h in 75 of the 80 cases (94%), and no deaths were attributed to PEF or ES episodes. Interestingly, the presence of ES was significantly associated with improved overall survival and event-free survival, potentially reflecting a composite effect of trends toward lower relapse rates and reduced non-relapse mortality in affected patients. ES in PTCy-based allogeneic HCT is frequent but rarely meets traditional criteria, highlighting the potential value of a refined three-category classification. Our findings suggest an unexpected survival benefit, possibly linked to the immunomodulatory effects of PTCy, and underscore the need for further studies to validate this classification and investigate the underlying biological mechanisms.

Keywords: Allogeneic HCT; Engraftment syndrome; PTCy; Transplant outcomes.