Engraftment Syndrome after Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Graft-Versus-Host Disease Prophylaxis and T Cell Dose.

Engraftment syndrome (ES), defined as noninfectious fever, rash, and noncardiogenic pulmonary edema occurring at the time of hematopoietic recovery after stem cell transplantation, may cause significant morbidity in the peri-transplant period. However, its association with GVHD is unclear, and it remains controversial whether T-cell alloreactivity, nonspecific neutrophil activation, or other factors contribute to the pathogenesis of this syndrome. To study this question, we retrospectively analyzed patients enrolled in 3 separate protocols of reduced-intensity allogeneic hematopoietic stem cell transplantation (RIST). Group A included patients with relapsed/refractory hematologic malignancies undergoing RIST with T-cell replete allografts and cyclosporine for GVHD prophylaxis (n=49). Group B consisted of patients with hematologic malignancies receiving T-cell replete allografts and cyclosporine/methotrexate for GVHD prophylaxis (n=20). Group C included patients with metastatic breast cancer undergoing RIST with T-cell depleted allografts (1 x 10⁵ CD3⁺ cells/kg) and cyclosporine for GVHD prophylaxis (n=17). All patients received an identical reduced-intensity conditioning regimen with fludarabine and cyclophosphamide, followed by infusion of filgrastim-mobilized peripheral blood stem cells and post-transplantation filgrastim until neutrophil recovery. The incidences of ES and acute GVHD varied according to treatment group (ES: chi-squared test, p=0.066; acute GVHD: chi-squared test, p=NS):

Incidence of Engraftment Syndrome and Acute GVHD by Treatment Group

Logistic regression analysis identified hypoxemia requiring oxygen (OR 38.46, 95% CI 6.51 to 227.1; p=0.002), fever greater than 37 degrees C (OR 6.97, 95% CI 2.47 to 19.7; p<0.0001), and the maximum neutrophil count after engraftment (OR 1.07, 95% CI 1.02 to 1.125; p=0.0093) as factors strongly associated with steroid administration for ES. Subjects with acute GVHD displayed a modest trend toward increased frequency of ES (exact Cochran-Armitage trend test, p=0.103). The association of the intensity of GVHD prophylaxis and the maximum neutrophil count with the incidence of ES implies that both alloreactive T cells and donor granulocytes may play a role in the development of this complication after RIST. These results suggest that additional studies are warranted to explore the contribution of alloreactivity to the pathogenesis, prevention, and treatment of ES.