CCL1 As a Biomarker of Engraftment Syndrome of Hematological Stem Cell Transplantation

Abstract

BACKGROUND Many complications occur in the practice of hematopoietic stem cell transplantation, especially those presenting with fever, which can be caused by infection as well as engraftment syndrome (ES), which is difficult to distinguish. The mechanism of ES is unknown, and no characteristic biomarkers have been identified. METHODS We attempted to identify cytokines specific to the engraftment syndrome by cytokine array analysis of sera from 7 patients who underwent HSCT at our institution from January 2019 to March 2022 and who developed fever between 1 week before and the day of engraftment. Cases in which pathogens were detected in blood culture at the time of fever were diagnosed as infections, and cases in which blood culture was negative or clinically treated as engraftment syndrome or fever associated with engraftment were diagnosed as engraftment syndrome. Cases that did not present with fever from infusion to engraftment were used as negative controls. RESULTS. Three of the seven patients had fever due to infection and four had fever due to engraftment syndrome. Median age was 41 (21-62) years, 5 males and 2 females. Four patients had acute leukemia, one had chronic myelomonocytic leukemia, and two had nonhematologic tumors. The donors were blood related in 3 cases, unrelated in 3 cases, and cord blood in 2 cases. Pretreatment was myeloablative (MAC) in 2 patients and reduced intensity pretreatment (RIC) in 5 patients. Cytokine arrays identified five cytokines that were elevated in the ES group. Of these, cytokine The cytokine CCL1 (I-309) tended to be elevated in the ES group (p=0.06). The validity of CCL1 with respect to the diagnosis of fever of engraftment was examined using sera from another 16 hematopoietic stem cell transplant cases performed at the same period, and the results showed that CCL1 was only mildly elevated in cases diagnosed with infection, regardless of the elevated values of fever and inflammatory response, but tended to be elevated in fever of engraftment (area under ROC curve: 0.74 (95% confidence interval 0.422-1)). CONCLUSIONS. CCL1 was identified as a cytokine specific for ES, indicating that CCL1 may be useful in differentiating ES from infection. CCL1 is mainly secreted by T lymphocytes and its oversecretion during the hematopoietic recovery process may be involved in immune activation and the engraftment syndrome.