Investigating the Relationship between Cytokine Release Syndrome, Graft-Versus-Host Disease, and One-Year Mortality after Haploidentical Hematopoietic Stem Cell Transplantation

Abstract

Haploidentical hematopoietic cell transplantation (haplo-HCT) has become an increasingly popular alternative to traditional HLA-matched hematopoietic cell transplant more recently. Cytokine release syndrome (CRS) is an observed phenomenon that occurs as a consequence of haplo-HCT with recent data suggesting a relationship between the severity of CRS and worse clinical outcomes. As the use of haplo-HCT is increasing, the importance of studying the impact of CRS on overall survival continues to grow. We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 21) who received haplo-HCT from 2014 to 2017 and identified those who developed CRS after infusion of stem cells until D+14. Patients found to have confirmed sources of infection were not considered to have CRS. Grading of CRS severity was performed using the proposed system by Lee et al. One-year mortality and incidence of both acute and chronic graft-versus-host disease (GVHD) were also assessed. Those who died more than one year after haplo-HCT were excluded as they likely decompensated from unrelated causes. A total of 37 adult haplo-HCT recipients were reviewed. Approximately 57% (n = 21) were male and 43% (n = 16) were female. The age range was between 21-71 years (mean = 43, median = 45), and the most common underlying hematologic disorders included ALL (37.8%), AML (32.4%), and aplastic anemia (10.8%). Of the 37 haplo-HCT recipients, 48.6% (n = 18) of patients were noted to have developed CRS with 72.2% (n = 13) of these patients developing Grade 1 symptoms. One patient developed Grade 4 CRS symptoms and died within 30 days of transplant. Among those that developed CRS symptoms, 33% (n = 6) developed acute GVHD and 27.7% (n= 5) developed chronic GVHD while 63% (n = 12) of patients not diagnosed with CRS developed GVHD. The primary end-point was the incidence of GVHD in those who developed CRS symptoms between D0 and D14 of stem cell infusion. Secondary end-points included one-year mortality based on the severity of CRS and one-year mortality in those that developed CRS symptoms at D0 of haplo-HCT compared with later in the course. Though no statistically significant associations were observed between the incidence of GVHD and CRS symptoms or between one year mortality and the severity of CRS, we did observe those who developed CRS symptoms early during the transplant course at D0 had an increased risk of one year mortality (71% of patients with CRS symptoms at D0 through D+6 died within 1 year of haplo-identical transplant vs. 29% of patients with CRS symptoms D+1 through D+6 in the transplant course p = 0.0584) with a relative risk of 3.57. Our results suggest an association between one-year mortality and development of CRS symptoms early at D0 rather than late in haplo-HCT. Further research with a larger sample size is warranted in order to better understand the relationship and to improve outcomes in haplo-HCT recipients.