IntroductionT cell-replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by cytokine release syndrome (CRS). The deleterious impact of severe CRS has been reported in single institution analyses.ObjectivesTo determine the effect of CRS on outcomes after haplo-HCT using a large international multi-center cohort.MethodsThis retrospective analysis includes all patients who underwent haplo-HCT at four academic centers (two in the US, one in Italy, one in Colombia) between 2009 and 2018. CRS was graded based on criteria by Lee (Blood 2014).Outcomes were assessed using no CRS as the comparison group. We compared overall survival and cumulative incident functions across three CRS grade groups using log-rank and Fine-Gray tests. We performed the multivariable analysis using proportional hazards models to control for confounders (including age, gender, dri, HCT-CI, active disease, conditioning intensity, stem cell source).ResultsA total of 451 patients were included (Table 1). The incidence of CRS was high (89%), and 17% of patients had severe (grade 3-5) CRS. The incidence of severe CRS was higher in patients receiving peripheral blood grafts (19.5% vs. 4.9%, p=0.0026). Overall survival was better in mild CRS (HR 0.621, p=0.0319) and worse in severe CRS (HR 2.125, P=0.0022). Relapse was lower in both mild CRS (HR 0.429, p=0.0002) and severe CRS (HR 0.324, p=0.0004). Transplant related mortality was not significantly different in mild CRS, but much higher in severe CRS (HR 5.332, p=0.0002). Neutrophil and platelet engraftment were not significantly different in mild CRS, but worse in severe CRS (HR 0.476, p = 0.0008 and HR = 0.590, p = 0.0296). All grade chronic GVHD was significantly reduced in patients with severe CRS (HR 0.256, p=0.0273). There were no other statistical differences in rates of all grade or severe acute or chronic GVHD. Multivariable models adjusting for potential confounders confirmed these effects. These effects did not differ by stem cell source.ConclusionThis international, multi-center analysis in consistent with published single center experiences showing that CRS is a common complication after haplo-HCT and that severe (grade ≥3) CRS is associated with increased TRM and worse overall survival. Importantly, these data are the first to show that mild (grade 1-2) CRS is associated with lower rate of relapse without affecting TRM, thereby improving OS.