Abstract
Background: Graft-versus-host disease (GvHD) prophylaxis following stem cell infusion is critical in the success of allogeneic stem cell transplant (alloSCT), with the goal of achieving engraftment and improving survival. Post-transplant cyclophosphamide (PTCy) has become standard of care as it demonstrated benefits in reducing GvHD incidence, relapse, and all-cause mortality. However, an emerging challenge is the occurrence of cytokine release syndrome (CRS) after stem cell infusion and before PTCy is administered. CRS is characterized by a hyperinflammatory immune response, independent of infection, and marked by elevated cytokine levels and immune dysregulation. Current management strategies involve immunosuppressive agents, their effect on long-term survival remains unclear. This study represents the first real-world analysis to evaluate the impact of CRS prior to PTCy on survival outcomes after alloSCT, and their outcomes with the different immunomodulatory therapies.
Methods:
We conducted a retrospective cohort study using the TriNetX Research Network, a global, federated platform of HIPAA-compliant, de-identified patient records from 65 healthcare organizations (HCO) from the Global Collaborative Network. We identified patients ≥18 years who underwent alloSCT and received PTCy, with or without CRS prior to cyclophosphamide administration. CRS was defined using ICD-10-CM code D89.83 and constrained to events preceding PTCy. Tocilizumab and anakinra use were assessed with RxNorm codes 61286 and 72435, respectively, using binary Boolean filters (“must have” or “cannot have”).
Patients were stratified into cohorts: (1) CRS vs no CRS; (2) CRS + tocilizumab vs CRS without tocilizumab; and (3) CRS + anakinra vs CRS without anakinra. Matching and cohort balancing were performed and Kaplan-Meier and log-rank tests were used for survival analysis.
Results:
A total of 8,119 patients had undergone alloSCT with PTCy from 65 HCO. Among these, 562 developed CRS prior to PTCy, while 7,557 did not. The median age was 55.2 years in the CRS group and 48.2 in the non-CRS group. Males accounted for 50% and 54% of CRS and non-CRS groups, respectively. Most patients were White (58% CRS and 60% non-CRS), followed by Black (14% vs 10%), Asian (2% vs 5%), Pacific Islander (1% vs 1%) and American Indian (1% vs 0%). Unknown or other race accounted for 24% in both groups. Ethnicity distribution was similar: non-Hispanic or Latino (63% vs 66%), unknown (27% vs 25%) and Hispanic (10% vs 9%). Mean BMI was slightly higher in the CRS group (28.2 vs 27.1).
After matching, there was no difference is lab values including Lactate dehydrogenase, ferritin or C-reactive protein. Matched groups included 557 patients each. Patients with CRS demonstrated significantly worse overall survival (OS) [p=0.0028]. Not having CRS had implication in other variables including lower risk of developing sepsis 21% vs 27% [OR 0.71 95% CI: 0.55,0.916], ICU admission 22% vs 30% [OR: 0.646 95% CI: 0.503,0.828] and GvHD 40% vs 42% [OR 0.898, 95% CI: 0.721,1.12]. Among CRS patients, 179 patients received tocilizumab and 382 did not; after balancing, 139 matched pairs were analyzed. There was no significant difference in OS [p=0.3413]. Only 17 patients received anakinra, compared to 162 who did not. After matching, 10 patients were included in each group. Similarly, no significant difference in OS was observed [p = 0.1963], although sample size limits interpretation.
We were unable clarify the indications for transplant, conditioning agent used, or the type of transplant performed.
Conclusions: This is the first large scale study that demonstrates that CRS prior to PTCy is associated with inferior survival outcomes following alloSCT. In addition, CRS was correlated with increased risk of sepsis and GvHD. Differing rates of rapid expansion of T-cells subsets CD4, CD8, and Natural Killer may be playing a role these findings. Regardless, PTCy remains the standard of care. This exploratory analysis showing decreased OS in patients with CRS prior to PTCy lays the groundwork to better understand the pathophysiological changes during T-cell expansion that leads to CRS and dysregulated immune reconstitution. Biobanks such as Blood & Marrow Transplant Clinical Trials Network (BMT CTN 1801) and future GvHD prophylaxis studies by BMT CTN and National Marrow Donor Program may help understand the implications of CRS after alloSCT, as this will be key to improving patient survival after PTCy.
