Yared, Jean A

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy represents a major advance in cancer immunotherapy; however, it can be associated with life-threatening neurotoxicity linked to blood-brain barrier disruption and endothelial activation. Defibrotide was shown to reduce endothelial cell activation in vitro and is approved in the United States for treatment of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with renal or pulmonary dysfunction after hematopoietic cell transplantation (HCT), and in the European Union for severe VOD/SOS after HCT in patients aged >1 month. Defibrotide may stabilize the endothelium during CAR-T therapy and reduce the rate of CAR-T–associated neurotoxicity. This phase 2 study evaluated the safety and efficacy of defibrotide for prevention of CAR-T–associated neurotoxicity in patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel. Part 1 established the recommended phase 2 dose (RP2D; 6.25 mg/kg); 20 patients (from parts 1 and 2) receiving the RP2D were evaluable for efficacy. Rate of CAR-T–associated neurotoxicity by day 30 (primary end point) was ∼50%, lower than reported in the ZUMA-1 trial (64%). Median event duration of grade ≥3 neurotoxicity was 7 days. No unexpected defibrotide-related safety findings and defibrotide-related treatment-emergent adverse events or deaths were reported. Results showed modest reduction in rate of CAR-T–associated neurotoxicity and high-grade neurotoxicity event duration relative to historical data; however, reduction was unlikely to meet the primary end point, so the study was terminated early. Nevertheless, results contribute valuable data for potential therapeutic insight on the management of CAR-T–associated neurotoxicity. This trial was registered at www.clinicaltrials.gov as #NCT03954106.

AbstractTo develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.

Abstract Presumably, reduced-intensity/nonmyeloablative conditioning (RIC/NMA) for allogeneic hematopoietic cell transplantation (alloHCT) results in reduced infections compared with myeloablative conditioning (MAC) regimens; however, published evidence is limited. In this Center for International Blood and Marrow Transplant Research study, 1755 patients (aged ≥40 years) with acute myeloid leukemia in first complete remission were evaluated for infections occurring within 100 days after T-cell replete alloHCT. Patients receiving RIC/NMA (n = 777) compared with those receiving MAC (n = 978) were older and underwent transplantation more recently; however, the groups were similar regarding Karnofsky performance score, HCT–comorbidity index, and cytogenetic risk. One or more infections occurred in 1045 (59.5%) patients (MAC, 595 [61%]; RIC/NMA, 450 [58%]; P = .21) by day 100. The median time to initial infection after MAC conditioning occurred earlier (MAC, 15 days [range, <1-99 days]; RIC/NMA, 21 days [range, <1-100 days]; P < .001). Patients receiving MAC were more likely to experience at least 1 bacterial infection by day 100 (MAC, 46% [95% confidence interval (CI), 43-49]; RIC/NMA, 37% [95% CI, 34-41]; P = .0004), whereas at least a single viral infection was more prevalent in the RIC/NMA cohort (MAC, 34% [95% CI, 31-37]; RIC/NMA, 39% [95% CI, 36-42]; P = .046). MAC remained a risk factor for bacterial infections in multivariable analysis (relative risk, 1.44; 95% CI, 1.23-1.67; P < .0001). Moreover, the rate of any infection per patient-days at risk in the first 100 days (infection density) after alloHCT was greater for the MAC cohort (1.21; 95% CI, 1.11-1.32; P < .0001). RIC/NMA was associated with reduced infections, especially bacterial infections, in the first 100 days after alloHCT.