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Noradrenaline levels in patients with grade 0, grade 1, grade 2 and grade 4 CRS respectively.

Purpose:One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).Experimental Design:Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.Results:We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.Conclusions:These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.

Institutional management guidelines for CRS adapted from the CARTOX working group criteria.

Validation of serum cytokine samples using the Ella with the Luminex.

Supplementary tables and figure legends

Institutional management guidelines for NT adapted from the CARTOX working group criteria.

Correlation of baseline IL6 levels(pg/mL) with IL6 levels collected on day of axi-cel infusion (A) and peak levels (B)

Myeloid and Tregs associated with severe CRS in patients treated with axi-cel.

Allogeneic hematopoietic cell transplantation (allo HCT) remains a valuable alternative for relapsed/refractory (R/R) Hodgkin lymphoma (HL). Data on allo HCT outcomes in the era of new HL therapies are needed. We evaluated 72 R/R HL patients who received reduced intensity conditioning (RIC) allo HCT and compared the time periods 2009-2013 (n=20) to 2000-2008 (n=52). Grafts included HLA-matched sibling (35%), unrelated donor (8%) and umbilical cord blood (UCB, 56%). In recent period, patients more often received brentuximab vedotin (BV, 60% vs 2%), had fewer comorbidities (Sorror index 0: 60% vs 12%) and were in complete remission (50% vs 23%). Median follow-up was 4.4 years. Three-year progression-free survival (PFS) improved for patients treated between 2009-2013 (49%, 95% CI 26-68%) as compared to the earlier era (23%, 95% CI 13-35%, p=0.02). Overall survival (OS) at 3-years was 84% (95% CI 57-94%) vs 50% (95% CI 36-62%, p=0.01), reflecting lower non-relapse mortality and relapse rates. In multivariate analysis mortality was higher among those with chemoresistance (HR 3.83, 95% CI 1.38-10.57), while treatment during the recent era was associated with better OS (HR for period 2009-2013: 0.24, 95% CI 0.07-0.79) and PFS (HR 0.46, 95% CI 0.23-0.92). Allo HCT in patients with R/R HL is now a more effective treatment.

A large single-institution series of patients who recently underwent pancreaticoduodenectomy for resectable pancreatic cancer was analyzed to determine prognostic factors for overall survival, including the impact of adjuvant radiation and chemotherapy. Medical records were reviewed for 179 consecutive patients treated at The Cleveland Clinic with pancreaticoduodenectomy for resectable pancreatic adenocarcinoma from 1999 to 2006. Clinical data were collected, and Kaplan–Meier method was used to estimate overall survival. Univariate and multivariate analysis was performed. One hundred seventy-nine patients with pT1-3N0-1M0 pancreatic cancer met the above criteria. But analysis was available for 158 patients. Median age at diagnosis was 67 (range 35–93). Peri-operative mortality rate was 0.6%. On univariate analysis, poor prognostic factors for overall survival were poorly differentiated histology, lymph node positive disease, elevated alkaline phosphatase, elevated total bilirubin, elevated AST, age at diagnosis >70, and high T stage. On multivariate analysis, poorly differentiated histology (p = .001), age >70 (p = .007), lymph node involvement (≥3 positive vs