Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy

Abstract

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies; however, it is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high-grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this deficit, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov; NCT01865617), with primary end points of absolute neutrophil count and platelet count at day-28 after CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75%, respectively, at 28 days after infusion. Hematologic toxicity was noted in a significant subset of patients, with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Using debiased least absolute shrinkage selector and operator regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower prelymphodepletion platelet count as an independent predictor of both decreased neutrophil and platelet counts after CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of interleukin-6 and lower day-28 cell counts; in contrast, higher serum concentrations of transforming growth factor-β1 were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery after CD19 CAR T-cell therapy.

Graphical abstract

Figure 1.

Patient selection. Inclusion and exclusion criteria for analysis. Patients excluded from analysis at time of first competing event after CAR T-cell infusion, defined as relapse with marrow involvement, new cytotoxic therapy, second lymphodepletion or CAR T-cell infusion, death, or loss to follow-up.

Figure 2.

Severity of hematologic toxicities. Percentage of patients with neutropenia (A), thrombocytopenia (B), and anemia (C) by post-CAR T-cell infusion day, stratified by CTCAE grade. Because of the variability in collection dates, for day = n, the minimum cell count falling within an arbitrary range of n was selected for each patient (ie, day 0 = days −7 and 0, day 14 = days 12-16, day-28 = days 23-33, day 60 = days 55-65, day 90 = days 85-95, day 120 = days 110-130, and day 180 = days 160-200). Patients were no longer included in this analysis pending receipt of a subsequent line of therapy, second CAR T-cell infusion, or withdrawal from the study.

Figure 2.

Severity of hematologic toxicities. Percentage of patients with neutropenia (A), thrombocytopenia (B), and anemia (C) by post-CAR T-cell infusion day, stratified by CTCAE grade. Because of the variability in collection dates, for day = n, the minimum cell count falling within an arbitrary range of n was selected for each patient (ie, day 0 = days −7 and 0, day 14 = days 12-16, day-28 = days 23-33, day 60 = days 55-65, day 90 = days 85-95, day 120 = days 110-130, and day 180 = days 160-200). Patients were no longer included in this analysis pending receipt of a subsequent line of therapy, second CAR T-cell infusion, or withdrawal from the study.

Figure 3.

Kinetics of hematopoietic recovery. Longitudinal ANC (A) and platelet counts (log scale) (B) are depicted in spaghetti plots, with the application of a nonparametric smoother to subjects grouped by CRS grade.

Figure 4.

Multivariable analysis of factors associated with day-28 ANC and platelet counts. Forest plots of regression coefficients for day-28 neutrophil (A,C) or platelet (B,D) counts determined by high-dimensional inference for selected patient, disease, and treatment characteristics (A-B) or serum cytokine concentrations (C-D). Regression coefficient and associated 95% CI, denoted by circles and lines from a linear regression model, respectively. P-value of regression coefficient denoted by color gradient. CRS and ICANS variables are stratified by grade. Disease cohorts (CLL and NHL) and sex (female) are compared against a reference variable, ALL and male, respectively. All other variables are modeled as continuous variables. ALC, absolute lymphocyte count; IFN, interferon; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; PT, prothrombin time; PTT, partial thromboplastin time, TIM, T-cell immunoglobulin and mucin domain-containing protein; TNF, tumor necrosis factor; sTNFR, soluble TNF-receptor.

Figure 5.

Cumulative incidence of hematopoietic recovery. Cumulative incidence of neutrophil (A,C) and platelet (B,D) recovery, as defined by CIBMTR criteria. Cumulative incidence estimated by the Kalbfleisch and Prentice method with univariate comparisons across categories according to Gray’s test and stratified by entire cohort (A-B) or by pre-LD platelet count (C-D, grouped by quartiles). Shaded areas represent 95% CIs.