In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 3020-3020
Abstract:
3020 Background: CD19 CAR-T cells have produced impressive responses in CD19 + ALL, NHL and CLL. Detailed understanding of the presentation and pathogenesis of CRS and NT will facilitate safe CAR-T cell use in multicenter trials. Methods: We treated 161 adults with B-ALL, NHL or CLL with anti-CD19 CAR-T cells, formulated in a 1:1 CD4/CD8 ratio and infused after lymphodepletion chemotherapy in a dose finding study (NCT 01865617) to identify a MTD in each disease. Results: 133 patients (pts) completed toxicity assessment. CRS developed in 71% (60% gr 1-2, 4% gr 3, 8% gr ≥4). Fever was the first sign of CRS and preceded organ toxicity, allowing safe outpatient administration of CAR-T cells. NT was observed in 40% (19% gr 1-2, 16% gr 3, 5% gr ≥4) and gr ≥3 NT presented a median of 4.5 days after CRS onset. The time from onset to peak of NT was 2 days. CRS and NT were reversible with the exception of 6 pts who died, 4 during the dose-finding phase of the study. In multivariable analyses, higher CAR-T cell dose and malignant B cells in marrow (BM) were associated with CRS; and CAR-T cell dose, malignant BM B cells, more intensive lymphodepletion, and prior neurologic comorbidities were associated with NT. Probability curves of response, CRS and NT in relation to blood CAR-T cell counts show that toxicity mitigation by CAR-T cell dose reduction may be feasible in B-ALL without impairing BM response; however, dose reduction may reduce nodal response in NHL and CLL. Analysis of clinical parameters revealed that pts who later developed severe CRS or NT could be identified early after CAR-T cell infusion by higher fever, greater vascular instability, and more severe hypoalbuminemia. Paired serum-CSF studies and autopsy data suggest blood-brain barrier disruption in severe NT. High serum IL-6, IL-15, MCP-1 and IL-10, and endothelial activation markers on day 1 after infusion correlated with subsequent toxicity, which identifies pts for early intervention to prevent severe toxicity. Conclusions: CAR-T cells can be safely administered in the outpatient setting. Clinical and laboratory biomarkers allow early identification of a small subset of pts who might develop serious toxicity, facilitating study of preventive strategies. Clinical trial information: NCT 01865617.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2017.35.15_suppl.3020
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2017
detail.hit.zdb_id:
2005181-5
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