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      Decreased Rates of Severe CRS Seen with Early Intervention Strategies for CD19 CAR-T Cell Toxicity Management

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          Abstract

          Introduction: CD19 CAR-T cell therapy is a promising strategy in the treatment of pre-B ALL, with early phase trials showing results of >90% CR rates. Over 90% of patients develop CRS concurrent with proliferation of CAR-T cells. Rates of severe CRS (sCRS) in previously reported studies have ranged from 23% to 43%. Concerns have been raised that the use of immunomodulation may impact engraftment and proliferation of CAR-T cells, potentially impairing efficacy. Additionally, concern has been raised that the use of tocilizumab (toci) may lead to an increased risk of neurotoxicity. Here we report our clinical experience with early treatment of CRS in a cohort of patients who received pre-emptive toci and dexamethasone (dex) with the goal to lessen the occurrence of sCRS.

          Methods: Subjects enrolled on the PLAT-02 study (NCT02028455) underwent apheresis and CAR-T cell manufacturing followed by lymphodepletion and CAR-T cell infusion. In this phase 1 dose escalation study, subjects were treated from 0.5- 10 x 106 CAR T cells/kg. sCRS included the use of pressors or inotropes. Severe neurotoxicity included any grade 3/4 neurotoxicity, excluding headache, and grade≥ 2 seizure. The first 23 subjects received toci (8mg/kg) with or without steroids for dose limiting toxicity (DLT). Subsequently the protocol was modified to provide guidelines for early intervention with CRS. The next 20 subjects received toci and subsequent dex (5-10mg every 6-12 hours prn) for persistent symptoms using clinical criteria, with the goal to prevent sCRS. Clinical criteria included persistent fever of ≥ 39°C despite antipyretics for 10 hours, persistent/recurrent hypotension after initial fluid bolus, and initiation of oxygen supplementation. Engraftment of CAR T cells and B cell aplasia was determined by flow cytometry

          Results: The two cohorts had similar overall rates of CRS: 91% (21/23) vs 95% (19/20), with higher rates of sCRS in the initial cohort: 30% (7/23) vs 15% (3/20) (p=0.3). Neurotoxicity was seen in 48% v 50% with similar rates of severe neurotoxicity, 22% v 25%. In the first cohort of subjects, 22% (5/23) received toci and 17% (4/23) received steroids due to DLT. In the second cohort, there was an increase in the number of subjects receiving toci to 50% (11/20, p=0.032) with an increase in steroid use as well to 30% (6/20, p=0.5)

          The overall rate of MRD-negative CR in this study was 93% (40/43) and this was not impacted by the use of toci or dex. The rate of MRD-negative CR in those subjects receiving toci without steroids, toci with steroids, and steroids alone were also similar (89% vs 100% vs 100%). Additionally the MRD-negative CR rate in the first cohort was similar to the early intervention cohort (91% v 95%). Continued peripheral blood expansion of CAR+ T cells can be seen in subjects who have received tocilizumab and/or steroids. There were no differences detected among the immunomodulatory groups with regards to peak percentage engraftment, area under the curve, or functional persistence of CAR T cells.

          Conclusions: Despite encouraging efficacy, the toxicity associated with CD19 CAR-T cell therapy gives rise to concerns about its widespread use. Early intervention with immunomodulation appears to decrease the rates of sCRS while preserving the high rates of MRD-negative CR. Additionally, the engraftment and persistence of CAR+T cells is not impacted by the use of toci and/or steroids when given early after the onset of clinical symptoms of CRS. Although not intended to assess the impact of toci on neurotoxicity, it is of note that the rates of neurotoxicity, and in particular severe neurotoxicity, did not increase. These results warrant further study of the impact of early immunomodulation for the prevention of sCRS.

          Disclosures

          Gardner: Amgen: Honoraria. Li:Juno Therapeutics: Employment, Equity Ownership. Jensen:Juno Therapeutics, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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          Author and article information

          Journal
          Blood
          American Society of Hematology
          0006-4971
          1528-0020
          December 02 2016
          December 02 2016
          : 128
          : 22
          : 586
          Affiliations
          [1 ]Department of Pediatics, University of Washington, Seattle, WA
          [2 ]Seattle Children's Hospital, Seattle, WA
          [3 ]Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
          [4 ]Department of Pediatrics, UW, Seattle, WA
          [5 ]Department of Pediatrics, Seattle Children's Hospital, Seattle, WA
          [6 ]Juno Therapeutics, Seattle, WA
          [7 ]Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA
          [8 ]Department of Pediatrics, University of Washington, Seattle, WA
          [9 ]Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA
          Article
          10.1182/blood.V128.22.586.586
          3624b4f8-e377-4109-a680-ac303d1d1732
          © 2016
          History

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