IL-2R, IL-6, IL-8, IL-10, monocyte chemoattractant protein (MCP)-1, macrophage-inflammatory protein (MIP)1B, and INF-γ were elevated, and IL-1B, IL-4, IL-5, IL-7, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-a, and granulocyte macrophage–colony-stimulating factor (GM-CSF) were normal. Standard curve quantification ranges were determined by the 80% to 120% (observed/expected value) range.
M.E.A.T. THERAPY SOFTWARE
Data were acquired on a FlexMAP-3D and analyzed using XPonent 4.0 software and 5-parameter logistic regression analysis. Each sample was evaluated in duplicate at 1:3 dilution calculated percentage (%) of coefficient of variation for the duplicate measures was in most cases less than 5% and always less than 15%. Assays were performed according to the manufacturer’s protocol with the 9-point standard curve generated using a 3-fold dilution series. Cytokine and chemokine levels were measured 4 days after treatment with blinatumomab and 1 day prior to tocilizumab (toci) (red lines) and repeated 3 days later (2 days after tocilizumab) (blue lines), using Luminex bead array technology and kits purchased from Life Technologies (Invitrogen 30-plex Carlsbad, CA). A complete list of all cytokines tested with absolute values before and after tocilizumab treatment is included, which is described in supplemental Table 1.Ĭytokine and chemokine levels relative to timing of blinatumomab and tocilizumab. A number of additional cytokines that have not been studied in the published HLH literature were also measured.
Numbers beside red/blue line pair represent fold changes in cytokine level pre- and post-tocilizumab. The bottom half of the figure (below the black horizontal line) indicate cytokines expected to be normal in HLH. 7, 8, 14, 15 The top half of the figure (above the black horizontal line) indicate cytokines expected to be elevated in HLH. IL-2 can be normal or elevated in HLH however, IL2R is universally elevated in HLH, as was found in this patient. 7, 8, 14, 15 IL-2 was normal in this patient. This cytokine prolife is identical to other published work investigating cytokines in children with HLH.
M.E.A.T. THERAPY TRIAL
This trial was registered at as #NCT00103285.Ĭytokine and chemokine levels relative to timing of blinatumomab and tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. The HLH continued to progress after discontinuation of blinatumomab however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH.
He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor–activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia.
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