Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy

Abstract

Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). 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). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with 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. This trial was registered at www.clinicaltrials.gov as #NCT00103285.

Figure 1

Clinical and laboratory parameters relative to timing of blinatumomab and tocilizumab. Serum ferritin and temperature rapidly rose and serum fibrinogen rapidly fell after starting blinatumomab. Poor systemic perfusion and respiratory failure continued to deteriorate after blinatumomab was stopped; however, these improved significantly after tocilizumab. Initiation of blinatumomab is depicted by arrow and total treatment duration depicted by black line. The blue line represents serum ferritin in ng/mL with circles showing tested values. Red line represents maximum temperature in centigrade (°C) per 24-hour period with triangles demarcating each day. The black line represents fibrinogen with squares depicting tested values. Horizontal axis = treatment days. Time on vasoactive medications (dopamine and epinephrine) is indicated by a black line under “vasoactives” (days 2 to 6). Time on ventilator is indicatedby a black line under “ventilator” (days 2 to 11).

Figure 2

Cytokine and chemokine levels relative to timing of blinatumomab and tocilizumab. 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). Assays were performed according to the manufacturer’s protocol with the 9-point standard curve generated using a 3-fold dilution series. 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%. Data were acquired on a FlexMAP-3D and analyzed using XPonent 4.0 software and 5-parameter logistic regression analysis. Standard curve quantification ranges were determined by the 80% to 120% (observed/expected value) range. 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. This cytokine prolife is identical to other published work investigating cytokines in children with HLH.^,,, IL-2 was normal in this patient. IL-2 can be normal or elevated in HLH; however, IL2R is universally elevated in HLH, as was found in this patient.^,,, The top half of the figure (above the black horizontal line) indicate cytokines expected to be elevated in HLH. The bottom half of the figure (below the black horizontal line) indicate cytokines expected to be normal in HLH. X-axis is cytokine level in pg/mL. Numbers beside red/blue line pair represent fold changes in cytokine level pre- and post-tocilizumab. A number of additional cytokines that have not been studied in the published HLH literature were also measured. A complete list of all cytokines tested with absolute values before and after tocilizumab treatment is included, which is described in supplemental Table 1.