HHE Haematology supplement 2018 - Page 20

malignancies that are not responsive to standard therapies. 6 CAR T-cell therapies have shown promising results in other indications and have also been studied in early stages for solid tumours. 2,3,5 Currently, the main pharmaceutical players leading this field are Kite Pharma (KTE-C19), Novartis (CTL019) and Pfizer (UCART19). Tisagenlecleucel (Kymriah, Novartis Pharmaceuticals Corp) and axicabtagene ciloleucel (Yescarta, Kite Pharma) have been FDA approved. However, following CAR T-cell infusion, potentially severe and unique side effects including immune-mediated adverse events have been observed. These can be acute, delayed, mild, severe, and/or persist for the duration of the genetically modified T-cell lifespan. CAR T-cell-related toxicities CAR T-cell therapy is associated with serious toxicities. The most acute, feared, troublesome and common toxicity in patients treated with CD19-specific CAR T-cells is cytokine release syndrome (CRS). 3,4,7 Other toxicities include macrophage activation syndrome/haemophagocytic lymphohistiocytosis, neurotoxicity, febrile neutropenia, tumour lysis syndrome, fever and hypogammaglobulinaemia. 3,4,7 CRS CRS, a potentially life-threatening condition, is a systematic inflammatory response caused by cytokines released by the infused CAR T-cells or other immune cells, such as macrophages, that might produce cytokines in response to cytokines produced by the infused CAR T-cells. 3,6,7 The expected time of onset varies depending on the type of CAR T-cells used. 3,6 Following CAR T-cell infusion, unique and potentially severe side-effects can occur 20 HHE 2018 | hospitalhealthcare.com When CRS occurs, there is a rapid and huge release of cytokines into the patient’s bloodstream, leading to high fevers and drops in blood pressure. 3,6 Symptoms in general can range from mild to life-threatening. CRS caused by CAR T-cells often manifests as high fever, myalgia, fatigue, anorexia, hypotension, pulmonary oedema, and coagulopathy. 8,9 Progressively worsening CRS can lead to multi-organ dysfunction including (but not limited to) cardiovascular, pulmonary and renal failure. Fortunately, with timely and appropriate management, CRS is reversible in the vast majority of patients despite severe abnormalities. A modification of the Common Terminology Criteria for Adverse Events 10 has resulted in a grading mechanism suitable for grading CRS due to T-cell therapies. 6,10,11 β€’ Grade 1 symptoms: require symptomatic management β€’ Grade 2 symptoms: respond to moderate intervention, including oxygen requirement < 40%, grade 2 organ toxicity, or hypotension responding to intravenous fluids or low d ½Ν•Μ)½˜½Ή”Ω…Ν½ΑΙ•ΝΝ½Θ+ŠˆΙ…‘”€Μ ILθ₯Ή±Υ‘•Μ½α坕ΈΙ•ΕΥ₯Ι•΅•ΉΠƒŠ&”(Πΐ”°‘εΑ½Ρ•ΉΝ₯½ΈΙ•ΕΥ₯Ι₯Ήœ‘₯ ΅‘½Ν”½Θ΅Υ±Ρ₯Α±”)Ω…Ν½ΑΙ•ΝΝ½ΙΜ°Ι…‘”€ΠΡΙ…ΉΝ…΅₯Ή₯Ρ₯Μ°)…ΉΙ…‘”€Μ½Ι…ΈΡ½α₯₯Ρ䁅Ё½Ρ‘•ΘΝ₯Ρ•ΜΈ+ŠˆΙ…‘”€Π IL聱₯™”΅Ρ‘Ι•…Ρ•Ή₯ΉœΝε΅ΑΡ½΅Μ)Ι•ΕΥ₯Ι₯ΉœΩ•ΉΡ₯±…ѽȁΝΥΑΑ½ΙЁ½ΘΙ…‘”€Π½Ι…Έ)Ρ½α₯₯Ρ䁽ё•ΘΡ‘…ΈΡΙ…ΉΝ…΅₯Ή₯Ρ₯Μ)5…Ή…•΅•ΉΠ)΅‰Μ……₯ΉΝЁ%0΄ΨΙ••ΑΡ½ΙΜ°ΝՍ …́ѽ₯±₯ιΥ΅…ˆ(‘…ΑΑΙ½Ω•™½ΘΡΙ•…Ρ΅•ΉΠ½˜Ν•Ω•Ι”°…Ρ₯Ω”…Ή)ΑΙ½Ι•ΝΝ₯Ω”Ι‘•Υ΅…Ρ½₯…ΙΡ‘Ι₯Ρ₯Μ€°‘…Ω”‰••ΈΥΝ•)½™˜΅±…‰•°™½ΘΡ½α₯₯Ρ䁙½±±½έ₯Ήœ HP΅•±°Ρ‘•Ι…ΑδΈ)Q½₯±₯ιΥ΅…ˆ‘…́ɕ•ΉΡ±δ‰••Έ…ΑΑΙ½Ω•™½Θ)Ρ‘”ΡΙ•…Ρ΅•ΉΠ½˜ HP΅•±°΅₯Ή‘Ս• ILΈMՍ