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
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
6 , 10 , 11
due to T-cell therapies .
• Grade 1 symptoms : require symptomatic management
• Grade 2 symptoms : respond to moderate intervention , including oxygen requirement < 40 %, grade 2 organ toxicity , or hypotension responding to intravenous fluids or low doses of one vasopressor
• Grade 3 CRS : includes oxygen requirement ≥ 40 %, hypotension requiring high-dose or multiple vasopressors , grade 4 transaminitis , and grade 3 organ toxicity at other sites .
• Grade 4 CRS : life-threatening symptoms requiring ventilator support or grade 4 organ toxicity other than transaminitis
Management mAbs against IL-6 receptors , such as tocilizumab ( approved for treatment of severe , active and progressive rheumatoid arthritis ), have been used off-label for toxicity following CAR T-cell therapy . Tocilizumab has recently been FDA approved for the treatment of CAR T-cell-induced CRS . Such
Following CAR T-cell infusion , unique and potentially severe side-effects can occur
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