mAbs could represent a therapeutic option for the management of CRS . 3 , 6 Tocilizumab , a humanised mAb , blocks the IL-6 receptor and subsequent signalling . This results in decreased production of anti-inflammatory mediators . Its use as a rescue medication for severe CRS due to CAR T-cell therapy , has been associated with near-immediate reversal of CRS symptomatology ( for example , fever , hypotension , respiratory distress ). 3
Dosages for tocilizumab can range from 4mg / kg to 8mg / kg ( maximum of 800mg per dose ) for patients ≥30kg . Tocilizumab is infused intravenously over 60 minutes . 3 A subsequent dose can be considered for patients with persistent symptoms after 12 – 24 hours . The acquisition of tocilizumab should be considered for all patients undergoing CAR T-cell therapy . 3
Pharmacists and clinicians must ensure that tocilizumab ( or other anti-cytokine therapy ) is available on site and available for administration prior to CAR T-cell infusion so that patients can receive the drug as quickly as possible when needed . Because of the high cost and the potential of severe adverse events ( for example , infections , reactivation of viruses , tuberculosis , and hepatotoxicity ), the use of tocilizumab should be limited strictly to critically ill patients . 1
The use of corticosteroids remains controversial . Administration of high-dose corticosteroids in the treatment of CRS results in decline in detectable CAR T-cells via apoptosis . 3 Dosing of steroids ( intravenous methylprednisolone and dexamethasone ) should be performed on protocol-specific recommendations and characteristics of the individual patient . Dexamethasone is the preferred agent , due to superior central nervous system penetration . 4 , 7 The corticosteroids should be tapered quickly based on symptom resolution to diminish the CAR T-cell effect .
Other agents that have been considered or used in the management of CRS are siltuximab , etanercept , infliximab and anakinra ; however , there are limited data so far . 4 , 6 , 7
Macrophage activation syndrome / haemophagocytic lymphohistiocytosis Some patients might experience CRS with symptoms similar to macrophage activation syndrome ( MAS ) or haemophagocytic lymphohistiocytosis ( HLH ). 3 , 7
Studies have shown that tocilizumab does not prevent the development of MAS / HLH and its complications . 3
Central nervous system toxicities Patients may also experience severe neurological toxicities such as altered mental status , confusion , aphasia , delirium and even seizures and coma . 7 It remains important to monitor the degree of confusion , somnolence and encephalopathy to determine appropriate management of symptoms ( CAR T-cells detectable in the cerebrospinal fluid ). 6 Some case-reports of lethal cerebral oedema in patients treated with CAR T-cells have been described . 12 The pathophysiology of these neurotoxic effects is still unclear but inflammatory cytokines seem to be involved . 1 , 7
Because dexamethasone has excellent CNS penetration , its use can considered in cases of severe and life-threatening neurologic symptoms requiring urgent medical intervention . 3 , 6 Antiepileptic prophylaxis , such as levetiracetam , can be given to patients at risk of seizures .
Tumour lysis syndrome Tumour lysis syndrome ( TLS ) has been reported in patients treated with CD19-targeted cells , especially in patients with chronic lymphocytic leukaemia . 7 , 13 TLS complications are usually managed as per standard of care , that is , prophylactic allopurinol , fluids and rasburicase as needed . 7 , 13
Neutropenia Following administration of chemotherapy followed by CAR T-cells , patients frequently become neutropenic and lymphopenic . This can predispose patients to opportunistic infections . The degree and rates of neutropenia vary depending on the conditioning regimen received . Prophylaxis with granulocyte colony-stimulating factors may be initiated 24 hours after completion of the conditioning regimen and continued until neutrophil recovery . Prophylactic antimicrobials may also be considered for patients with neutropenia .
Fever Nearly all patients develop fever after CAR T-cell infusion with 80 – 100 % having grade 3 or greater fever . Supportive treatments include use of acetaminophen for all patients who develop fever . Non-steroidal anti-inflammatory drugs should be avoided . 6
Hypogammaglobulinaemia This is a common condition observed with the profound and prolonged B-cell aplasia that occurs following anti-CD19 CAR T-cell infusions .
Pharmacists and physicians must ensure that anti-cytokine therapy is available on site prior to CAR T-cell infusion
Replacement therapy with intravenous immunoglobulins has been used . 6 , 7
Conclusions CAR T-cell therapy is a powerful new tool in the oncologist ’ s arsenal and can induce remissions ( CD19 CAR T-cell ) in otherwise refractory children and young adults with acute lymphoblastic leukaemia . Recently , tisagenlecleucel ( Kymriah ® Novartis ) and axicabtagene ciloleucel ( Yescarta ® , Kite Pharma ) have been FDA approved . CAR T-cells bring spectacular opportunities , but also challenges , for pharmacists , especially in the management of side effects and toxicities . Supportive care and early anti-cytokine therapy is absolutely required to mitigate the lifethreatening consequences of severe CRS . Education of pharmacists involved in CAR T-cell infusion and knowledge of potential side effects is important .
105 HHE 2018 | hospitalhealthcare . com
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