HHE Haematology supplement 2018 - Page 21

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 life- threatening consequences of severe CRS. Education of pharmacists involved in CAR T-cell infusion and knowledge of potential side effects is important. 21 HHE 2018 | hospitalhealthcare.com References 1 Kroschinsky F e t al; Intensive Care in Hematological and Oncological Patients (iCHOP) Collaborative Group. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care 2017;21(1):89. 2 Shoushtari AN et al. Principles of cancer immunotherapy. www.uptodate.com/ contents/principles-of-cancer- immunotherapy (accessed December 2017). 3 Shank BR et al. Chimeric antigen receptor T cells in hematologic malignancies. Pharmacotherapy 2017;37(3):334–45. 4 Bonifant C et al. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016;20;3:16011. 5 Clinical trials. http:// www.Clinicaltrials.gov 6 Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 2016;127(26):3321–30. 7 Namuduri M, Brentjens R. Medical management of side effects related to CAR T cell therapy in hematologic malignancies. Expert Rev Hematol 2016;9:511–13. 8 Maude SL et al. Managing cytokine release syndrome associated with novel T cell- engaging therapies. Cancer J 2014;20(2):119–22. 9 Minagawa K, Di Stasi A. Novel toxicology challenges in the era of chimeric antigen receptor T-cells therapies. Transl Cancer Res 2016;doi: 10.21037/ tcr.2016.09.06. 10 Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published: May 28, 2009 (v4.03: June 14, 2010). https://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010- 06-14_QuickReference_8.5x11. pdf (accessed December 2017). 11 Lee DW et al. Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126(8):1048]. Blood 2014;124(2):188–95. 12 Garde D, Keshavan M. 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