Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer

Abstract

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

Figure 1.. Grading and Management of Cytokine Release Syndrome (CRS)

Cytokine release syndrome (CRS) is a potentially life-threatening complication of immunotherapy. Patients post immunotherapy should be vigilantly monitored for this complication, incorporating paediatric considerations like age appropriate vital signs to facilitate the early recognition and prompt management of CRS. ASTCT: American Society for Transplantation and Cellular Therapy, NC: Nasal Cannula, O₂: Oxygen, HFNC: High Flow Nasal Cannula, ICU: Intensive Care Unit, IV: Intravenous, HC: Hydrocortisone, IEC: Immune Effector Therapy. ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome ^aFor patients who have CRS and have received antipyretic or anti-cytokine therapy, fever is no longer required to subsequently grade CRS but rather, grading is driven by hypotension and/or hypoxia and is determined by the more severe event ^b Hypotension is defined by age-specific normal ranges and/or in comparison to their baseline values. When baseline systolic blood pressures (SBPs) are unknown, hypotension may be determined as follows: (a) term neonates (0-28 days) SBP <60 mm Hg; (b) infants (1-12 months) SPB <70 mm Hg; (c) children 1-10 years SBP<70 mm Hg + (age in years x 2) mm Hg and (d) children > 10 years SBP <90mm Hg ^c10-20 mL/kg (maximum 1,000 mL) normal saline. Repeat once as needed to maintain normal BP above baseline or within normal range for age as defined above ^dFor hypotension consider hydrocortisone 12.5 – 25 mg/m²/day divided every 6 hours ^eGrade 2 hypotension: methylprednisolone 1 –2 mg/kg for one dose or dexamethasone 0.15 –0.5 mg/kg/dose (maximum 10 mg) IV for 1 dose Grade 2 hypoxia: methylprednisolone 1 -2 mg/kg for one dose or dexamethasone 0.5 mg/kg/dose (maximum 10 mg) IV for 1 dose Grade 3 hypotension: If on one vasopressor: methylprednisolone 1-2 mg/kg/day divided every 6 to 12 hours or dexamethasone 0.5 mg/kg/dose (maximum 10 mg) IV every 6 hours. If on two vasopressors methylprednisolone 1-2 mg/kg/day divided every 6 to 12 hours or dexamethasone 1 mg/kg/dose (maximum 20 mg) IV every 6 hours. If vasopressin and norepinephrine equivalent is ≥ 15 mcg/minute, follow as in Grade 4 CRS Grade 3 hypoxia: methylprednisolone 1 –2 mg/kg/day divided every 6 to 12 hours or dexamethasone 0.5 mg/kg/dose (maximum 10 mg) IV every 6 hours. If there is no improvement in hypoxia within 24 hours or there is rapid progression of pulmonary infiltrates or sharp increase in FiO₂ requirements, methylprednisolone 1-2 mg/kg/day divided every 6 to 12 hours or dexamethasone 1 mg/kg/dose (maximum 20 mg) IV every 6 hours Grade 4 hypotension or hypoxia: Methylprednisolone 30 mg/kg/day (maximum 1,000 mg/day) in divided doses IV for 3 days followed by rapid taper as per clinical situation For grade 2-4 ,once CRS improves to Grade 1 or less, taper and/or stop corticosteroids depending on clinical situation ^fSiltuximab 11mg/kg IV once, anakinra: Children ≥ 2 years and Adolescents: 1 mg/kg (maximum 100 mg) subcutaneously daily for 7 days , cyclophosphamide 1500mg/m² IV once(with mesna), anti-thymocyte globulin (rabbit)- 1 to 2 mg/kg IV daily for 3 days References: 1 Lee, D. W. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 25, 625-638, doi:10.1016/j.bbmt.2018.12.758 (2019).

Figure 2.. Grading and Management of Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS)

Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) is a potentially life-threatening complication of immunotherapy. Patients receiving immunotherapy should be vigilantly monitored for ICANS, incorporating paediatric considerations (e.g. age-appropriate vital signs and use of pediatric delirium scores) to facilitate the early recognition and prompt management of ICANS. ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome; MRI: Magnetic Resonance Imaging; CT: Computer Tomography; EEG: Electroencephalogram ; LP: Lumbar Puncture: ICE: Immune Effector Cell-associated Encephalopathy; CAPD: Cornell Assessment of Pediatric Delirium; ASTCT: American Society for Transplantation and Cellular Therapy; IV: Intravenous, CNS: Central Nervous System; HTN: Hypertension; IEC: Immune Effector Cell; max: maximum ^aDepressed level of consciousness not attributable to any other case ^bICE score: For patients > 12 years of age; CAPD for patients ≤ 12 years of age and/or for children > 12 years of age for whom this is developmentally appropriate ^c Any clinical seizure (focal or generalized) that resolves rapidly (< 5 minutes) or non-convulsive seizures on EEG that resolve with intervention ^dLife-threatening prolonged seizure (≥ 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between ^eControl blood pressure with the goal of maintaining mean arterial pressure(MAP) within 20-25 mmHg of baseline MAP ^fDexamethasone can be started at 0.5mg/kg/dose (maximum 10 mg) and repeated up to every 6 hours as needed or methylprednisolone 1-2mg/kg/day divided every 6-12 hours. If grade 3 ICANS is persistent for > 24 hours, dexamethasone 1mg/kg/dose (maximum dose 20 mg) ever 6 hours or methylprednisolone 1-2mg/kg/day divided every 6-12 hours. For focal oedema or grade 4 ICANS, methylprednisolone 30mg/kg/day (maximum dose 1000mg) ^gSiltuximab 11mg/kg IV once, Anakinra Children ≥ 2 years and Adolescents: 1 mg/kg (maximum 100 mg) subcutaneously daily for 7 days , cyclophosphamide 1500mg/m² IV once(with mesna), anti-thymocyte globulin (rabbit)- 1 to 2 mg/kg IV daily for 3 days References: 1 Lee, D. W. et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant 25, 625-638, doi:10.1016/j.bbmt.2018.12.758 (2019).