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Cytokine Release Syndrome (CRS) and Immune Cell Associated Neurotoxicity Syndrome (ICANS)

Presented by:

Sarah Featherston, BS, RN, CPNSajad Khazal, MD

Critical Care Management of Pediatric HSCT andCell Therapy Patients Workshop

February 20th, 2019

Disclosures

The presenters have no financial relationships to disclose

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Objectives

• Provide an overview of immune effector cell (IEC) therapy including chimeric antigen receptor cell therapy (CAR-T)

• Describe current clinical indications• Define unique toxicities of IEC• Discuss the role of nurses in the assessment and management of

IEC therapy and its toxicities• Discuss evidence-based algorithms for the management of IECs

related toxicities

CAR-T Therapies: An Overview

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Emily Whitehead-A Pioneer for CAR-T Therapy

Currently utilize the patients own T-cells (autologous)

Genetically engineered

in the lab (viral or non viral)

Target the surface

antigen of interest (e.g

CD19)

CAR T cells will destroy the cells expressing the target antigen

Chimeric Antigen Receptor (CAR) T Cell Therapy Overview

CAR T Cells have the potential for

lifelong anti-tumor effect

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Chimeric Antigen Receptor T-Cell Therapy: How it works

Apheresis catheter

placement

T-cells are collected from

the patient through

apheresis

CAR T-cells are then infused into the patient

CAR T-cells recognize and kill tumor cells

T-cells are genetically engineered in a laboratoryto manufacture “Chimeric Antigen Receptor (CAR) T-cells”

The CAR T cells are then expanded

1 2 3

4

5

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Current FDA ApprovedCAR-T Cell Therapy

• Agent: Tisagenlecleucel (Kymriah™)

• Indication: treatment of relapsed (second or later) or refractory B-cell acute lymphoblastic leukemia (ALL) (pediatric and young adults up to 25) and relapsed or refractory large b-cell lymphoma (adults >18 years)

• Agent: Axicabtagene ciloleucel(Yescarta™)

• Indication: treatment of relapsed or refractory large B cell lymphomas

Introduction to Research Nursing

CAR-T cell therapy, a cellular product, has been approved by the FDA as a drug, described as a “living drug”, the first of its kind

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IECs Therapy-Associated Toxicities

Target cell destruction and IEC expansion

Release of cytokines

associated with IEC expansion

Inflammatory response

throughout organ systems (including

the CNS)

Mechanisms of Toxicity in Patients Receiving IEC Therapy

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Unique IEC Toxicities

Cytokine Release Syndrome (CRS)

• Elevation in circulating cytokines in response to the infused IEC

• Characteristics: fever, hypotension, hypoxia

Immune Cell Associated Neurotoxicity Syndrome (ICANS)

• Associated with elevated cytokines in the CSF including IL-6 (passive diffusion from the blood)

• Characteristics: confusion, delirium, encephalopathy, seizures and cerebral edema

• Pathophysiology poorly understood

• CRS/ICANS can occur concurrently or with no apparent association

• Nearly half of patients require intensive monitoring/ critical care support

• Generally reversible but can be fatal

Unique IEC Toxicities

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One or more of the following:• Fever ≥ 38°C

• Hypotension• Ages 1-10yr: SBP < (70+2 x age in years)

• Greater than 10yr: SBP < 90

• Hypoxia• O2 < 92% on room air

CRS Clinical Signs

• High disease burden

• Comorbidities

• Active Inflammatory Process

• Early onset of CRS (within 3 days)

CRS Risk Factors

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Grading CAR-T Related CRS

• Impaired expression affecting language and handwriting

• Delirium

• Seizures

• Age appropriate assessments are imperative for early recognition in young children

ICANS Clinical Signs

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• There are currently no known risk factors for ICANS

ICANS Risk Factors

Grading Immune Effector Cell Associated-

Neurotoxicity Syndrome

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Management ofCRS & ICANS

CRS

• Corticosteroids – believed to be associated with

suppression of CAR-T cell expansion and unfavorable patient outcomes

– Should not be used as premed for cell infusion or blood transfusions

– Should be easy to identify CAR-T patients in electronic Medical Record to avoid accidental administration

ICANS

• Tocilizumab– IL-6 receptor antagonist

– FDA approved for treatment of CRS

– Must have 2 doses per patient on site

• Siltuximab– Binds to both soluble and membrane

bound IL-6

– Used as off label indication for CRS

– Must have consent signed prior to infusion

Management ofCRS

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Management ofICANS

• Hypersensitivity Reactions

• B-cell aplasia/ Hypogammaglobinemia

Other Side Effects

• Prolonged cytopenias• Increased risk of infection• Tumor lysis syndrome

(TLS)

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Assessing Neurotoxicity in Patients Receiving IEC Therapies

Nursing Assessment

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Handwriting Assessment

• Cornell Assessment of Pediatric Delirium (CAPD)⁻ All CAR-T patients <18 years old

⁻ Documented at 0600 and 1800

⁻ Assessed 11 hour period to provide accurate assessment

⁻ Notify provider if score is 9 or greater

• Pediatric Early Warning Score (PEWS) Algorithm• Uses objective data to predict patient deterioration early

• Uses baseline and age appropriate vital signs, age appropriate behavior and clinical judgment

Pediatric Specific Nursing Documentation

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CAPD Documentation Template

Cornell Assessment of Pediatric Delirium: Criteria by Age

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Pediatric Early Warning Score (PEWS)

Nursing Management: Key Considerations

• Quick & subtle changes require frequent and standardized assessment

• The use of handwriting samples can identify changes that may be related to underlying neurotoxicity

• Have a plan - Who to Call & What to Expect

• Thorough documentation is important to support identification of changes, toxicities

• Communication between nurse and patient/interprofessional colleagues is critical

• Holistic care of and education for patients is fundamental

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Application to Practice: Case Studies and Nursing Considerations

Case Study #1

• 25 year old female, multiply relapsed ALL, Day +7 post Kymriah Infusion

• Persistent, refractory fevers• Persistent headache• SBP <90mmHg, required

fluid bolus and low dose norepinephrine

• SpO2<90% on room air, requiring oxygen

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Grading CAR-T Related CRS

Treatment of CRS

• Transferred to ICU

• Complete infectious work up to rule out sepsis

• Hypotension responded to low dose vasopressors

• Given tocilizumab x3 doses

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ICANS Assessment

• Hallucinations

• Confused/ Disoriented

• Handwriting changes

• CARTOX-10 score 5/10

• No seizures

Grading Immune Effector Cell Associated-

Neurotoxicity Syndrome

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Treatment of ICANS

• Previously transferred to ICU

• Corticosteroids given

• Symptoms resolved in ---- days

Case Study #2

• 19 year old female, multiply relapsed ALL, post infusion Day +5

• Tachycardia• Persistent Fever• Hypoxia requiring 2L NC

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Grading CAR-T Related CRS

Treatment of CRS

• Tocilizumab x2 doses

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ICANS Assessment

• AOx3

• CARTOX-10 score of 10/10

• Headaches

ReferencesBayer, V., Amaya, B., Baniewicz, D., Callahan, C., Marsh, L., & McCoy, A.S. (2017). Cancer immunotherapy: An evidence-based overview and implications for practice. Clinical Journal of Oncology Nursing, 21(Suppl. 2), 13–21. https://doi.org/10.1188/17.CJON.S2.13-21Brahmer, J.R.,Bonifant, C.L., Jackson, H.J., Brentjens, R.J., & Curran, K.J. (2016). Toxicity and management in CAR T-cell therapy. Molecular Therapy Oncolytics, 3, 16011. https://doi.org/10.1038/mto.2016.11Callahan, C., Baniewicz, D., & Ely, B. (2017). CAR T-cell therapy: Pediatric patients with relapsed and refractory acute lymphoblastic leukemia. Clinical Journal of Oncology Nursing, 21(Suppl. 2), 22–28. https://doi.org/10.1188/17.CJON.S2.22-28Mahadeo KM, Khazal SJ, Abdel-Azim H, et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nature reviews. Clinical oncology. 2018.Maude, S.L., Shpall, E.J., & Grupp, S.A. (2014). Chimeric antigen receptor T-cell therapy for ALL. Hematology: American Society of Hematology Education Program Book, 559–564. https://doi.org/10.1182/asheducation-2014.1.559Maus, M.V., Grupp, S.A., Porter, D.L., & June, C.H. (2014). Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood, 123, 2625–2635. https://doi.org/10.1182/blood-2013-11-492231McConville, H., Harvey, M., Callahan, C., Motley, L., Difilippo, H., & White, C. (2017). CAR T-cell therapy effects: Review of procedures and patient education [Online exclusive]. Clinical Journal of Oncology Nursing, 21, E79–E86. https://doi.org/10.1188/17.CJON.E79-E86Neelapu, S.S., Locke, F.L., & Go, W.Y. (2018). CAR T-cell therapy in large b-cell lymphoma. New England Journal of Medicine,15;378(11):1065. doi: 10.1056/NEJMc1800913. Neelapu, S.S., Tummala, S., Kebriaie, P., et. al. (2017). Chimeric antigen receptor T-cell therapy assessment and management of toxicities. Nature Review Clinical Oncology, 15(1): 47-52. doi: 10.1038/nrclinonc.2017.148. Reimschissel, E., Dela Cruz, B., Gonzalez, M., Buitrago, J., Goodman, C., & Johnston, P. (2017). ImmunothDOI: 10.1188/17.CJON.S2.41-44erapy Toxicities: A New Electronic Documentation Template to Improve Patient Care. Clinical Journal of Oncology Nursing, 21(2), 41-44. Kymriah. [Package insert]. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM573941.pdfYescarta [Package Insert]. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM581226.pdfLee, Daniel W. et al. “ASBMT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells.” Biology of Blood and Marrow Transplantation (2018), doi: https://do.org/10.1016/j.bbmt.2018.12.758

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Many Thanks To:

TEAM Pedi SCTCT at MD Anderson• Dr. Kris Mahadeo, Section Chief

• Dr. Sajad Khazal, Assistant Professor

• Dr. Demetrios Petropoulos, Professor

• Jeffrey Miller, MSN, RN, FNP

• Silvia Saenz, RN, CPN

• Estela Ceja, PharmD, BCOP

• Suzanne Gettys, PharmD, BCOP

• Lindsay Robusto, BCOP

AND • Patricia Amado, MS, RN, CNL

• Sherry Adkins, RN

• Kelly Brassil, PhD, RN

• Misha Hawkins, MSN, RN, OCN

• Jessica Pena, BSN, RN, OCN

• Maritza Salazar-Abshire, Med, MSN, RN, CPON

• Shea Simon, MS, RN, OCN

• Carra Hartley, BSN, RN, CPN

• Janet Smith, BSN, RN, CPON

• Chloe Tillman, MSN, RN, CPN

Sarah Featherston

skfeatherston@mdanderson.org

Sajad Khazal

sjkhazal@mdanderson.org

Questions?