Tips For the Bedside Nurse By: Jolene Staszek RN,BSN,OCN Car T-cell Therapy Tips For the Bedside Nurse By: Jolene Staszek RN,BSN,OCN This presentation is a summary of what I learned from an industry sponsored event by the Leukemia and Lymphoma Society, form this years ONS congress. This event was called CAR T Cell Therapy, The Nurse’s Role in treating Patients.

What is CAR T-Cell Therapy? It stands for (Chimeric Antigen Receptor) T-Cell Therapy T-Cells are isolated from the patient The T-Cells are then engineered to express CARS that recognize cancer cells Modified T-Cells are grown and expanded, and then infused into the patient This adoptive cellular therapy transfers cells into the patient with the goal of targeting malignant cells It is an immunotherapy, where the patient’s own immune system is used, The T Cells are isolated, modified, expanded, and then infused back into the patient. The patient becomes a genetically Modified Organism. The T Cell attack and destroy the cancer.

Success Rates With Studies completed with CD19, there has been much success. CD19 is expressed on most B Cell malignancies. Complete Remission (CR) success rates: Pediatric patients with ALL : 70-94% CR Adults patients with ALL: 82-94% CR CR for Lymphoma is not as good, but pts have responded to treatment: CLL 39-74% overall response rate, 21-28% CR NHL 67-76% overall response rate, and 12-47% CR I got so excited about CAR T Cell Therapy because, Its Working!

Infusion Process Patients undergo conditioning chemotherapy prior to the infusion of the Car T-Cells This particular institution uses Fludarabine and Cyclophosphamide on day -5, or day -3 depending their protocol Car T-Cells are administered on day 0, via a side port of a Normal Saline infusion Once the Car T-19 Cells enter the patients body, the T-Cells get revved up and start the cytokine release response, which causes the killing of the CD19 leukemia This process is similar to stem cell reinfusion

Infusion Reinfusion takes place at the clinic Similar to a platelet transfusion it takes about an hour Labs are drawn, and vital signs are monitored Patients can have reactions to the cells (rigors, chills, fevers) Patients stay in the clinic until 5pm before being discharged At this particular facility the infusion is completed at an out patient clinic. I’m excited to see how it would work in my hospital in the future.

Toxicity No significant acute infusion toxicity Hepatotoxicity, renal toxicity- dialysis B Cell aplasia and Hypogammaglobulinemia IVIG infusions Tumor Lysis Syndrome Monitor daily labs for Elevated uric acid , LDH, CR Rasburicase, allopurinol, fluids, etc. Cytokine Release Syndrome (CRS) Patients have long term treatment wit IVIG infusions. The treatment eliminates all B Cells.

CRS Fevers are the first sign of cytokine release syndrome (CRS) ALL: 12-24 hours up to 5 days post infusion CLL: 5-10 days post infusion Lymphoma: 2-10 days post infusion CRS can occur between 12 hours and 3 weeks post CAR T-19 reinfusion Can also cause ARDS or hypotension Sepsis Because the fever could be from another source, other than the therapy, a Sepsis workup must be completed.

CRS Cytokine release syndrome Fevers as high as 106F Result of CAR T-Cells attacking CD19+leukemia Fevers as high as 106F Hypotension, ARDS, Capillary leak-Pulmonary edema Profound tumor lysis Cytopenias Hyperferritinemia (as high as 20K) Acute Kidney Failure (dialysis) CRS can be persistent for up to 2 weeks and patients may need to be transferred to the ICU, for hemodynamic stability

CRS Occurs with immune activation after administration of T-Cells Most common side effect of Car T-Cell infusion Pathophysiology: Lymphocytes and myeloid cells become activated and release large numbers of cytokines Cytotoxic T-Cells (CAR T-Cells) proliferate Elevated IL-1,TNF, IL-5, and IL-6 among others IL-6 central mediator of toxicity Will see elevated CRP, ferritin, and coagulopathy

Nursing Management CRS can range from mild response to severe Can be fatal response: Nursing recognition, assessment, and management is of utmost importance Symptoms can mimic sepsis or infection Can be present immediately to weeks after the infusion Patients with larger tumor burden seem to be at greater risk for severe CRS Flow Cytometry with bone marrow biopsy will show the effectiveness of the treatment, not the dramatic response.

Neurologic Toxicities May occur apart from CRS IL-6 can cross the blood-brain barrier, which is thought to be responsible for neurotoxicity Signs and Symptoms include: Confusion Somnolence Tremors Gait instability Aphasia, other speaking difficulties Seizures Give supportive care, reorient pt, and antiepileptic Assess patient by completing neurological examination.

Severe CRS – Organ Dysfunction Cardiomyopathy ARDS Renal Failure Liver Failure Lab abnormalities: Elevated C-Reactive Protein Elevated PT/INR, PTT: decreased fibrinogen; elevated D-Dimer Elevated Liver Enzymes + increased bilirubin Elevated ferritin

Antidote IV corticosteroids (only used in life threatening situations) It is thought that it damages the CAR T-Cells and stops their functioning Tocilizumab mediates IL-6 One dose is usually sufficient

Tocilizumab Anti-cytokine agent, drug for arthritis Works to inhibit IL-6, which is believed to cause CRS Reverses the CRS reaction and shuts down the T-Cells Temperatures and BPs back to normal within hours The drug is only used if the patient is becoming unstable Administering it too early can cause the T-Cells to shut down, thus defeating the purpose of the treatment

Management of CRS Control fevers Acetaminophen, ice packs, cooling blanket is not recommended Maintain oxygenation ** DO NOT give steroids** Maintain blood pressure **Monitor lab values closely** Organ function is likely to be severely altered Tbili >7, Creatinine >3 The goal is to get the patient through the CRS without administering the antidote (tocilizumab)

Nursing Assessments Premedicate prior to infusion Vital signs pre-infusion, 15 minutes into infusion and then immediately after Neurological assessment every shift and on going (listen to the family) Look for new onset tremors, lethargy, slurred speech, expressive aphasia, gait issues Intake and output q8 hours Watch labs: CRP, liver enzymes, creatinine, PTT, PT/INR, CBC/diff, chemistries Fever of 37.8C if outpt, and 38C or above as inpt Educate family if outpt to call for any neurological concerns or fever

Nursing Management Head to toe assessment: Avoid confirmation bias look for capillary leak (lung sounds), or any other complaints Avoid confirmation bias CRS can mimic sepsis- think of differential diagnosis Prepare family and pt for possible ICU admission Reinforce signs/symptoms of CRS Support: Some patients who experience mild symptoms may think the CAR T-Cells are “not working”

References Lee, D., Gadner, R., Porter, D., Louis., Ahmed, N., Jensen, M….Mackall, C. 92014). Current concepts in the diagnosis and manaement of cytockine release syndrome. Blood Journal, 118-195. doi10.1182/blood-2014-05-552729. Mause, S. L., Barrett, D., ., Grupp, S. (2014). Managing cytokine release syndrome associated iwth novel T cell-engaging therapies. Then Cancer Journal, 20(2): 119-122. National Institutes of Health (2014). Procedure: Infusion of cellular theapy products via syringe. Procedure: Administration of Cellular Therapy Products. Retrieved from http://intranet.cc.nih.gov/nursing/practicedocs/procedures_pdf/PR O_Cellular_Therapy_Infusion.pdf.

References (cont.) Amedeo Amedei et al. Clinical and Developmental Immunology, vol. 2011, Aricle ID 320571. Park JH, Geyer MB, Brentjens RJ. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date. Blood. 2016; 17926):3312-3320. Turtle et al, J Clin Invest, 2016; ASCO#102, 2016.

Keep Learning! ONS Immunotherapy Course Article in the May 2017, edition of: ONS Voice, Nursing Considerations for Adverse Events From CAR T-Cell Therapy, by Elisa Becze, BA, ELS, Editor