1. 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.

2. 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.

3. 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!

4. 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

5. 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.

6. 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.

7. CRS Fevers are the first sign of cytokine release syndrome (CRS)
ALL: 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.

8. 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

9. 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

10. 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.

11. 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.

12. 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

13. 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

14. 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

15. 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)

16. 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

17. 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”

18. References
Lee, D., Gadner, R., Porter, D., Louis., Ahmed, N., Jensen, M….Mackall, C ). Current concepts in the diagnosis and manaement of cytockine release syndrome. Blood Journal, doi /blood
Mause, S. L., Barrett, D., ., Grupp, S. (2014). Managing cytokine release syndrome associated iwth novel T cell-engaging therapies. Then Cancer Journal, 20(2):
National Institutes of Health (2014). Procedure: Infusion of cellular theapy products via syringe. Procedure: Administration of Cellular Therapy Products. Retrieved from O_Cellular_Therapy_Infusion.pdf.

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

20. 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