CAR T – nursing perspective Órla Stewart Lead Nurse, Haematology Kings College NHS Foundation Trust
CAR T – nursing perspective
Órla Stewart
Lead Nurse, Haematology
Kings College NHS Foundation Trust
CAR-T
Immunotherapy using genetically engineered T cells to express a chimeric antigen receptor is a relatively new technology in haematological malignancies, which has demonstrated promising results in early clinical trials1–3
There are significant toxicities1,2
The nature of the cellular therapy product can dictate the variability in side effects1–3
CAR-T: chimeric antigen receptor T cell.1. Locke FL, et al. Lancet Oncol. 2019;20:31–42; 2. Schuster SJ, et al. N Engl J Med. 2019;380:45–56; 3. Miliotou AN, Papadopoulou LC. Curr Pharm Biotechnol. 2018;19:5–18.
The commercial CARs
Axicabtagene ciloleucel made by Kite Gilead, licensed and approved for use in England for DLBCL, TFL and PMBL treated with two or more prior lines of therapy1
Tisagenlecleucel made by Novartis, licensed and approved for use in England for DLBCL and TFL treated with two or more prior lines of therapy2
Tisagenlecleucel made by Novartis, licensed and approved for use in England for ALL in the under 25s following two lines of prior therapy3,4
ALL: acute lymphoblastic leukaemia; DLBCL: diffuse large B cell lymphoma; PMBL: primary mediastinal B cell lymphoma;
TFL: transformed follicular lymphoma.
1. Axicabtagene ciloleucel SmPC. Available at: https://www.medicines.org.uk/emc/product/9439; 2. Tisagenlecleucel SmPC. Available at: https://www.medicines.org.uk/emc/product/9456; 3. NHS England. CAR-T therapy. Available at: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/ [Accessed June 2019]; 4. National Institute for Health and Care Excellence. TA554. December 2018.
The commercial CARs
Seven UK Adult/TYA, two paediatric in first-phase CAR-T centres in UK1,2
September 2018 – NHS announces funding for ALL in under 25s1,3
October 2018 – NHS announces funding for DLBCL1,4
A service is needed!
TYA: teenager and young adult.1. NHS England. CAR-T therapy. Available at: https://www.england.nhs.uk/cancer/cdf/car-t-therapy/ [Accessed June 2019]; 2. Órla Stewart, personal communication; 3. National Institute for Health and Care Excellence. TA554. December 2018; 4. National Institute for Health and Care Excellence. TA567. March 2019.
Nursing challenges
Training – managing toxicities
Capacity – apheresis, stem cell lab, manufacturing slots, wards
Patient demographic
Follow-up
Referral centre
Órla Stewart, personal communication.
Consultant Clinic-1
- Initial discussion about risks and benefits of treatment, management of toxicities. Appropriate PIL given- Define core work-up to be completed prior to national MDT- Define staging investigations needed- Arrange apheresis slot request within appropriate timeline- CAR-T CNS to liaise with manufactuing site to align harvest dates
Consultant Clinic-2
- Recommend and plan bridging therapy- Define re-staging investigations needed- Provisional TCI date given- Referral to ambulatory care
- CAR-T fellow and CAR-T CNS see patient in designated consent clinic- Apheresis nurse consultation - KCH ATMP/ATIMP collection consent- Product-specific consent
Apheresis/
product consent
Pre CAR-T Clinic- Once successful manufacture has been confirmed- CAR-T consultant/fellow and CAR-T CNS see patient in designated clinic- KCH ATMP/ATIMP consent completed
Within ten days of referral
CAR-T
referral
Ap
he
resi
s/p
rod
uc
t co
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nt
nat.
MDT
Corework-up
Additionalwork-up
Co
nsu
lta
nt
Cli
nic
-2
CA
R-T
D-4
Co
nsu
lta
nt
Cli
nic
-1
Bridging chemo
Repeat work-up
Pre
-CA
R-T
clin
ic
TCI D-1
Lympho-depletion
Re-staging
Staging
Ap
her
esis
Within four weeks of consultant clinic
KC
H M
DT
KC
H M
DT
Ambu
ATIMP: advanced therapy investigational medicinal product; ATMP: advanced therapy medicinal product; CNS: clinical nurse specialist; KCH: King’s College Hospital; MDT: multidisciplinary team; nat.: national;
PIL: product information leaflet; TCI: To come in. Órla Stewart, personal communication.
Education of patient and carer
Offer referral for psychological support
Ensure patient has a keyworker
Housing
Benefits advice
Childcare
Patient and carer support
Órla Stewart, personal communication.
Apheresis
Vein assessment
Ensure adequate lymphocyte count
Virology testing
Cessation of prior therapies
Consider slot availability for:
• Apheresis
• Stem cell lab
• Manufacturing slot
Órla Stewart, personal communication.
Nursing considerations pre CAR-T administration
Assessment of eligibility (variable dependent on trial/product)
Consider: carer availability, disease status, work-up, toxicities from previous treatment
Communication is the key
Órla Stewart, personal communication.
Nursing considerations pre CAR-T administration
Ensure free of active infection
Prophylactic medications
Inform ITU outreach
ITU: intensive care unit.Órla Stewart, personal communication.
Lymphodepletion
Usually ~3 days
Consider location: inpatient vs ambulatory
Central venous access device
Consent
CARTOX: CART-T cell therapy-associated TOXicity program; ICANS: immune effector cell-associated neurotoxicity syndrome.Órla Stewart, personal communication.
Nursing care on day of administration
• Clinically stable – CAR-T review on D0
• Baseline CARTOX/ICANS
• Liaison with Stem Cell Lab & Pharmacy
• Tocilizumab prescribed and available in clinical area
• Administer pre-meds (NO STEROIDS)
• Infuse cells as per local policy
• Documentation to be completed as per local policy and trial protocols
Infusion reactions
Unusual
Usually related to DMSO
Principles:
• Increased vital signs
• Administer anti-emetics
• Inform medical team and outreach teams if indicated
• Treat symptomatically
• Avoid steroids
DMSO: dimethyl sulfoxide.
Nursing care after CAR-T cell administration
Regular vital signs
Neurotoxicity assessment (ICANS)
CRS assessment
Daily bloods (include ferritin, blood film)
Fluid balance chart
Daily weight
CMV/adeno for allogeneic products
Adeno: adenovirus; CMV: cytomegalovirus; CRS: cytokine release syndrome.Órla Stewart, personal communication.
Toxicity
Cytokine Release Syndrome (CRS)
Neurotoxicity
Sepsis
HLH
HLH: heamophagocytic lymphohistiocytosis. 1. Locke FL, et al. Lancet Oncol. 2019;20:31–42; 2. Schuster SJ, et al. N Engl J Med. 2019;380:45–56; 3. Órla Stewart, personal communication.
Trial Product Disease area G3/4 CRS G3/4 ICANS
ZUMA-11 axicabtageneciloleucel
DLBCL, PMBCL 13% 28%
Transcend2 tisagenlecleucel DLBCL 1% 13%
Juliet3 tisagenlecleucel DLBCL 23% 12%
CRB-4014 BB2121 Myeloma 2% <1%
Incidence of CRS/neurotoxicity
1. Locke FL, et al. Lancet Oncol. 2019;20:31–42; 2. Abramson JS, et al. J Clin Oncol. 2018;36:120;3. Schuster SJ, et al. N Engl J Med. 2019;380:45–56; 4. Raje N, et al. ASCO 2018; Abstract 8007.
CRS
Unpredictable timing – product-dependent
Differing grading schemas
The need for collaboration between centres
ASBMT consensus grading
ASBMT: American Society for Blood and Marrow Transplantation.Órla Stewart, personal communication.
Case study 1
61-year-old male
2014 May with DLBCL with BG of FL
2014 July RCHOP + radiotherapy + rituximab maintenance x two years
2016 radiotherapy
2017 Feb–June PERSISTENT DISEASE GDP/IVE + LEAM transplant
2017 Oct–Nov radiotherapy due to small area of positivity
2018 relapsed with DLBCL
BG: background; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; GDP: gemcitabine, dexamethasone, cisplatin; IVE: ifosfamide, epirubicin, etoposide; LEAM: lomustine, etoposide, cytarabine, melphalan; R: rituximab.
Case study 1 – What next?
Referred for CAR T therapy
First NHS Lymphoma patient to be approved & infused in UK
Started collecting material in December 2018
Patient very well – no bridging required
Case study 1 – clinical course
Tolerated lymphodepletion well as an outpatient
Admitted D -1
D 0 – uneventful
D +3 developed fevers of 40 °C
Continued to feel well
Heamodynamically stable
Started on first-line antibiotics
Fevers continued 39–40 °C every 3–4 hours
ASBMT consensus grading of CRSCRS parameter* Grade 1 Grade 2 Grade 3 Grade 4
Fever#† Temperature 38 °C Temperature 38 °C Temperature 38 °C Temperature 38 °C
With either:
Hypotension# NoneNot requiring vasopressors
Requiring one vasopressor with or without vasopressin
Requiring multiple vasopressors (excluding vasopressin)
And/or‡
Hypoxia# NoneRequiring low-flow nasal cannula^or blow-by
Requiring high-flow nasal cannula^, facemask, non-rebreather mask, or Venturi mask
Requiring positive pressure (e.g. CPAP, BiPAP, intubation and mechanical ventilation)
* Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.# Not attributable to any other cause.† In patients who have CRS then receive tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.‡ CRS grade is determined by the more severe event.^ Low-flow nasal cannula is 6 L/min and high-flow nasal cannula is >6 L/min.Lee DW, et al. Biol Bone Marrow Transplant. 2019;25:625–38.
BiPAP: bilevel positive airway pressure; CPAP: continuous positive airway pressure;
CTCAE: common terminology criteria for adverse events.
ALT: alanine aminotransferase; ECG: echocardiogram; GI: gastrointestinal; IEC: immune effector cell.Órla Stewart, personal communication.
Órla Stewart, personal communication.
CRS treatment
Tocilizumab1
• Monoclonal antibody targeting IL6
• Now licensed for the treatment of CRS
• Dose 8 mg/kg (not to exceed 800 mg per dose) Can give 8-hourly, up to a maximum of 4 doses
Steroids
Other agents: infliximab, siltuximab, anakinra, etanercept (none licensed)2
1. Tocilizumab Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/9086/smpc [Accessed May 2019]; 2. Órla Stewart, personal communication.
Case Study 1 contd
CRS grade 1
However, remained pyrexial for greater than 72 hours despite IV Abs
Two doses of tocilizumab given
Patient discharged at D +14
D +28 PET scan, vgPR
D +90 PET scan, vgPR
Abs: antibiotics; vgPR, very good partial response; IV: intravenous; PET: positron emission tomography.
Case study 2
38-year-old male
Diagnosed early 2018 with stage IVb DLBCL
Treatment
• R-CHOP x 6 (rev x 3) + HD methotrexate x 2 + R x 2 relapse
• R-DHAP x 2 Persistent disease November 2018 referred for axicabtagene ciloleucel seen at KCH November 2018
• R-IVE 3rd Dec 2018 progressive disease
• Steroids over Christmas
• Planned admission for CAR-T treatment (axicabtagene ciloleucel)
DHAP: dexamethasone; high dose cytarabine, cisplatin; HD: high dose.
PET pre CAR T
treatment Dec 2018
Case study 2 – clinical course
Admitted with fevers, feeling unwell 24 hours after stopping steroids
Differential
• Infection or disease
Management
• Temp 38.5 °C, swollen right leg, right groin lymphadenopathy
• Cultures/CXR neg, U/S – groin lymph node, no DVT
• CRP 182, then ↑300
• Tazobactam 48 hours then meropenem/vancomycin
• CRP 209 fevers
• Lymphodepletion started 5th January
CXR: chest x-ray; CRP: c-reactive protein; DVT: deep vein thrombosis; U/S: ultrasound.
Case study 2 – clinical course
Lymphodepletion – uneventful
Day 0 – cell infusion
• CRS grade 19 hours post-infusion Temp 39, pulse 120,
BP 116/77
• Tocilizumab #1Day +2 persistent fevers,
tachycardia (Grade 1 CRS)
• Tocilizumab #2• IV fluids
Day +3 ongoing fevers, hypotension
(Grade 2 CRS)
• Tocilizumab #3• Dex 10 mg BD
Day +4
BD: twice daily; BP: blood pressure; dex: dexamethasone.
Case study 2 – clinical course
Day +9 to Day +12
• Headache, unsteadiness, tremor, restless, anxious, insomnia
• CARTOX score 10 but handwriting slightly worse?
• MRI head normal
• EEG (Day +12) abnormal
• LP raised CSF protein, lymphocytosis
• Diagnosis: CRES grade 2
• Restarted dex, anakinra for grade 2 CRES
• Also zopiclone
• Clinical improvement in 24 hours
Day +14
• Steroids weaned off, last dose anakinra,
• Discharged Day +18
CRES: CAR-related encephalopathy syndrome; CSF: cerebrospinal fluid; EEG: electroencephalogram; LP: lumbar puncture; MRI: magnetic resonance imaging.
Órla Stewart, personal communication.
Neurotoxicity
Immune-Effector- Cell- Associated Encephalopathy Neurotoxicity Syndrome – ICANS1
New consensus grading system2
Training implications1
Treated with steroids, anti-epileptics (if indicated) and supportive care1
1. Órla Stewart, personal communication; 2. Lee DW, et al. Biol Bone Marrow Transplant. 2019;25:625–38.
ASBMT consensus encephalopathy assessment tool
CARTOX tool ICE tool
Orientation: orientation to year, month, city, hospital, President: 5 points
Naming: name 3 objects (e.g. point to clock, pen, button): 3 points
Writing: ability to write a standard sentence (e.g. our national bird is the bald eagle): 1 point
Attention: count backwards from 100 by ten: 1 point
Orientation: orientation to year, month, city, hospital: 4 points
Naming: Name 3 objects (e.g. point to clock, pen, button): 3 points
Following commands: (e.g. show me two fingers or close your eyes and stick out your tongue): 1 point
Writing: ability to write a standard sentence (e.g. our national bird is the bald eagle): 1 point
Attention: count backwards from 100 by ten: 1 point
ICE: immune-effector cell-associated encephalopathy.1. Órla Stewart, personal communication; 2. Lee DW, et al. Biol Bone Marrow Transplant. 2019;25:625–38.
Órla Stewart, personal communication.
Órla Stewart, personal communication.
Three months post CAR-T April 2019
Follow-up
Will usually need to stay in close proximity to centre until 28 days following infusion
Route back in to hospital
Carer responsibility
Arrange scanning – consider patient location
Potential for late onset side effects
Órla Stewart, personal communication.
Future challenges
Training
Close liaison with referring centres
Volume of patients vs infrastructure of the hospital
Turnover of staff
Media – friend or foe?!
Monitoring of long-term side effects
Órla Stewart, personal communication.
Opportunities
• Long-term follow-up: nurse-led
• Shared learning/collaboration
• Nurse-focused study events