nursing Órla Stewart perspective

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

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MDT

Corework-up

Additionalwork-up

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Bridging chemo

Repeat work-up

Pre

-CA

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TCI D-1

Lympho-depletion

Re-staging

Staging

Ap

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esis

Within four weeks of consultant clinic

KC

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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


Apheresis

Vein assessment

Ensure adequate lymphocyte count

Virology testing

Cessation of prior therapies

Consider slot availability for:

• Apheresis

• Stem cell lab

• Manufacturing slot


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


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.

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


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.


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.


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.

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.

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


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


Opportunities

• Long-term follow-up: nurse-led

• Shared learning/collaboration

• Nurse-focused study events

Thank you

[email protected]

mailto:[email protected]

nursing Órla Stewart perspective

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