neurotoxicity in car-t learning objectives therapy

2/17/20

1

Neurotoxicity in CAR-T Therapy

Haneen Shalabi, DOAssistant Research Physician

Pediatric Oncology BranchNational Cancer Institute

TCT Meeting February 20, 2020

1

Learning Objectives

• To provide a brief overview of chimeric antigen receptor T cell therapy (CAR-T) and side effects

• To review neurotoxicity associated with CAR-T therapy

• To use case-based vignettes to discuss the current evaluation and treatment of CAR-T related neurotoxicity

2

American Society for Transplantation and Cellular Therapy Practice Guidelines

• There is an APP for that!

3

Chimeric Antigen Receptor T cells (CAR T) are Reprogrammed T cells Used to Target and Eliminate Cancer Cells

• Customized receptor• Extracellular antigen-binding domain• Intracellular signaling domain of T cells

• Recognize cell surface antigens independent of MHC, have co-stimulatory signals integrated

• Retains the functionality of a T-cell with the antigen recognition properties of antibody

Lee DW, et al. Clin Cancer Res 2012

4

2/17/20

2

Making a CAR-T Cell

1. Apheresis

2. Stimulation and Transduction

3. Expansion

4. Lymphodepletion

5. Infusion

Image, Courtesy of NIH Medical Arts

5

CD19 CAR Therapy is Effective in ALL and Lymphoma

Maude, SL NEJM 2018Gardner, RA Blood 2017Lee, DW Lancet 2015Locke, FL Lancet Oncol 2019Schuster, SJ Blood 2017

Trial CARConstruct

Name Disease Age Response rate

Eliana CD19-41BB Tisagenlecleucel* ALL Peds 81% CR

PLAT-02 CD19-41BB ALL Peds 89% CR

NCI CD19-28z ALL Peds 67% CR

Zuma-1 CD19-28z AxicabtageneCiloleucel*

DLBCL Adult 84% ORR

Juliet CD19-41BB DLBCL Adult 53% ORR

MSKCC CD19-28z ALL Adult 83% CR

* Represents FDA approved products

6

CD22 CAR Therapy is Effective as a Salvage Therapy After CD19 Directed Therapy

• NCI Phase I experience

• 51/58 patients infused had prior CD19 targeted therapy

• 40/57 patients had complete response 57 62 20 1 6 5 3 4 10 13 15 19 29 41 45 59 42 2 7 8 9 1214 16 17 18 21 22 23 25 26 27 31 32 3334 35 36 37 38 39 40 44 4647 48 49 50 51 52 53 54 55 56 58 61 63

-100

-50

0

50

100

Subject ID

%M

axim

um C

hang

e in

Leu

kem

ia B

urde

n

No CRSNo CRS

Grade 1-2 CRSGrade 3-4 CRS

Dose Level 1Dose Level 2

Dose Level 3Dose Level 2 TCS

Dose Level 1 TCS

Fry/Shah Nat Med 2018Shah et al. In revisions

7

FDA Approval Granted for First Gene Therapy in Pediatric Patients in US

• Kymriah™ (tisagenlecleucel, Novartis):• For children up to age 25 with ALL (August 2017)• For adults with diffuse large b cell lymphoma (May 2018)

• Yescarta™ (axicabtagene ciloleucel, KITE): • For adults with diffuse large B cell lymphoma (October 2017)

• CD22 CAR T cell (NCI):• Breakthrough Drug Designation by FDA in August 2019

• For pediatric patients that are CD19 negative or relapsed/refractory to CD19 directed therapy

• Complete remission rates: +/- 50-80%

8

2/17/20

3

Cytokine Release Syndrome is the Most Common Side Effect

• Constellation of symptoms due to supraphysiologic cytokine production.

• Onset occurs within hours to days post infusion

• Severity of CRS correlates with:• Disease burden• Lymphodepleting chemotherapy• Cell dose

Brudno/Kochenderfer Blood 2017

9

Discrepancies Existed Amongst Published CRS Grading Scales (2009-2017)

Grading System

Grade 1 Grade 2 Grade 3 Grade 4

Lee Criteria Symptoms are not life threatening, and require symptomatic treatment only

Symptoms require and respond to moderate intervention:• Hypotension responsive to

IV fluids or low dose pressors

• Hypoxia: requiring FiO2< 40%

• Grade 2 organ toxicity

Symptoms require and respond to aggressive intervention:• Hypotension requiring high

dose or multiple pressors• Hypoxia requiring FiO2 >

40%• Grade 3 organ toxicity • Grade 4 transaminitis

Life threatening symptoms:• Requirement for

ventilatory support• Grade 4 organ toxicity

(excluding transaminitis)

Penn Criteria Mild reaction, treated with supportive care such as antipyretics, antiemetics

Moderate reaction: • Organ dysfunction• Hospitalization for

management of CRS-related symptoms including neutropenic fevers, IV fluids

More severe reaction:• Hypotension treated with

multiple boluses or low-dose pressors

• Hypoxia• Organ dysfunction • Coagulopathy requiring

transfusions

Life threatening complications:• Hypotension requiring

high dose vasopressors

• Hypoxia requiring mechanical ventilation

CARTOX Temperature > 38Grade 1 organ toxicity

• Hypotension responds to IV fluids or low-dose pressors

• Hypoxia: requiring FiO2< 40%

• Grade 2 organ toxicity

• Hypotension requiring multiple or high-dose vasopressors

• Hypoxia requiring FiO2 > 40%

• Grade 3 organ toxicity or grade 4 transaminitis

Life threatening symptoms:• Ventilatory support• Grade 4 organ toxicity

(excluding transaminitis)

10

ASTCT CRS Consensus Guidelines

New Guidelines:• CRS Severity is determined by hypotension and hypoxia

• Grade is determined by the more severe event• Notably, organ toxicities are not included in new CRS definitions and do not affect grading

• *Once anti-cytokine treatment is given, fever is no longer applicable

CRS Parameter Grade 1 Grade 2 Grade 3 Grade 4Fever* Temp > 38 C Temp > 38 C Temp > 38 C Temp > 38 C

WITH

Hypotension None Not requiring vasopressors

Requiring a vasopressor with or without vasopressin

Requiring multiple vasopressors (excluding vasopressin)

AND/OR

Hypoxia None Requiring low-flow nasal cannula or blow by

Requiring high-flow nasal cannula, face mask, non-rebreather

Requiring positive pressure (CPAP, BIPAP, intubation and mechanical ventilation)

11

Treatment of CRS • Tocilizumab

• Humanized IL-6 receptor inhibiting monoclonal antibody

• FDA approval August 31, 2017:• Indication approval for treatment of CAR

T cell induced CRS

• Steroids

• Siltuximab• Anti-IL-6 chimeric monoclonal antibody • Second/Third line CRS agent

• Anakinra• IL1 receptor antagonist• Used to block pro-inflammatory effects

of IL-1

have additional comorbidities that put them atincreased risk and for grade 3 and 4 CRS for all patients(Table 5.7). However, many practitioners will choose tointervene earlier. For example, an elderly patient with afever for more than 72 hours or a very high fever(>40.5!C) may not tolerate the resulting sinus tachy-cardia as well as a younger patient, so tocilizumabmay be indicated. A shift toward intervening with anti-cytokine therapy at grade 2may be forthcoming, even inyoung, fit patients, as we gain more confidence thatsuch a maneuver does not decrease the efficacy of theCAR T-cell therapy. Every clinical situation is unique.The practitioner must use his or her best clinical judg-ment when deciding when to employ anticytokinetherapy.

Tocilizumab is the only FDA-approved therapy forsevere or life-threatening CRS and as such should begiven as first-line therapy (Table 5.6 ). However, somepractitioners will concurrently give at least one dose of

steroids (Table 5.6 ) with the first dose of tocilizumab.The theory behind this practice is that steroids mayhelp offset any increased risk of developing ICANS inpatients treated with tocilizumab for CRS. No

TABLE 5.6Recommended Anti-Cytokine Agents and Dosing (Where Reasonable Data are Available).

Drug Dose Route Comments

Tocilizumab40 8 mg/kg/dose (max 800 mg/dose)over 60 minutes

IV Premedicate with acetaminophen anddiphenhydramineMay repeat q6e8 hours;Give steroids with second doseDecreased utility with >3 doses

Dexamethasone 1 mg/kg/dose (max 10 mg/dose) IV Preferred if concurrent ICANSConsider over methylprednisolonedue to improved CNS penetrationeven in absence of neurotoxicityMay dose q6-24 hours depending onclinical response/needsRapid (5 e7 day) wean once CRS "grade 1

Methylprednisolone 1 mg/kg/dose (max 100 mg/dose) q4e6 hoursOr 30 mg/kg/dose (max 1000 mg/day)

IV Consider dexamethasone due toimproved CNS penetrationUse lower doses for stable-appearingpatientUse high dose for unstable patientsRapid (5 e7 days) wean once CRS "grade 1

Siltuximab 11 mg/kg/dose IV Third-line agentPremedicate with acetaminophen anddiphenhydramine

Anakinra44 2e4 mg/kg/day (may increase to8 mg/kg/day)

SC Third-line agent

Cyclophosphamide Variable IV Third-line agent

Dosing applies to pediatric patients.IV, Intravenous; SC, Subcutaneous; ICANS, Immune effector celleassociated neurotoxicity syndrome; CRS, Cytokine release syndrome.

TABLE 5.7Recommended Timing of Initial Intervention WithTocilizumab and Corticosteroids Based on Gradeof Cytokine Release Syndrome.

Grade CRS (as per ASTCTconsensus criteria) Tocilizumab Steroids

1 No No

2dno comorbidities No No

2dwith comorbidities Yes Consider

3 Yes Consider

4 Yes Yes

60 Chimeric Antigen Receptor T-Cell Therapies for Cancer

Lee DW, et al 2019

12

2/17/20

4

Severe CRS May be Effectively Prevented with Early Treatment

• Increasing use of pre-emptive tocilizumab and/or steroids to prevent more severe CRS

• Early treatment with tocilizumab and/or steroids demonstrated equipotent efficacy of CAR with reduced severity of CRS (Gardner et al)

• New ASTCT guidelines support use of early tocilizumab to reduce severity of CRS

Gardner, RD. Blood 2019Neelapu,S. Nat Rev Clin On 2018Lee, DW. Bio Blood Marrow Transplant 2018

13

Neurotoxicity

14

Reported Incidence of Neurotoxicity is Variable and Depends on CAR construct

• Incidence ranges from 0-64% depending on specific trial, CAR construct, and target

• Severe neurotoxicity (sNT defined as CTCAE > grade 3, and/or seizures) occurs in 5-50% of patients

Lee et al, Bio Blood Marrow Transplant 2018

15

Immune effector Cells Associated Neurotoxicity Syndrome (ICANS)

• Similar to CRS grading, no uniform grading existed prior to ASTCT ICANS

• ICANS: A disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells

16

2/17/20

5

Risk Factors Associated with More Severe Neurotoxicity

• Severity of CRS

• Neurologic co-morbidities

• Disease burden

• Lymphodepletion with Fludarabine/Cyclophosphamide

• Higher CAR T cell doseGust, Cancer Disc 2017

17

Timing of Neurotoxicity Depends on Construct of CAR

*Gust J, Cancer Disc 2017^Santomasso BD, Cancer Disc 2018

NT started at a median of 4 days post CD19-41BBMean highest grade NT was 7 days*

Biomarkers of Neurotoxicity in CD19 CAR T-cell Therapy RESEARCH ARTICLE

AUGUST 2018!CANCER DISCOVERY | 961

Figure 1. Timeline of neurotoxicity (NTX) and association with CRS after conditioning chemotherapy and 19-28z CAR T-cell infusion. A, Colors on the swimmer lane plot indicate the highest grade of any neurologic symptom recorded on each day for patients who developed grade ≥ 1 NTX through the first 30 days after CAR T infusion (n = 33; 11 grade 1–2 NTX, 22 grade 3–4 NTX). Two patients died within 30 days of CAR T-cell infusion (CRS, n = 1; sepsis, n = 1). Two patients had ongoing grade 3 or 4 NTX (sensorimotor neuropathy) at day 30 which improved to mild by days 39 and 96, respectively. Median time to first fever (≥38°C) for patients with mild NTX (blue dotted line) and severe NTX (red dotted line) and median time to first severe (grade ≥3) NTX (red dashed line) are indicated. B, Number of patients with each grade of CRS and neurotoxicity.

A

B

Gra

de 1

–2 N

TX

NTX Gr 0NTX Gr 1NTX Gr 2NTX Gr 3NTX Gr 4

Death

NTX Gr 0NTX Gr 1NTX Gr 2NTX Gr 3NTX Gr 4

0

0 1 2 3CRS grade

4 5

Num

ber o

f pat

ient

s

7 14Days post CAR T cells

21 28

Gra

de 3

–4 N

TX

Treatment of NeurotoxicityThe anti-IL6R monoclonal antibody tocilizumab, with or

without corticosteroid, is often used to mitigate CRS and neu-rotoxicity. Six (18%) of 33 patients with neurotoxicity received tocilizumab alone; 14 (42%) received tocilizumab plus corticos-teroid; 4 (12%) received corticosteroid alone; and 9 (27%) received neither tocilizumab nor corticosteroid (Supplementary Fig. S1). In the 16 patients with severe neurotoxicity who received tocili-zumab, 9 (56.3%) had peak neurotoxicity after the first dose of tocilizumab, whereas 7 (43.7%) had peak neurotoxicity prior to or on the day of tocilizumab administration. Therefore, neuro-toxicity did not respond to tocilizumab administration in most patients. The time from first tocilizumab and/or steroid dose to resolution of neurotoxicity (median, 9 days; range, 4–21 days)

was longer than the time to resolution of CRS (median, 1 day; range, 0–3 days; P < 0.001), confirming previous findings that neurotoxicity is less responsive than CRS to these treatment interventions. Serum cytokines, most notably IL6, but also IL8, IFNγ, G-CSF, and IL10 in some cases, peaked after tocilizumab administration (Supplementary Fig. S2).

Radiographic Findings of NeurotoxicityMRI neuroimaging was obtained in 5 patients with grade

1 to 2 neurotoxicity and was normal in all. Fourteen of 22 patients who developed severe neurotoxicity had cranial MRI performed during acute symptoms. The MRI was normal in 9 patients, and 4 had a common pattern of T2/FLAIR hyper-intensities involving the bilateral thalami and brainstem,

Research. on January 30, 2020. © 2018 American Association for Cancercancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst June 7, 2018; DOI: 10.1158/2159-8290.CD-17-1319

NT started at a median of 5 days post CD19-28zMean highest grade NT 9 days^

18

Etiology of Neurotoxicity is an Area of Active Research

• Cytokines have been implicated

• Endothelial activation can cause disruption of blood brain barrier, increasing permeability

• Endothelial disruption activates angiopoetin (ANG) leading to a proinflammatory/prothrombotic state

• Astrocyte/microglial injury à cerebral edemaGust J, Cancer Disc 2017Santomasso BD, Cancer Disc 2018

19

Clinical Presentations Vary Amongst Patients

Mild

• Tremor

• Dysgraphia: inability to write

• Expressive aphasia

• Apraxia: difficulty following commands

• Confusion

• Headache

Severe

• Seizures in ALL patients receiving CD19 CAR T cells

• CD19-41BB ranges 3-14% • CD19-28z ranges 0-30%

• Delirium

• Global toxic-metabolic encephalopathy^

• Tremors• Hallucinations• Peripheral neuropathy• Weakness

• Cerebral edema

^ Encephalopathy now graded with new grading scale

20

2/17/20

6

Non-Specific Symptoms & Signs are Now Excluded from ICANS Definition

• Headache

• Tremors

• Weakness

• Hallucinations

• Myoclonus

• Intracranial Hemorrhage

21

100 Abbreviated Title: CD19/CD22 T-cell in Peds Version Date: 08/19/2019

2. Cornell Assessment of Pediatric Delirium (CAPD) *For use with children <12 years of age.

Answer the following based on interaction with the child over the course of the shift

Never

4

Rarely

3

Sometimes

2

Often

1

Always

0

1. Does the child make eye contact with the caregiver?

2. Are the child’s actions purposeful?

3. Is the child aware of his/her surroundings?

4. Does the child communicate needs and wants?

Never

0

Rarely

1

Sometimes

2

Often

3

Always

4

5. Is the child restless?

6. Is the child inconsolable?

7. Is the child underactive – very little movement while awake?

8. Does it take the child a long time to respond to interactions?

Encephalopathy Grading Scales

99 Abbreviated Title: CD19/CD22 T-cell in Peds Version Date: 08/19/2019 15.7 APPENDIX G: GUIDELINES FOR EVALUATION, GRADING AND TREATMENT OF CAR-T

RELATED NEUROTOXICITY

15.7.1 Appendix G 1: Encephalopathy assessment tools for grading of Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS)

To determine the ICANS grade, complete the appropriate encephalopathy assessment below:

1. Immune effector Cell-associated Encephalopathy (ICE) *For use with adolescents and adults ≥12 years of age.

Field Suggested Assessment Points

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 2 fingers or close your eyes and stick out your tongue 1 point

Writing Ability to write a standard sentence (e.g. It is a sunny day) 1 point

Attention Count backwards from 100 by 10 1 point

Score ICANS Grade

10 No Impairment

7-9 Grade 1 ICANS

3-6 Grade 2 ICANS

0-2 Grade 3 ICANS

Patient unarousable and unable to perform ICE Grade 4 ICANS

22

ASTCT ICANS Consensus Grading Neurotoxicity Dom ain Grade 1 Grade 2 Grade 3 Grade 4

ICE Score >12 7-9 3-6 0-2 Patient unable to perform ICE

CAPD Score <12 <9 <9 >9 Unable to perform CAPD

Depressed Level of Consciousness

Awakens spontaneously

Awakens to voice Awakens to tactile stim ulation Patient unarousable or requires vigourousstim ulation

Seizure N/A N/A Any clinical seizure focal or generalized that resolve rapidly; or non-convulsive seizures on EEG that resolve with intervention

Life threatening prolonged seizure > 5 m inutes; or repetitive clinical or electrical seizures without return to baseline in between

Motor Weakness N/A N/A N/A Deep focal m otor weakness; hem iparesis, or parapersis

Raised ICP/ Cerebral Edem a

N/A N/A Focal edem a on neuroim aging Decerebrate or decorticate posturing; cranial nerve VI palsy, papilledem a, Cushing’s triad, diffuse edem a on im aging

23

Bedside Assessments are Critical in Monitoring Patients for Neurotoxicity

• Clinical Exam is Key

• History of Events from Family members

• Mini Mental Status Exam/Review of Symptoms

24

2/17/20

7

Further Evaluation of Patients with Neurotoxicity Depends on Degree of Impairment

• Neurology Consult

• CNS Imaging• MRI preferred• CT for acutely ill

• Lumbar puncture to evaluate CSF: • Leukocytosis, lymphocyte predominant• Increased protein

• EEG• Diffuse slowing, non-specific for encephalopathy

25

Prevention of CAR-associated Neurotoxicity

• Seizure prophylaxis

• Tocilizumab • To prevent severe CRS

• Leads to increased IL-6 levels which can cross blood brain barrier potentially worsen neurotoxicity

26

Treatment of CAR T cell Associated Neurotoxicity

• Corticosteroids• First line therapy for CNS neurotoxicity• Excellent penetration into CNS• Steroids can affect T cell function à decrease efficacy of CAR• Dexamethasone is most routinely used

• Role for IT steroids• Anecdotal evidence suggests its safe and can decrease severity of NT

27

Can We Identify Patients Prospectively Who are at Risk of Developing Severe Neurotoxicity?

• Multiple studies are exploring whether biomarker-based stratification can identify patients who are at significant risk of developing severe neurotoxicity

• Early fever and several elevated serum cytokines (MCP-1, IL-10, IL-15, IL-2) have been correlated with more severe NT

• Elevated levels of ANG2:ANG1 pre-lymphodepletion correlated with patients who had >grade 4 NT

Gust, Cancer Disc 2017Santomasso BD, Cancer Disc 2018Shalabi H, J Immunother 2018

28

2/17/20

8

Complementary Evaluations

29

Prospective Neurocognitive Studies Were Feasible in an Acutely Ill Population

• Serial Neurocognitive evaluations were performed testing:

• Working memory

• Attention

• Processing Speed

• Executive Function

• Neurosymptom Checklist

Shalabi/Wolters J Immunother 2018

88 Abbreviated Title: Phase I Anti-CD 22 CAR Version Date: 07/18/2016

12.7.1 Appendix G.1. Neuro Symptom Checklist

30

Neurocognitive Assessments Demonstrated Stable to Improved Scores Post CD22 CAR T

Therapy

• No irreversible neurotoxicity was seen

• Cytokine levels were significantly higher in patients with hallucinations or disorientation

Shalabi/Wolters J Immunother 2018

31

Patient Reported Outcomes Demonstrated Improved Quality of Life Post CAR therapy

• Patients treated with tisagenlecleucelwhere prospectively assessed for quality of life outcomes using 2 questionnaires

• Results demonstrated rapid improvement in broad aspects of quality of life among all patients who had treatment response

Laetsch Lancet Oncol 2019

Articles

6 www.thelancet.com/neurology Published online October 9, 2019 https://doi.org/10.1016/S1470-2045(19)30493-0

For each patient-reported quality-of-life measureexcept social functioning, proportions of patientsachieving the normative mean at all postbaseline studyvisits were greater than those at baseline even when allpatients with missing data were assumed to not achievethe normative mean (figure 3A). Across all postbaselinevisits, proportions were smallest in physical functioningand greatest in emotional functioning for the PedsQL.For the EQ-5D VAS, the proportions of patientsachieving the normative mean value were 17 (39%) of 44patients at day 28, 21 (54%) of 39 patients at month 3,15 (48%) of 31 patients at month 6, 13 (62%) of 21patients at month 9, and nine (64%) of 14 patients atmonth 12 (figure 3B).

As expected, the proportion of patients achieving thenormative mean at postbaseline visits were greater whenbased on the observed data than in the worst-casescenario (figure 3). However, overall results were similarbetween the two methods. Thus, notable global increasesin quality-of-life scores were observed regardless oftreatment of missing data.

Post-hoc subgroup analyses suggested that patientswith severe cytokine release syndrome (23 patients forthe PedsQL and 22 for the EQ-5D VAS) had lower meanimprovement in quality of life at day 28 than patientswithout severe cytokine release syndrome (27 patients forthe PedsQL and 26 for the EQ-5D VAS; mean of 0·3 [SD20·8] vs 7·1 [13·0] for PedsQL total score and 3·3 [27·5] vs12·2 [26·4] for EQ-5D VAS), but that improvementswere similarly observed in both groups by months 3 and6 and sustained at month 12 (appendix p 5). Similarresults were observed by severe neurotoxicity status(appendix p 6).

DiscussionThe findings from this study suggest that rapidimprovements in broad aspects of patient-reportedquality of life occurred after one-time treatment withtisagenlecleucel. To our knowledge, this is the first reporton patient-reported quality of life after CAR T-cell therapyfor patients with relapsed or refractory B-cell acutelymphoblastic leukaemia. Patients began to reportimprovements in patient-reported quality-of-life scores atday 28 after tisagenlecleucel therapy across mostdomains. By month 3, observed increases in score wereclinically meaningful (greater than or equal to theMCIDs), which persisted at months 6, 9, and 12. Somedelay in quality-of-life improvement was noted in patientswho had severe cytokine release syndrome or neuro-toxicity, but meaningful improvements in quality of lifewere still evident in these groups of patients by months3–6. This temporal pattern of improvement is consistentwith the temporal pattern of common side- effectsrelated to tisagenlecleucel. Cytokine release syndromeoccurs a median of 3 days (range 1–22) after infusion andresolves after a median of 8days (1–30),20

and most neurological adverse events occur duringcytokine release syndrome or shortly after its resolution.These findings, taken together with the preliminaryactivity and safety results,20 suggest a favourable benefit–risk profile of tisagenlecleucel in the treatment ofpaediatric and young adult patients with relapsed orrefractory B-cell acute lymphoblastic leukaemia.

This timeframe of improvement in quality of life isshorter than that of traditional therapy for relapsed orrefractory B-cell acute lymphoblastic leukaemia, whichmight include months of chemotherapy followed bystem-cell transplantation and the potential for graft-versus-host disease and other life-threatening toxicities.A recent systematic review27 on health-related quality oflife in children on treatment for acute lymphoblasticleukaemia revealed substantial reductions in quality oflife during treatment that were especially associated withintensive phases of chemotherapy and corticosteroidtherapy. Furthermore, although quality of life improvedover time in longitudinal studies, it remained lower thanthat of the general population after treatment, withlasting effects observed particularly in the social andemotional quality-of-life domains. Similarly, a long-term

follow-up study28 of childhood survivors of acute lymphoblastic leukaemia reported that both medical and

psychosocial conditions related to theiroriginal diagnosis persist into adulthood more than 20years from diagnosis.

Patient-reported quality-of-life outcomes in adults with relapsed and refractory acute lymphoblastic leukaemia

treated with other immunotherapies have recently beenreported. In the phase 3 TOWER study,11 blinatumomabdelayed deterioration in quality of life compared withstandard therapy, although minimal improvement inquality of life was seen with blinatumomab. In the phase3 INO-VATE study,10 inotuzumab ozogamicin

Emotional Social School Physical Psychosocial Total PedsQL EQ-5D VAS

functioning functioning functioning functioning health score

summary score

Mean c

hange in

score fro

mbaseline 40

30

20

10

0

–10

–20

60

50

Day28Month 3Month 6Month 9Month 12

Figure 2: Change from baseline inPedsQL and EQ-5D VASError bars represent 95% CIs, which were derived from the observed standard errors assuming a t distribution.

Analysis was based on patients with non-missing data at both baseline and the postbaseline study assessment of

interest. EQ-5D VAS=European Quality ofLife-5 Dimensions questionnaire visual analogue scale. PedsQL=Pediatric

Quality of LifeInventory.

32

2/17/20

9

QUESTIONS

33

Clinical Vignettes

ASTCT app has CRS and ICANS guidelines and algorithms at your fingertips

34

• 20 yo with primary refractory ALL

• Enrolled on CD19 CAR T cell trial @ dose level 1

• High dose lymphodepletion

• Disease status:• 85% ALL (M3 marrow) • CNS1 (flow+ disease)

Patient 1

What are his risk factors for CRS?Neurotoxicity?

35

• Clinical Manifestation:

• Day+2 developed fevers, hypotension, and tachycardia prompting ICU transfer

• Required multiple fluid boluses for hypotension• Started on broad spectrum antibiotics for fever and neutropenia• Received Tocilizumab

• Ejection Fraction dropped to 25%

https://tct.confex.com/tandem/2020/audiencepoll/ask.cgi?password=151925&Entryid=14249&EntryTable=Paper&Questionid=482#ask

36

https://tct.confex.com/tandem/2020/audiencepoll/ask.cgi?password=151925&Entryid=14249&EntryTable=Paper&Questionid=482

2/17/20

10

• D+11 developed delirium and agitation• He was able to name three objects, follow commands, and count backwards• What was his ICE score?

• D+12 had generalized seizure and was intubated due to neurologic status

Patient 1 Continued


5

37

Work up, Findings, and TreatmentWork up: • CT head: normal• MRI brain: normal, no white matter changes• EEG: no epileptiform activity noted• Lumbar puncture

• LP showed NO disease and 77% CAR T cells

Treatment:Dexamethasone for neurotoxicityIT hydrocortisone

Patient neuro status was back to baseline 48 hrs after administration of steroids, and he achieved an MRD negative remission

38

Patient 2• 5 yo with primary refractory ALL


• Standard Lymphodepletion

• Disease status• 3% ALL (M1 marrow) • CNS1- no evidence of leukemia


39


• Day+3 developed fevers• Started on broad spectrum antibiotics for non-neutropenic fever


40



2/17/20

11

Work up, Findings, TreatmentWork up:• CT was normal• Lumbar puncture

• LP showed no disease and 81% CAR T cells• MRI showed non-specific diffuse white matter injury

Treatment:Patient received IV dexamethasone for neuro symptoms and within 12 hours of dexamethasone, symptoms resolved. He had an MRD negative response to CAR therapy and went on to receive a curative bone marrow transplant

42

Patient 3• 13 yo male with relapsed/refractory ALL


• Standard Lymphodepletion

• Disease status• 20% ALL (M2 marrow)• CNS1- no evidence of leukemia


43


• Day+8 developed fevers• Started on broad spectrum antibiotics for neutropenic fever

• Day+10 he developed hypotension and coagulopathy and was transferred to ICU

• Received multiple fluid boluses and was started on epinephrine• Tocilizumab was administered


44

Patient 3 Continued• Day + 12 patient developed altered mental status with

confusion

• He was able to name three objects, state the month and year, follow commands, and count backwards

• What was his ICE score?


7

45



2/17/20

12

Work up, Findings, TreatmentWork up:• CT head was normal

Treatment:Patient did not receive any therapy for neuro symptoms and recovered over the course of 3 days. He had a complete response to CAR therapy

46

Future Directions• Active areas of research in CAR-associated neurotoxicity:

• Cytokine evaluations in serum and CSF• Identification of blood brain barrier permeability biomarkers• Imaging studies• Neurocognitive assessments• Quality of life measures

• Consortium amongst CAR pediatric centers has been established to share data and work more closely towards assessing later effects post CAR therapy

47

Thank you for your attention!

Questions/Comments:[email protected]

48

mailto:[email protected]

neurotoxicity in car-t learning objectives therapy

Documents