Clinical features, pathophysiology, and management of acute myelopathy following CAR T-cell therapy

2.

Santomasso

BD

,

Gust

J

,

Perna

F

.

How I treat unique and difficult-to-manage cases of CAR T-cell therapy-associated neurotoxicity

.

Blood

.

2023

;

141

(

20

):

2443

-

2451

.

3.

Maus

MV

,

Alexander

S

,

Bishop

MR

, et al.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune effector cell-related adverse events

.

J Immunother Cancer

.

2020

;

8

(

2

):

e001511

.

4.

Santomasso

BD

,

Nastoupil

LJ

,

Adkins

S

, et al.

Management of immune-related adverse events in patients treated with chimeric antigen receptor T-cell therapy: ASCO Guideline

.

J Clin Oncol

.

2021

;

39

(

35

):

3978

-

3992

.

5.

Thompson

JA

,

Schneider

BJ

,

Brahmer

J

, et al.

Management of immunotherapy-related toxicities, version 1.2022, NCCN Clinical Practice Guidelines in oncology

.

J Natl Compr Canc Netw

.

2022

;

20

(

4

):

387

-

405

.

6.

Handley

G

,

Khawaja

F

,

Kondapi

DS

, et al.

Human herpesvirus 6 myelitis after chimeric antigen receptor T-cell therapy

.

Int J Infect Dis

.

2021

;

112

:

327

-

329

.

7.

de Groot

PM

,

Arevalo

O

,

Shah

K

, et al.

Imaging primer on chimeric antigen receptor T-cell therapy for radiologists

.

Radiographics

.

2022

;

42

(

1

):

176

-

194

.

8.

Li

N

,

Zhang

R

,

Wang

J

, et al.

Case report: acute HHV6B encephalitis/myelitis post CAR-T cell therapy in patients with relapsed/refractory aggressive B-cell lymphoma

.

Front Neurol

.

2024

;

15

:

1334000

.

9.

Le Calvez

B

,

Eveillard

M

,

Decamps

P

, et al.

Extensive myelitis with eosinophilic meningitis after chimeric antigen receptor T cells therapy

.

EJHaem

.

2022

;

3

(

2

):

533

-

536

.

10.

Frigault

MJ

,

Dietrich

J

,

Martinez-Lage

M

, et al.

Tisagenlecleucel CAR T-cell therapy in secondary CNS lymphoma

.

Blood

.

2019

;

134

(

11

):

860

-

866

.

11.

Shah

R

,

Venur

V

,

McGranahan

T

.

Spinal cord infarct after CAR-T treatment

.

Neuro Oncol

.

2021

;

23

(

suppl 6

):

149

.

12.

Aghajan

Y

,

Yu

A

,

Jacobson

CA

, et al.

Myelopathy because of CAR-T-related neurotoxicity treated with siltuximab

.

Neurol Clin Pract

.

2021

;

11

(

6

):

e944

-

e946

.

13.

Nair

R

,

Drillet

G

,

Lhomme

F

, et al.

Acute leucoencephalomyelopathy and quadriparesis after CAR T-cell therapy

.

Haematologica

.

2021

;

106

(

5

):

1504

-

1506

.

14.

Beauvais

D

,

Cozzani

A

,

Blaise

AS

, et al.

A potential role of preexisting inflammation in the development of acute myelopathy following CAR T-cell therapy for diffuse large B-cell lymphoma

.

Curr Res Transl Med

.

2022

;

70

(

2

):

103331

.

15.

Giguère

P

,

Deschênes-Simard

X

,

Bernard

M

, et al.

Acute myelopathy resulting in paraplegia following axicabtagene ciloleucel therapy for refractory primary mediastinal B-cell lymphoma: a case report[poster]

.

EBMT-European Hematology Association 4th European CAR T-cell Meeting (virtual)

.

10 -12 February 2022

.

16.

Sheikh

S

,

Mokhtari

S

,

Silverman

JA

, et al.

Transverse myelitis after anti-CD19 directed CAR T cell therapy for relapsed large B cell lymphoma

.

EJHaem

.

2022

;

3

(

1

):

223

-

227

.

17.

Firestein

H

.

The role of physical therapy following CAR T-cell therapy: a case report

.

JACPT

.

2022

;

13

(

3

):

152

-

158

.

18.

Khanli

HM

.

An unusual case of transverse myelitis after anti-CD19 CAR T cell therapy for a patient with diffuse large B cell lymphoma

.

Neurol J

.

2024

(

suppl 1

):

102

.

19.

Sirven-Villaros

L

,

Belin

C

,

Di Blasi

R

, et al.

Myelitis of spontaneous recovery after anti-CD19 CAR T-cells injection

.

Eur J Neurol

.

2020

;

27

(

suppl 1

):

1198

-

1199

.

20.

Crombie

JL

,

Nastoupil

LJ

,

Redd

R

, et al.

Real-world outcomes of axicabtagene ciloleucel in adult patients with primary mediastinal B-cell lymphoma

.

Blood Adv

.

2021

;

5

(

18

):

3563

-

3567

.

21.

Chiappella

A

,

Casadei

B

,

Chiusolo

P

, et al.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study

.

Leukemia

.

2024

;

38

(

5

):

1107

-

1114

.

22.

Gazeau

N

,

Fiorenza

S

,

Kimble

EL

, et al.

CAR T-cell therapy for relapsed or refractory large B-cell lymphoma using a fully human CD19-targeted single chain variable fragment: results of a First-in-Human Phase I/II Study [abstract]

.

Blood

.

2022

;

140

(

suppl 1

):

10363

-

10365

.

23.

Gazeau

N

,

Fiorenza

S

,

Kimble

EL

, et al.

Fully human CD19-targeted CAR T-cell therapy for relapsed or refractory large B-cell lymphoma: results of a First-in-Human Phase I/II Study

.

Transplant Cell Ther

.

2023

;

29

(

2

):

S13

.

24.

Diorio

C

,

Hernandez-Miyares

L

,

Espinoza

DA

, et al.

Quadriparesis and paraparesis following chimeric antigen receptor T-cell (CART) therapy in children and adolescents

.

Blood

.

2024

;

144

(

13

):

1387

-

1398

.

25.

Bachy

E

,

Le Gouill

S

,

Di Blasi

R

, et al.

A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B cell lymphoma

.

Nat Med

.

2022

;

28

(

10

):

2145

-

2154

.

26.

Maude

SL

,

Laetsch

TW

,

Buechner

J

, et al.

Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

.

N Engl J Med

.

2018

;

378

(

5

):

439

-

448

.

27.

Van Oekelen

O

,

Aleman

A

,

Upadhyaya

B

, et al.

Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy

.

Nat Med

.

2021

;

27

(

12

):

2099

-

2103

.

28.

Mailankody

S

,

Devlin

SM

,

Landa

J

, et al.

GPRC5D-targeted CAR T cells for myeloma

.

N Engl J Med

.

2022

;

387

(

13

):

1196

-

1206

.

29.

Parker

KR

,

Migliorini

D

,

Perkey

E

, et al.

Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies

.

Cell

.

2020

;

183

(

1

):

126

-

142.e17

.

30.

Jess

J

,

Yates

B

,

Dulau-Florea

A

, et al.

CD22 CAR T-cell associated hematologic toxicities, endothelial activation and relationship to neurotoxicity

.

J Immunother Cancer

.

2023

:

11:e005898

.

31.

Pluvinage

JV

,

Sun

J

,

Claes

C

, et al.

The CD22-IGF2R interaction is a therapeutic target for microglial lysosome dysfunction in Niemann-Pick type C

.

Sci Transl Med

.

2021

;

13

(

622

):

eabg2919

.

32.

Kuhn

S

,

Gritti

L

,

Crooks

D

,

Dombrowski

Y

.

Oligodendrocytes in development, myelin generation and beyond

.

Cells

.

2019

;

8

(

11

):

1424

.

33.

Lowe

KL

,

Mackall

CL

,

Norry

E

,

Amado

R

,

Jakobsen

BK

,

Binder

G

.

Fludarabine and neurotoxicity in engineered T-cell therapy

.

Gene Ther

.

2018

;

25

(

3

):

176

-

191

.

34.

Li

Y

,

Drappatz

J

,

Mantica

M

.

Fludarabine neurotoxicity in patients undergoing CAR T-cell therapy - a report of 2 cases

.

Neuro-Oncology

.

2023

;

25

(

suppl 5

):

v211

-

v212

.

35.

Toomey

D

,

Phan

TL

,

Phan

T

,

Hill

JA

,

Zerr

DM

.

Viral encephalitis after hematopoietic cell transplantation: a systematic review

.

Transplant Cell Ther

.

2023

;

29

(

10

):

636.e1

-

636.e9

.

36.

Rebechi

MT

,

Bork

JT

,

Riedel

DJ

.

HHV-6 encephalitis after chimeric antigen receptor T-cell therapy (CAR-T): 2 case reports and a brief review of the literature

.

Open Forum Infect Dis

.

2021

;

8

(

11

):

ofab470

.

37.

Spanjaart

AM

,

van der Valk

FM

,

van Rooijen

G

,

Brouwer

MC

,

Kersten

MJ

.

Confused about confusion

.

N Engl J Med

.

2022

;

386

(

1

):

80

-

87

.

38.

Shah

M

,

Kuhnl

A

,

Shields

G

, et al.

Human herpesvirus 6 encephalitis following axicabtagene ciloleucel treatment for refractory diffuse large B cell lymphoma

.

Hemasphere

.

2021

;

5

(

3

):

e535

.

39.

Cousin

E

,

Belicard

F

,

Michel

L

, et al.

Severe cytomegalovirus disease with encephalitis after CAR-T cell therapy: a rare but potentially fatal complication

.

J Med Virol

.

2021

;

93

(

11

):

6398

-

6403

.

40.

Lareau

CA

,

Yin

Y

,

Maurer

K

, et al.

Latent human herpesvirus 6 is reactivated in CAR T cells

.

Nature

.

2023

;

623

(

7987

):

608

-

615

.

41.

Graeff-Teixeira

C

,

da Silva

AC

,

Yoshimura

K

.

Update on eosinophilic meningoencephalitis and its clinical relevance

.

Clin Microbiol Rev

.

2009

;

22

(

2

):

322

-

348

.

42.

Santomasso

BD

,

Park

JH

,

Salloum

D

, et al.

Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia

.

Cancer Discov

.

2018

;

8

(

8

):

958

-

971

.

43.

Wong

CS

,

Fehlings

MG

,

Sahgal

A

.

Pathobiology of radiation myelopathy and strategies to mitigate injury

.

Spinal Cord

.

2015

;

53

(

8

):

574

-

580

.

44.

Schultheiss

TE

.

The radiation dose-response of the human spinal cord

.

Int J Radiat Oncol Biol Phys

.

2008

;

71

(

5

):

1455

-

1459

.

45.

DeSelm

C

,

Palomba

ML

,

Yahalom

J

, et al.

Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape

.

Mol Ther

.

2018

;

26

(

11

):

2542

-

2552

.

46.

Sim

AJ

,

Jain

MD

,

Figura

NB

, et al.

Radiation therapy as a bridging strategy for CAR T cell therapy with axicabtagene ciloleucel in diffuse large B-cell lymphoma

.

Int J Radiat Oncol Biol Phys

.

2019

;

105

(

5

):

1012

-

1021

.

47.

Wright

CM

,

LaRiviere

MJ

,

Baron

JA

, et al.

Bridging radiation therapy before commercial chimeric antigen receptor T-cell therapy for relapsed or refractory aggressive B-cell lymphoma

.

Int J Radiat Oncol Biol Phys

.

2020

;

108

(

1

):

178

-

188

.

48.

Pinnix

CC

,

Gunther

JR

,

Dabaja

BS

, et al.

Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma

.

Blood Adv

.

2020

;

4

(

13

):

2871

-

2883

.

49.

Saifi

O

,

Breen

WG

,

Lester

SC

, et al.

Does bridging radiation therapy affect the pattern of failure after CAR T-cell therapy in non-Hodgkin lymphoma?

.

Radiother Oncol

.

2022

;

166

:

171

-

179

.

50.

Hubbeling

H

,

Silverman

EA

,

Michaud

L

, et al.

Bridging radiation rapidly and effectively cytoreduces high-risk relapsed/refractory aggressive B cell lymphomas prior to chimeric antigen receptor T cell therapy

.

Transplant Cell Ther

.

2023

;

29

(

4

):

259.e1

-

259.e10

.

51.

Farooq

MZ

,

Aqeel

SB

,

Lingamaneni

P

, et al.

Association of immune checkpoint inhibitors with neurologic adverse events: a systematic review and meta-analysis

.

JAMA Netw Open

.

2022

;

5

(

4

):

e227722

.

52.

Farina

A

,

Villagran-Garcia

M

,

Vogrig

A

, et al.

Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes

.

Lancet Neurol

.

2024

;

23

(

1

):

81

-

94

.

53.

Johnson

DB

,

Manouchehri

A

,

Haugh

AM

, et al.

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

.

J Immunother Cancer

.

2019

;

7

(

1

):

134

.

54.

Gritsch

D

,

Valencia-Sanchez

C

.

Drug-related immune-mediated myelopathies

.

Front Neurol

.

2022

;

13

:

1003270

.

55.

Chatterton

S

,

Xi

S

,

Jia

JX

, et al.

Case series: immune checkpoint inhibitor-induced transverse myelitis

.

Front Neurol

.

2023

;

14

:

1130313

.

56.

Picca

A

,

Berzero

G

,

Bihan

K

, et al.

Longitudinally extensive myelitis associated with immune checkpoint inhibitors

.

Neurol Neuroimmunol Neuroinflamm

.

2021

;

8

(

3

):

e967

.

57.

Perez-Moreno

MA

,

Ciudad-Gutierrez

P

,

Jaramillo-Ruiz

D

.

Reguera-Ortega JL Combined or sequential treatment with immune checkpoint inhibitors and Car-T cell therapies for the management of haematological malignancies: a systematic review

.

Int J Mol Sci

.

2023

;

24

(

19

):

14780

.

58.

Masucci

C

,

Pepe

S

,

La Rocca

U

, et al.

Case report: severe cutaneous adverse event associated with checkpoint inhibition in the setting of CAR T-cell therapy: beyond CRS

.

Front Oncol

.

2023

;

13

:

1171031

.

59.

Kambhampati

S

,

Gray

L

,

Fakhri

B

, et al.

Immune-related adverse events associated with checkpoint inhibition in the setting of CAR T cell therapy: a case series

.

Clin Lymphoma Myeloma Leuk

.

2020

;

20

(

3

):

e118

-

e123

.

60.

Chang

VA

,

Simpson

DR

,

Daniels

GA

,

Piccioni

DE

.

Infliximab for treatment-refractory transverse myelitis following immune therapy and radiation

.

J Immunother Cancer

.

2018

;

6

(

1

):

153

.

61.

Bover

M

,

Otero

I

,

Yarza

R

.

Nivolumab induced immune mediated transverse myelitis in a patient with metastatic melanoma: the broad clinical spectrum of immune mediated neurologic disorders

.

Curr Probl Cancer Case Rep

.

2021

;

4

:

100076

.

62.

Charabi

S

,

Engell-Noerregaard

L

,

Nilsson

AC

,

Stenor

C

.

Case report: longitudinal extensive transverse myelitis with novel autoantibodies following two rounds of pembrolizumab

.

Front Neurol

.

2021

;

12

:

655283

.

63.

Maggioli

E

,

McArthur

S

,

Mauro

C

, et al.

Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

.

Brain Behav Immun

.

2016

;

51

:

212

-

222

.

64.

Diotel

N

,

Charlier

TD

,

Lefebvre d'Hellencourt

C

, et al.

Steroid transport, local synthesis, and signaling within the brain: roles in neurogenesis, neuroprotection, and sexual behaviors

.

Front Neurosci

.

2018

;

12

:

84

.

65.

Villa

A

,

Rizzi

N

,

Vegeto

E

,

Ciana

P

,

Maggi

A

.

Estrogen accelerates the resolution of inflammation in macrophagic cells

.

Sci Rep

.

2015

;

5

:

15224

.

66.

Bereshchenko

O

,

Bruscoli

S

,

Riccardi

C

.

Glucocorticoids, sex hormones, and immunity

.

Front Immunol

.

2018

;

9

:

1332

.

67.

Klein

SL

,

Flanagan

KL

.

Sex differences in immune responses

.

Nat Rev Immunol

.

2016

;

16

(

10

):

626

-

638

.

68.

Sehn

LH

,

Salles

G

.

Diffuse large B-cell lymphoma

.

N Engl J Med

.

2021

;

384

(

9

):

842

-

858

.

69.

Fulop

T

,

Larbi

A

,

Dupuis

G

, et al.

Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?

.

Front Immunol

.

2017

;

8

:

1960

.

70.

Chihara

D

,

Liao

L

,

Tkacz

J

, et al.

Real-world experience of CAR T-cell therapy in older patients with relapsed/refractory diffuse large B-cell lymphoma

.

Blood

.

2023

;

142

(

12

):

1047

-

1055

.

71.

Mauget

M

,

Lemercier

S

,

Quelven

Q

, et al.

Impact of diagnostic investigations in the management of CAR T-cell-associated neurotoxicity

.

Blood Adv

.

2024

;

8

(

10

):

2491

-

2498

.

72.

Hines

MR

,

Knight

TE

,

McNerney

KO

, et al.

Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome

.

Transplant Cell Ther

.

2023

;

29

(

7

):

438.e1

-

438.e16

.

73.

Costa

NA

,

Gut

AL

,

de Souza Dorna

M

, et al.

Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock

.

J Crit Care

.

2014

;

29

(

2

):

249

-

252

.

74.

Hazell

AS

,

Butterworth

RF

.

Region-selective permeability of the blood-brain barrier to alpha-aminoisobutyric acid during thiamine deficiency and following its reversal

.

Metab Brain Dis

.

2021

;

36

(

2

):

239

-

246

.

75.

Schneider

BJ

,

Naidoo

J

,

Santomasso

BD

, et al.

Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update

.

J Clin Oncol

.

2021

;

39

(

36

):

4073

-

4126

.

76.

Brahmer

JR

,

Abu-Sbeih

H

,

Ascierto

PA

, et al.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events

.

J Immunother Cancer

.

2021

;

9

(

6

):

e002435

.

77.

Thompson

JA

,

Schneider

BJ

,

Brahmer

J

, et al.

NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020

.

J Natl Compr Canc Netw

.

2020

;

18

(

3

):

230

-

241

.

78.

Morris

EC

,

Neelapu

SS

,

Giavridis

T

,

Sadelain

M

.

Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy

.

Nat Rev Immunol

.

2022

;

22

(

2

):

85

-

96

.

79.

Locke

FL

,

Neelapu

SS

,

Bartlett

NL

, et al.

Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory, aggressive non-Hodgkin lymphoma [abstract]

.

Blood

.

2017

;

130

(

suppl 1

):

1547

.

80.

Strati

P

,

Ahmed

S

,

Kebriaei

P

, et al.

Clinical efficacy of anakinra to mitigate CAR T-cell therapy-associated toxicity in large B-cell lymphoma

.

Blood Adv

.

2020

;

4

(

13

):

3123

-

3127

.

81.

Diorio

C

,

Vatsayan

A

,

Talleur

AC

, et al.

Anakinra utilization in refractory pediatric CAR T-cell associated toxicities

.

Blood Adv

.

2022

;

6

(

11

):

3398

-

3403

.

82.

Norelli

M

,

Camisa

B

,

Barbiera

G

, et al.

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells

.

Nat Med

.

2018

;

24

(

6

):

739

-

748

.

83.

Gazeau

N

,

Liang

EC

,

Wu

QV

, et al.

Anakinra for refractory cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome after chimeric antigen receptor T cell therapy

.

Transplant Cell Ther

.

2023

;

29

(

7

):

430

-

437

.

84.

Mokhtari

S

,

Asquith

JM

,

Bachmeier

A

, et al.

The use of intravenous immunoglobulin (IVIG) during severe neurotoxicity among the recipients of chimeric antigen receptor T-cell (CAR-T) therapy [abstract]

.

Blood

.

2019

;

134

(

suppl 1

). 5627.