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. 2022 Apr 10;14(8):1919. doi: 10.3390/cancers14081919

Table 3.

Clinical characteristics and management of severe CNS neurotoxicity in the LTI study and the HR-NBL1 study.

Pt Study Schedule Time of
Onset		 Symptoms MRI Findings CSF HSV/VZV DB Level (Serum) * DB Level (CSF) Treatment Rechallenge
with DB		 Symptom
Resolution		 MRI
Follow-Up
1 LTI DB LTI
+ scIL-2		 C1/D13

  • Dysphagia

  • Apnoea

  • Paraparesis

  • Fixed pupils

 Cytotoxic
oedema in brain stem		 ND No 2.5 µg/mL ND

  • IVIG

  • Steroids

  • Ventilation

 No No
(minimal
improvement)		 NA
2 LTI DB LTI
+ scIL-2		 C1/D14

  • Back pain

  • Neurogenic bladder

  • Paraplegia

  • Sensory loss

 Myelitis
(thoracic to lumbar)

  • Protein 1.8 g/L

  • Glc 3.7 mmol/L

  • Leucocytes 26/µL

  • Oligoclonal band

 Yes
(thoracic
shingles 6 wks before therapy)		 4.3 µg/mL ND

  • IVIG

  • Steroids

 No No Partial resolution after 8 months
3 LTI DB LTI
+ scIL-2		 C1/D15

  • Paraplegia

  • Neurogenic bladder

  • Pain

  • Hyposthenia of upper extremities

  • Diaphragm paresis

 Myelitis
(thoracic)

  • Protein 0.96 g/L

  • Glc 3 mmol/L

  • Leukocytes 4/µL

  • VZV PCR neg

 Yes
(skull skin
shingles after the first round of scIL-2 during C1/D1–D5) 		5.8 µg/mL ND

  • IVIG

  • Steroids

  • Plasmapheresis

 No Yes Complete resolution
4 LTI DB LTI
+ IL-2		 C3/D17

  • Ataxia

  • Tetraparesis

  • Pain

  • Paresthesia

 Myelitis
(thoracic)

  • Protein 0.55 g/L

  • Leukocytes 2/µL

 Yes
(HSV 3 wks
before DB)		 14.8 µg/mL 0.02 µg/mL

  • IVIG

  • Steroids

 No Yes Complete resolution
5 LTI DB LTI
+ scIL-2		 C1/D15

  • Urinary retention

  • Hyposthenia

  • Sensorimotor demyelinating polineuropathy

 Demyelinating neuropathy of dorsal roots

  • Albumino-cytologic dissociation

 No 4.6 µg/mL <0.01 µg/mL

  • IVIG

 Yes
(symptoms reoccurred after 4 h at 50% dose)		 Yes NA
6 LTI DB LTI
+ scIL-2		 C1/D9

  • Blurred vision,

  • Neurogenic bladder

  • Paraplegia

 Myelitis ND No ND <0.01 µg/mL

  • Steroids

 No No
(persistent neurogenic bladder)		 NA
7 LTI DB LTI
+ scIL-2		 C1/D9

  • Somnolence

  • Encephalopathy on EEG

 ND ND ND ND ND No treatment No Yes NA
8 LTI DB LIT
+ scIL-2		 C2/D11

  • Urinary retention

 ND ND ND 2.0 µg/mL ND No treatment No Yes NA
9 LTI DB LTI
+ scIL-2		 ND

  • Encephalopathy

 ND ND ND 14.9 µg/mL ND ND ND ND ND
10 LTI DB LTI
+ scIL-2		 ND

  • Seizures

 ND ND ND ND ND ND ND ND ND
11 HR-NBL1R2 DB STI
+ scIL-2		 C4/D10

  • Coma

  • Paresis (no DB given in the cycle)

 Encephalomyelitis ND ND ND ND

  • Steroids

 No No NA
12 HR-NBL1R2 DB STI C2/D7

  • 6th cranial nerve palsy

 PRES ND ND ND ND

  • Steroids

 Yes
(no recurrence)		 Yes Complete resolution
13 HR-NBL1R2 DB STI
+ scIL-2		 C2/D3

  • Seizures Ondine syndrome

 ND ND ND ND ND

  • Antibiotics (merpenem, vancomycin)

 ND Yes NA
14 HR-NBL1R2 DB STI
+ scIL-2		 C1/D5

  • Seizures

 ND ND ND ND ND

  • Midazolam

 Yes
(no recurrence)		 Yes NA
15 HR-NBL1R2 DB STI
+ scIL-2		 C1/ND

  • Seizures

 ND ND ND ND ND ND Yes (only DB, no scIL-2; no recurrence) Yes NA
16 HR-NBL1R2 DB STI
+ scIL-2		 C1/D9

  • Seizures

 ND ND ND ND ND ND ND ND NA
17 HR-NBL1R2 DB STI
+ scIL-2		 C1/D9

  • Mood disturbances

  • Motor weakness/hypotonia

  • Mydriasis

  • Photophobia

  • Taste change

 ND ND ND ND ND No treatment ND Yes
(child needs glasses)		 NA
18 HR-NBL1R2 DB STI
+ scIL-2		 C1/D15

  • ND

 PRES ND ND ND ND ND ND ND NA
19 HR-NBL1R2 DB STI
+ scIL-2		 ND

  • Paresis

  • Urinary retention

  • Mydriasis

  • (patient initially classified as non- severe peripheral neuropathy)

 ND ND ND ND ND ND ND No ND
20 HR-NBL1R4 DB LTI
+ scIL-2		 C1/D10

  • Severe somnolence

  • Hypotonia

  • No reaction to pain

 Encephalitis Normal ND ND ND

  • IVIG,

  • Steroids

 No Yes Residual focal
lesions
21 HR-NBL1R4 DB LTI C3/D13

  • Behavioural change

  • Ataxia

  • Hyperkinesis

  • Gait disturbances

  • Torticollis

  • Blindness

 Encephalitis

  • Protein 0.18 g/L

  • Glc 44 mg/dL

 No
(blood and CSF)		 ND ND

  • IVIG,

  • Steroids

  • Plasma-

  • pheresis

 No Yes ND
22 HR-NBL1R4 DB LTI C3/D17

  • Facial paralysis

 Discreet
infiltration of the acoustic-
facial package		 Normal ND ND ND

  • Steroids

 Yes
(no recurrence)		 Yes ND
23 HR-NBL1R4 DB LTI C4/ND

  • Left sided facial palsy

 Mucosal
thickening of left mastoid cell		 ND ND ND ND

  • Meropenem

 ND ND ND
24 HR-NBL1R4 DB LTI C1/D22

  • Agitation with life threatening behaviour

  • (behavioural disturbances since treatment start)

 ND ND ND ND ND

  • Hydroxyzinum

 Yes
(symptoms reoccurred after 90 min of infusion)		 Yes NA
25 HR-NBL1R4 DB LTI C1/D11

  • Sensory disturbances in all extremities

  • Gait and fine catch disturbances

 Sensory
axonal
neuropathy

  • High protein

 ND ND ND

  • IVIG

  • Steroids

 ND ND ND
26 HR-NBL1R4 DB LTI
+ scIL-2		 C1/D15

  • Seizures

 Normal ND ND ND ND ND Yes
(no recurrence)		 Yes ND
27 HR-NBL1R4 DB LTI
+ scIL-2		 C1/D27

  • Dragging left foot

  • Gait disturbances

 ND ND ND ND ND ND ND Yes ND

* The expected maximum serum concentration of DB at the end of infusion was 12.56 ± 0.68 µg/mL, as previously reported for patients in the LTI study [23]. CNS, central nervous system; C, cycle; CSF, cerebrospinal fluid; D, day; DB: dinutuximab beta; EEG, electroencephalogram; glc, glucose; h, hours; HSV, herpes simplex virus; IVIG, intravenous immunoglobulins; LTI, long-term infusion; mins, minutes; MRI, magnetic resonance spectroscopy; NA, not available; ND, not determined; PCR, polymerase chain reaction; PRES, posterior reversible encephalopathy syndrome; pt, patient; scIL-2, subcutaneous IL-2; STI short-term infusion; VZV, varicella zoster virus, wks, weeks.