Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD₂ antibody ch14.18/CHO

Figures & data

Figure 1. Treatment schematic, pain assessment and intravenous morphine usage during LTI of ch14.18/CHO. A) Ch14.18/CHO was administered by LTI of 100 mg/m² (d8–17) (horizontal bar) with 6 × 10⁶ IU/m² s.c. IL-2 (d1–5; 8–12) (black arrows) and p.o. isotretinoin (160 mg/m²/day d22–35). Pain toxicity of anti-GD₂ antibody ch14.18/CHO was evaluated by systematic assessments of pain scores and intravenous morphine usage of 49/53 evaluable patients as described in the “Patients and Methods” section. B) Pain assessment scores were determined three times daily per patient and cycle. Data represent mean ± SEM. C) Usage of i.v. morphine in µg/kg/h was determined daily per patient and cycle and presented as mean ± SEM. When error bars are not visible, they are covered by the symbol. Total morphine usage per cycle ± SEM is indicated in mg/kg/cycle.

Figure 2. Analysis of survival and time to progression following LTI of ch14.18/CHO. Patients treated by LTI of 100 mg/m² ch14.18/CHO in combination with 6 × 10⁶ IU/m² s.c. IL-2 (d1–5; 8–12) and oral 13-cis RA (d19–32) were analyzed for progression-free survival (PFS) (A) and overall survival (OS) (B) using the Kaplan-Meier method. Patients of the entire cohort (n = 53) and patients with relapsed status at base line (n = 29) were analyzed separately. A) PFS curves of the entire LTI cohort (red) and relapsed patients (blue) (top panel). B) OS of the entire LTI cohort (red) and relapsed patients (blue) was compared to relapsed patients of the AIEOP data base not treated with ch14.18/CHO (green).²¹ The starting point of the AIEOP relapsed patients equals to the date of first relapse plus the median time between relapse and start of ch14.18/CHO therapy for the LTI patients (1 y 7 d). Patients in the AIEOP relapsed group who died before the auxiliary starting point were excluded. The difference between LTI relapsed- and AIEOP relapsed- patients was statistically significant (P = 0.002).

Table 1. Demographics and characteristics of high-risk NB patients treated by long term infusion (LTI) of ch14.18/CHO at initial diagnosis and at the time of LTI treatment start.

S
Parameter		No of Pts	total	percent
Gender	male	33	53	62%
	female	20	53	38%
age at diagnosis	<18 Months	11	53	21%
	>18 Months	42	53	79%
INSS Stage at diagnosis	1^a	1	53	2%
	2^a	1	53	2%
	3^a	4	53	8%
	4	47	53	88%
MYCN status	amplified	13	42^d	31%
	non-amplified	29	42^d	69%
	Missing	11
initial treatment	high intensity multimodality regimen	53	53	100%
	HDC and HSCR^a	53	53	100%
characteristics at LTI treatment start
status at presentation	frontline patients^b	5	53	9%
	refractory patients	19	53	34%
	relapsed patients	29	53	55%
systemic treatment of most recent relapse/ progression	irinotecan/ temozolomide	17	48^e	35%
	topotecan/ temozolomide	5	48^e	10%
	topotecan/ vincristin/ doxorubicin	5	48^e	10%
	topotecan/ cyclophosphamide/ etoposide	4	48^e	8%
	carboplatin/ etoposide	2	48^e	4%
	second HDC and HSCR^c	13	48^e	27%
	haploidentical stem cell transplantation	2	48^e	4%
local treatment of relapse/progression	Radiation therapy	7	48^e	15%
	surgery	5	48^e	10%
Patients with evaluable disease	Neuroblastoma detectable by mIBG scan and/or MRI/CT scan	37	48^e	77%

^a disseminated relapse

^b patients without refractory or relapsed disease after frontline multimodality regimen

^c High dose chemotherapy (HDC) followed by autologous hematopoietic stem cell rescue (HSCR)

^d total number of patients with information on MYCN status

^e total number of patients with relapsed or refractory disease

Table 2. Treatment Emergent Adverse Events (TEAEs) of Grade ≥3 related to ch14.18/CHO LTI combined with IL-2.

Treatment schematic	LTI
Total number of patients	N = 53
NCI CTCAE Grade^†^*	3		4		3 & 4
Preferred Term	N	(%)	N	(%)	N	(%)
Neuropathic Pain	16	30,2	4	7,5	20	37,7
Pruritus	8	15,1	0	0,0	8	15,1
Cough	8	15,1	0	0,0	8	15,1
Capillary leak syndrome	7	13,2	0	0,0	7	13,2
Pyrexia	5	9,4	0	0,0	5	9,4
Urticaria	4	7,5	0	0,0	4	7,5
GGT increased	4	7,5	0	0,0	4	7,5
Bronchospasm	4	7,5	0	0,0	4	7,5
Vomiting	3	5,7	0	0,0	3	5,7
Tachycardia	3	5,7	0	0,0	3	5,7
Leukopenia	3	5,7	0	0,0	3	5,7
Hypoxia	3	5,7	0	0,0	3	5,7
CRP increased	3	5,7	0	0,0	3	5,7
Weight increased	2	3,8	0	0,0	2	3,8
Thrombocytopenia	2	3,8	0	0,0	2	3,8
Rash	2	3,8	0	0,0	2	3,8
Pleural effusion	2	3,8	0	0,0	2	3,8
Pericardial effusion	2	3,8	0	0,0	2	3,8
Inflammation	2	3,8	0	0,0	2	3,8
Headache	2	3,8	0	0,0	2	3,8
Diarrhea	1	1,9	1	1,9	2	3,8
Ascites	2	3,8	0	0,0	2	3,8
Arthralgia	2	3,8	0	0,0	2	3,8
Petechiae	1	1,9	0	0,0	1	1,9
Peripheral Motoneuropathy	1	1,9	0	0,0	1	1,9
Neutropenia	1	1,9	0	0,0	1	1,9
Myalgia	1	1,9	0	0,0	1	1,9
Muscle spasm	1	1,9	0	0,0	1	1,9
Hypotension	1	1,9	0	0,0	1	1,9
Hypocalcaemia	1	1,9	0	0,0	1	1,9
Hypersensitivity	1	1,9	0	0,0	1	1,9
Fatigue	1	1,9	0	0,0	1	1,9
Edema	1	1,9	0	0,0	1	1,9
Dry Skin	1	1,9	0	0,0	1	1,9
Convulsion Seizure	0	0,0	1	1,9	1	1,9
Chest pain	1	1,9	0	0,0	1	1,9
Bronchial obstruction	1	1,9	0	0,0	1	1,9
Asthenia	1	1,9	0	0,0	1	1,9
Anaemia	1	1,9	0	0,0	1	1,9
ALT increased	1	1,9	0	0,0	1	1,9
Nausea	0	0,0	0	0,0	0	0,0

^† Sorted in descending order of overall frequency experienced by all 53 patients treated by LTI.

* Grade 5 toxicity was not observed in the LTI group.

Table 3. Treatment response in 37 evaluable relapsed/refractory patients with measurable disease at baseline.

	Response at end of cycle
Category	cycle 1 – 3	cycle 4 – 5/6	Best Response	End of treatment^*
Evaluable	N = 35/37^§	N = 23/37^†	N = 37/37	N = 34/37^**
N (%)	35 (100.0%)	23 (100.0%)	37 (100.0%)	34 (100.0%)
CR	5 (14.3%)	3 (13.0%)	5 (13.5%)^‡	3 (8.8%)^&
PR	7 (20.0%)	7 (30.4%)	10 (27.0%)^‡	8 (23.5%)^&
SD	15 (42.9%)	6 (26.1%)	12 (32.4%)	6 (17.6%)
PD	8 (22.9%)	7 (30.4%)	10 (27.0%)	17 (50.0%)

CR = Complete response, PR = Partial response, SD = Stable disease/no response, PD = Progressive disease

^‡ Best overall response: 40.5% (15/37) (CR 5/37 = 13.5%; 10/37 PR = 27.0%)

^& End of treatment response: 32.4% (11/34) (CR 3/34 = 8.8%; 8/34 PR = 23.5%)

* Last evaluation regardless of time (after 3^rd or 5/6^th cycle)

^§ Excluded patients 2 pts. with PD before completion of cycle 3

^† Excluded patients: 11 pts. with PD before completion of cycle 5/6 not included (2 pts. before cycle 3; 8 pts. at mid evaluation 1 pt. after cycle 4) and 3 pts. due to tumor surgery after mid evaluation.

** Excluded Patients: 3 pts due to tumor surgery after mid evaluation after cycle 3.

Table 4. Demographics and baseline characteristics of relapsed NB patients evaluable for historical comparison.

Parameter		LTI Patients (N = 29)	Historic Control (N = 28)
Gender	Male	15 (51.7%)	19 (67.9%)
	Female	14 (48.3%)	9 (32.1%)
Age (years) at initial diagnosis^a	N	29	28
	Mean (SD)	4.8 (4.1)	4.4 (2.4)
	Median	3.5	4.0
	Min, Max	1, 17	1, 13
Age category at initial diagnosis^a	≤ 5 years	22 (75.9%)	20 (71.4%)
	> 5 years	7 (24.1%)	8 (28.6%)
INSS Stage at initial diagnosis	Missing	1 (3.4%)	0 (0%)
	1^b	1 (3.4%)	0 (0%)
	2A^b	1 (3.4%)	0 (0%)
	3^b	1 (3.4%)	1 (3.6%)
	4	25 (86.2%)	27 (96.4%)
MYCN amplification	Yes	4 (13.8%)	7 (25.0%)
	No	17 (58.6%)	21 (75.0%)
	Missing	8 (27.6%)	0 (0%)

INSS = International Neuroblastoma Staging System; MYCN = v-myc myelocytomatosis viral related oncogene; SD = standard deviation.

^a Age was calculated as year of initial diagnosis – year of birth

^b Patients presented with disseminated relapse

Garaventa A, Parodi S, De BB, Dau D, Manzitti C, Conte M, Casale F, Viscardi E, Bianchi M, D'Angelo P, et al. Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry. Eur J Cancer. 2009;45(16):2835–2842. doi:10.1016/j.ejca.2009.06.010. PMID:19616426

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