Table A1.

Patient Characteristics, Treatment Variables, and Prognostic Factors by Regimen

Variable	Regimen A 3F8 (HR)		Regimen B 3F8 + IV GMCSF (HR)		Regimen C				P*
					3F8 + SC GMCSF (HR)		3F8 + SC GMCSF (UHR)
	No.	%	No.	%	No.	%	No.	%	PFS	OS
Immunotherapy regimen
No. of patients	43		41		57		28
Relapse or death	26		18		21		18
Death	26		18		11		7
Sex									.55	.56
Male	25	58	26	63	39	68	12	43
Female	18	42	15	37	18	32	16	57
Age, months									.5	.65
≥ 18	41	95	38	93	52	91	27	96
< 18	2	5	3	7	5	9	1	4
MYCN									.59	.29
Amplified	15	35	14	34	29	51	7	25
Not amplified	28	65	27	66	28	49	21	75
LDH, U/mL									.84	.64
> 1,500	14	33	15	37	18	32	4	14
< 1,500	28	65	18	44	28	49	16	57
Unknown	1	2	8	20	11	19	8	29
Bone									.45	.25
Yes	32	74	31	76	42	74	17	61
No	11	26	10	24	15	26	11	39
Bone marrow									.48	.22
Yes	39	91	33	80	50	88	23	82
No	4	9	8	20	7	12	5	18
SCT									.014	.19
Yes	1	2	41	100	37	65	9	32
No	42	98	0	0	20	35	19	68
FCGR2A polymorphism†									.8	.54
H/H	14	33	10	24	13	23	10	36
H/R or R/R	29	67	31	76	44	77	18	64
Missing KIR ligand									.37	.32
Favorable	31	72	23	56	38	67	20	71
Unfavorable	12	28	18	44	19	33	8	29
Pre-MRD									.85	.86
Positive	10	24	12	29	21	37	12	43
Negative	31	76	29	71	36	63	16	57
Post-MRD									< .001	< .001
Positive	12	29	7	18	7	13	7	25
Negative	29	71	32	82	48	87	21	75
UHR‡									.02	.46
Yes	0	0	0	0	0	0	28	100
No	43	100	41	100	57	100	0	0
HAMA response§									.12	.006
Yes	24	56	29	71	46	80	21	75
No	19	44	12	29	11	20	7	25
Median time to first positive HAMA, months	19.3		5.3		9.9		9.1
Median time to HAMA turning negative, months	3.97		4.62		5.71		3.09
Induction protocol∥									.84	.91
I. MSKCC-COG3973 regimen¶	43	100	28	69	50	87	22	78
II. Intensive but non–MSKCC-COG3973 regimen	0	0	3	7	5	9	3	11
III. Less intensive regimen	0	0	10	24	2	4	3	11
CRA
Yes	6	14	37	90	53	93	28	100
No	37	86	4	10	4	7	0	0

NOTE. Bold font indicates significance.

Abbreviations: 3F8, anti-GD2 monoclonal antibody 3F8; COG, Children's Oncology Group; CRA, 13-cis-retinoic acid; GM-CSF, granulocyte-macrophage colony-stimulating factor; HAMA, human antimouse antibody; HR, high risk; IV, intravenous; KIR, killer immunoglobulin-like receptor; LDH, serum lactate dehydrogenase; MSKCC, Memorial Sloan-Kettering Cancer Center; OS, overall survival; PFS, progression-free survival; post-MRD, minimal residual disease after two cycles of 3F8 therapy; pre-MRD, minimal residual disease before therapy; SC, subcutaneous; SCT, stem-cell transplantation; UHR, ultra high risk.

^*Each P value corresponds to log-rank test for association of clinical variable with PFS or OS.

^†FCGR2A polymorphism: one, H/H; two, H/R or R/R.

^‡UHR patients required additional cyclophosphamide ± topotecan or irinotecan¹⁵ for refractory disease after standard induction therapy before 3F8 immunotherapy.

^§HAMA modeled as time-dependent covariate. Early HAMA led to delay in antibody treatment. Forty of 169 patients developed HAMA within first 2 months, 65 in 6 months, 98 in 12 months, and 116 in 24 months. Median time for HAMA to turn negative was 143 days (95% CI, 119 to 180). Among the 112 patients who completed cycle four of immunotherapy, median duration to cycle four was 105 days (range, 70 to 491 days) for patients who were HAMA negative during first 4 months, and 216 (range, 84 to 567 days) for patients who turned HAMA positive before 4 months (P < .001).

^∥Although patients were treated on four sequential immunotherapy protocols over span of 20 years, inductions were mostly based on MSKCC-COG3973 induction backbone,¹⁴ with surgical (LaQuaglia MP, et al: J Pediatr Surg 29:1162-1166, 1994) and radiotherapy approach (Kushner BH, et al: J Clin Oncol 19:2821-2828, 2001) to primary sites remaining unchanged. Specifically, induction chemotherapy consisted of alternating cycles of cyclophosphamide (C; 70 mg/kg/d × 2), adriamycin (A; 75 mg/m²), and vincristine (V; 2 mg/m²) or cisplatin (P; 50 mg/m²/d × 4) plus etoposide (VP; 200 mg/m²/d × 3), in a sequence of CAV-CAV-PVP-CAV-PVP-CAV-PVP (regimen A), or CAV-CAV-PVP-CAV-PVP-CAV or CAV-CAV-PVP-CAV-PVP (regimens B and C). Reduction in the number of cycles from seven to six or five was designed to reduce risk of therapy-related acute myeloid leukemia.¹⁴ Surgical approach to achieve gross total resection at second look was by thoracoabdominal incision throughout these two decades, and radiotherapy of primary site has consistently been hyperfractionated at 21 Gy (Kushner BH, et al: J Clin Oncol 19:2821-2828, 2001). When we stratified patients based on induction regimen, we did not find any statistically significant difference in PFS or OS for the cohort (n = 169) or within immunotherapy regimen (B or C). When tested for association with PFS as binary variable (MSKCC-COG3973 v others), induction protocol had P values of .83 and .63 for regimens B and C (adjusted for UHR status), respectively. For OS, P values were .79 and .84, respectively.

^¶Induction regimen I: CAV-PVP combination chemotherapy initially developed at MSKCC¹⁴ (Cheung NK, et al: Med Pediatr Oncol 36:227-230, 2001) and adopted by COG3973.³ Induction regimen II: included rapid vincristine, carboplatin, etoposide, and cyclophosphamide⁴⁰ (OJEC), ANBL00P1, ANBL02P1, DFC-94-131, DFC-05-440. Induction regimen III: included POG9640, vincristine, cisplatin, etoposide, and cyclophosphamide (OPEC)/OJEC,⁴⁰ COG3891 (Matthay KK, et al: N Engl J Med 341:1165-1173, 1999), NB97 (Simon T, et al: BMC Cancer 11:21, 2011), and NB99.