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

Abstract

Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

Keywords: anti-GD2 antibody; ch14.18/CHO; immunotherapy; neuroblastoma.

Figures

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). 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).