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.

Inflammatory response and treatment tolerance of long‐term infusion of the anti‐GD2 antibody ch14.18/CHO in combination with interleukin‐2 in patients with high‐risk neuroblastoma

“…Therefore, the prolongation of the time of Ab infusion was evaluated when five to six cycles of ch14.18/CHO were given at 100 mg/m 2 /cycle as 10‐day continuous long‐term infusion (LTI) in combination with scIL‐2 and oral 13‐cis retinoic acid (RA). Objective clinical response and survival of treated patients showed clinical activity and efficacy in high‐risk NB patients as compared to historical controls . We also observed a lower frequency of neuropathic pain with LTI versus STI (37.7% vs. 51.8%, respectively) and other adverse events of Grade ≥3 were also less frequent in our cohort compared to STI: capillary leak syndrome (13.2% vs. 22.6%), pyrexia (9.4% vs. 38.7%), hypoxia (5.7 vs. 13.1%), diarrhea (3.8 vs. 13.1%), and hypotension (1.9 vs. 17.5%) …”

“…We observed that the frequencies of Treatment Emergent Adverse Events (TEAEs) of Grade ≥3 observed in our cohort were lower compared to STI (4 × 17.5 mg/m 2 , daily 8‐hr infusion on four consecutive days) of ch14.18/SP2/0 (capillary leak syndrome 13.2% vs. 22.6%, pyrexia 9.4% vs. 38.7%, hypoxia 5.7 vs. 13.1%, diarrhea 3.8 vs. 13.1%, hypotension 1.9 vs. 17.5%) . None of the TEAE frequencies of Grade ≥3 reported in the study with STI of ch14.18/SP2/0 2 were lower compared to LTI of ch14.18/CHO . In particular, we observed a lower frequency of neuropathic pain with LTI vs. STI at 37.7% vs. 51.8%, respectively.…”

“…A total of five to six cycles were given in 35‐day intervals. The treatment schematic and the patient characteristics of this cohort were reported . The data were collected retrospectively, and the procedure was reviewed and approved by the ethical committee.…”

“…Out of the 53 patients, 29 patients had relapsed disease. As first‐line therapy all 53 patients received intensive multimodality treatment including high‐dose chemotherapy followed by autologous stem cell transplantation …”

Treatment of relapse/progression of the disease in patients with neuroblastoma in the Republic of Belarus over a 20-year period: a cohort study

“…Так, использование различных блоков ПХТ 2-й линии, даже в сочетании с ауто-ТГСК не позволяет преодолеть порог ОВ в 15-20 % [11,17,20]. Внедрение гаплоидентичной трансплантации для больных, достигших хорошего ответа на ПХТ, увеличило 2-летнюю выживаемость до 30 % [21]. Благодаря широкому внедрению иммунотерапии (в частности анти GD2-антител) в сочетании с интерлейкином-2 после проведения гаплотрансплантации стало возможным достичь 40 % 5-летней выживаемости в этой группе больных [22].…”