By Lynda Williams, medwireNews Reporter
medwireNews: Children with relapsed, high-risk neuroblastoma may benefit from immunotherapy with dinutuximab beta (DB) after haploidentical stem-cell transplantation (haplo-SCT), investigators write in the Journal of Clinical Oncology.
Tim Flaadt (Eberhard Karls University Tuebingen, Germany) and co-authors say that the combined approach achieved “notable” 5-year event-free survival (EFS) and overall survival (OS) rates of 43% and 53%, respectively, compared with previously reported corresponding rates with haplo-SCT alone of 19% and 23%.
They explain that the use of the anti-GD2 antibody DB may “augment graft-versus-neuroblastoma effects after haplo-SCT through early expanding and persisting donor-derived [natural killer] cells.”
The phase 1–2 trial included 68 patients aged 3–20 years (median 6.5 years) with relapsed or treatment-refractory stage 4 neuroblastoma (94.1%) or relapsed MYCN-amplified stage 2–3 neuroblastoma.
These patients had previously been treated for relapse with chemotherapy (98.5%), surgery (57.4%) or radiation (38.2%), and 63.2% of patients received radioactive iodine-131 mIBG treatment targeted at neuroendocrine cells before undergoing haplo-SCT. A minority (14.7%) of patients had previously received anti-GD2 therapy.
Sixty days after transplantation, patients were given a daily 8-hour infusion of DB 20 mg/m2 for 5 days and this was repeated every 4 weeks, with an initial plan of six cycles and an additional three cycles for responding or stable patients. Low-dose subcutaneous interleukin-2 was given to prevent graft-versus-host disease (GvHD) during cycles 4–6.
The patients received a median six cycles of DB and three cycles of interleukin-2 and were followed up for a median of 7.8 years.
Overall, 54.4% of patients achieved the primary endpoint of survival for 180 days after ending treatment without evidence of progressive disease, unacceptable toxicity, grade 3 or more severe acute GvHD or extensive chronic GvHD.
Treatment was discontinued by 42.6% of patients most commonly because of progressive disease (19.1%) and treatment-related hypersensitivity or inflammatory reactions (20.6%).
Haematological grade 3 or 4 treatment-related adverse events (AEs) occurred in 42.6% of patients, including hemolytic anaemia in 8.8%. The most common non-haematological AEs at this severity were elevated liver enzymes (39.7%), allergy (36.9%), fever (30.9%), central neurotoxicity (14.7%), diarrhoea (10.3%) and capillary leak syndrome (10.3%).
Although 91.2% of patients reported pain in the first cycle of treatment, this fell to 38.2% by cycle 6, the researchers observe.
The team says that before the start of cycle 1 of DB, 36.8% of patients were in complete response and 52.0% maintained their response to the end of treatment, while 16.0% progressed. Of the 51.5% of patients with a partial response at the start of treatment, 40.0% achieved a complete response and 22.9% had progressive disease. Of the remaining patients with baseline nonresponsive, mixed response or progressive disease, four progressed during treatment, one achieved a complete response and one maintained stable disease but later progressed.
And among patients with evidence of disease after undergoing haplo-SCT, the objective response rate was 51.2% and the complete response rate was 34.9%, Flaadt et al write.
The researchers report that patients with a complete or partial response before immunotherapy had a better 5-year EFS rate than those without (52 and 44 vs 13%, respectively), and this was also true for OS.
By contrast, for patients who had bone marrow involvement before cycle 1, the 5-year EFS was 28% versus 52% for those with a complete response in their bone marrow.
Overall, 34 patients relapsed after a median 235 days from first DB cycle. Twenty-nine patients died from relapse, three from infection and there were individual fatalities from encephalopathy and secondary malignancy. Treatment-related mortality at day 100 and 1 year were 1.5% and 7.4%, respectively.
“DB therapy after haplo-SCT in patients with [relapsed high-risk neuroblastoma] is feasible, with low risk of inducing GvHD, and results in long-term remissions likely attributable to increased antineuroblastoma activity by donor-derived effector cells”, the researchers conclude.
They add: “Further prospective and randomized trials are warranted to evaluate the contribution of each component of the approach, and larger cohorts are needed to allow better risk stratification and patient selection.”
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J Clin Oncol 2023; doi.10.1200/JCO.22.01630