Anti-GD2 Antibody Dinutuximab Beta and Low-Dose Interleukin 2 After Haploidentical Stem-Cell Transplantation in Patients With Relapsed Neuroblastoma: A Multicenter, Phase I/II Trial

Abstract

Purpose: Patients with relapsed high-risk neuroblastoma (rHR-NB) have a poor prognosis. We hypothesized that graft-versus-neuroblastoma effects could be elicited by transplantation of haploidentical stem cells (haplo-SCT) exploiting cytotoxic functions of natural killer cells and their activation by the anti-GD2 antibody dinutuximab beta (DB). This phase I/II trial assessed safety, feasibility, and outcomes of immunotherapy with DB plus subcutaneous interleukin-2 (scIL2) after haplo-SCT in patients with rHR-NB.

Methods: Patients age 1-21 years underwent T-/B-cell-depleted haplo-SCT followed by DB and scIL2. The primary end point 'success of treatment' encompassed patients receiving six cycles, being alive 180 days after end of trial treatment without progressive disease, unacceptable toxicity, acute graft-versus-host-disease (GvHD) ≥grade 3, or extensive chronic GvHD.

Results: Seventy patients were screened, and 68 were eligible for immunotherapy. Median number of DB cycles was 6 (range, 1-9). Median number of scIL2 cycles was 3 (1-6). The primary end point was met by 37 patients (54.4%). Median observation time was 7.8 years. Five-year event-free survival (EFS) and overall survival from start of trial treatment were 43% (95% CI, 31 to 55) and 53% (95% CI, 41 to 65), respectively. Five-year EFS among patients in complete remission (CR; 52%; 95% CI, 31 to 69) or partial remission (44%; 95% CI, 27 to 60) before immunotherapy were significantly better compared with patients with nonresponse/mixed response/progressive disease (13%; 95% CI, 1 to 42; P = .026). Overall response rate in 43 patients with evidence of disease after haplo-SCT was 51% (22 patients), with 15 achieving CR (35%). Two patients developed GvHD grade 2 and 3 each. No unexpected adverse events occurred.

Conclusion: DB therapy after haplo-SCT in patients with rHR-NB 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.

Trial registration: ClinicalTrials.gov NCT02258815.

FIG 1.

Overview: Screening phase and trial treatment. Response assessment: ^aRecommended (not part of the trial); ^bMandatory: response evaluation before DB treatment, after cycles 3 and 6, after 1 year, and annually thereafter were integral part of this trial. Evaluations included mIBG scintigraphy, bone marrow aspirates (including minimal disease measurement with AIPF), and whole-body MRI or MRI-CT scans of tumor sites. AIPF, automatic immunofluorescence detection system; CT, computed tomography; DB, dinutuximab beta; haplo-SCT, haploidentical stem-cell transplantation; IL2, interleukin 2; mIBG therapy, 131I-meta-iodobenzylguanidine therapy; MRI, magnetic resonance imaging; s.c., subcutaneous.

FIG 2.

Response to trial treatment: Two patients were ineligible because of screening failure or substantial PD with impaired general condition (Lansky score < 20 before the first antibody cycle). The remaining 68 patients were included in this analysis. (A) The intention-to-treat population (all trial patients), ie, last antibody cycle refers to the last administered cycle of DB received by the respective patient. (B) Patients receiving full protocol treatment (per-protocol population), that is, response represents the remission status after completion of trial treatment, defined as six full cycles of DB treatment. Dropout patients are listed in the upper part of B (PD before treatment completion and dropout side effects or AE). Percentages in the lower part of B refer to patients treated according to protocol (n = 39) and to the whole cohort of 68 patients (intention-to-treat population). CR maintained: patients who started DB treatment in CR; CR improved: patients who achieved CR during/after DB treatment. Event-free survival and overall survival were calculated from start of trial treatment (first antibody cycle in this trial, ie, first day of first DB cycle after haplo-SCT). AE, adverse event; CR, complete remission; DB, dinutuximab beta; EFS, event-free survival; haplo-SCT, haploidentical stem-cell transplantation; MR, mixed response; NR, nonremission; OS, overall survival; PD, progressive disease; PR, partial remission; SD, stable disease.

FIG 3.

(A) OS and EFS of whole cohort; (B) CI of relapse; (C) EFS: remission status before first DB cycle; (D) OS: remission status before first DB cycle; (E) EFS: BM infiltration before first DB cycle; (F) OS: BM infiltration before first DB cycle; (G) EFS: age at study entry; and (H) OS: age at study entry. Event-free survival and overall survival were calculated from start of trial treatment (first antibody cycle in this trial, ie, first day of first DB cycle after haplo-SCT). BM, bone marrow; CI, cumulative incidence; CR, complete remission; DB, dinutuximab beta; EFS, event-free survival; haplo-SCT, haploidentical stem-cell transplantation; MR, mixed response; NR, nonremission; OS, overall survival; PD, progressive disease; PR, partial remission; SD, stable disease.