Improved Outcome in Children With Newly Diagnosed High-Risk Neuroblastoma Treated With Chemoimmunotherapy: Updated Results of a Phase II Study Using hu14.18K322A

Abstract

Purpose: We evaluated whether combining a humanized antidisialoganglioside monoclonal antibody (hu14.18K322A) throughout therapy improves early response and outcomes in children with newly diagnosed high-risk neuroblastoma.

Patients and methods: We conducted a prospective, single-arm, three-stage, phase II clinical trial. Six cycles of induction chemotherapy were coadministered with hu14.18K322A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose interleukin-2 (IL-2). The consolidation regimen included busulfan and melphalan. When available, an additional cycle of parent-derived natural killer cells with hu14.18K322A was administered during consolidation (n = 31). Radiation therapy was administered at the end of consolidation. Postconsolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin. Early response was assessed after the first two cycles of induction therapy. End-of-induction response, event-free survival (EFS), and overall survival (OS) were evaluated.

Results: Sixty-four patients received hu14.18K322A with induction chemotherapy. This regimen was well tolerated, with continuous infusion narcotics. Partial responses (PRs) or better after the first two chemoimmunotherapy cycles occurred in 42 of 63 evaluable patients (66.7%; 95% CI, 55.0 to 78.3). Primary tumor volume decreased by a median of 75% (range, 100% [complete disappearance]-5% growth). Median peak hu14.18K322A serum levels in cycle one correlated with early response to therapy (P = .0154, one-sided t-test). Sixty of 62 patients (97%) had an end-of-induction partial response or better. No patients experienced progressive disease during induction. The 3-year EFS was 73.7% (95% CI, 60.0 to 83.4), and the OS was 86.0% (95% CI, 73.8 to 92.8), respectively.

Conclusion: Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing.

Trial registration: ClinicalTrials.gov NCT01857934.

FIG 1.

Study schema. BuMel, busulfan and melphalan; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2, interleukin-2; NK, natural killer; PBSC, peripheral blood stem cell; XRT, radiation therapy.

FIG 2.

Disease response assessed by INRC for patients (A) after induction cycle 2 and (B) at the end of induction. Each bar represents an individual patient. The primary tumor response is demonstrated as a percentile change in volume of the primary tumor compared with the primary tumor volume at baseline. The color of the individual bars signifies the metastatic response including anatomic imaging, functional imaging (MIBG or PET), and bone marrow assessment. The blue bar represents a complete metastatic response. The red bar represents a metastatic VGPR. The teal bar represents a metastatic partial response. The orange bar represents no metastatic response. The purple bar signifies patients without metastatic disease at diagnosis. Bone marrow response is depicted by the following shapes: gray triangle represents the presence of bone marrow disease at the time of the assessment, blue oval represents bone marrow disease present at baseline that resolved at the time of the assessment, and the red star represents no bone marrow disease at baseline. Together, the primary tumor response, metastatic response, and bone marrow response are used to inform the INRC overall response. The overall response of the individual patient is presented by the letter below each bar. The letter C signifies a CR; V is a VGPR; P is a PR; N is a no response; and E means that the patient was not evaluable at that time point because of the primary tumor resection performed before therapy. X represents a stage IV patient who did not have a primary tumor at diagnosis. O represents two patients who discontinued protocol therapy before completing induction. CR, complete response; INRC, International Neuroblastoma Response Criteria; MIBG, [¹²⁵I]metaiodobenzylguanidine; PET, positron emission tomography; PR, partial response; VGPR, very good partial response.

FIG 3.

Association of hu14.18K322A peak serum levels (µg/mL) and response after two cycles of chemoimmunotherapy. Relationship between response (CR or PR [n = 42] v SD or PD [n = 17]) and peak hu14.18K322A levels, measured on first day of mAb infusion, 1 hour after a 4-hour infusion. P = .0154 (one-tailed t-test). CR, complete response; mAb, monoclonal antibody; PD, progressive disease; PR, partial response; SD, stable disease.

FIG 4.

Flow diagram. ASCT, autologous hematopoietic stem-cell transplant; mAb, monoclonal antibody; MRD, minimal residual disease; PD, progressive disease.

FIG 5.

EFS and OS for all patients enrolled. EFS, event-free survival; OS, overall survival.