Management of High-Risk Neuroblastoma with Soft-Tissue-Only Disease in the Era of Anti-GD2 Immunotherapy.

Neuroblastoma presents with two patterns of disease: locoregional or systemic. The poor prognostic risk factors of locoregional neuroblastoma (LR-NB) include age, MYCN or MDM2-CDK4 amplification, 11q, histology, diploidy with ALK or TERT mutations, and ATRX aberrations. Anti-GD2 immunotherapy has significantly improved the outcome of high-risk (HR) NB and is mostly effective against osteomedullary minimal residual disease (MRD), but less so against soft tissue disease. The question is whether adding anti-GD2 monoclonal antibodies (mAbs) benefits patients with HR-NB compounded by only soft tissue. We reviewed 31 patients treated at SJD for HR-NB with no osteomedullary involvement at diagnosis. All tumors had molecular genetic features of HR-NB. The outcome after first-line treatment showed 25 (80.6%) patients achieving CR. Thirteen patients remain in continued CR, median follow-up 3.9 years. We analyzed whether adding anti-GD2 immunotherapy to first-line treatment had any prognostic significance. The EFS analysis using Cox models showed a HR of 0.20, p = 0.0054, and an 80% decrease in the risk of relapse in patients treated with anti-GD2 immunotherapy in the first line. Neither EFS nor OS were significantly different by CR status after first-line treatment. In conclusion, adding treatment with anti-GD2 mAbs at the stage of MRD helps prevent relapse that unequivocally portends poor survival.

Naxitamab Combined with Granulocyte-Macrophage Colony-Stimulating Factor as Consolidation for High-Risk Neuroblastoma Patients in First Complete Remission under Compassionate Use-Updated Outcome Report.

Naxitamab is an anti-GD2 antibody approved for the treatment of relapsed/refractory HR-NB. We report the survival, safety, and relapse pattern of a unique set of HR-NB patients consolidated with naxitamab after having achieved first CR. Eighty-two patients were treated with 5 cycles of GM-CSF for 5 days at 250 µg/m2/day (-4 to 0), followed by GM-CSF for 5 days at 500 µg/m2/day (1-5) and naxitamab at 3 mg/kg/day (1, 3, 5), on an outpatient basis. All patients but one were older than 18 months at diagnosis and had stage M; 21 (25.6%) pts had MYCN-amplified (A) NB; and 12 (14.6%) detectable MRD in the BM. Eleven (13.4%) pts had received high-dose chemotherapy and ASCT and 26 (31.7%) radiotherapy before immunotherapy. With a median follow-up of 37.4 months, 31 (37.8%) pts have relapsed. The pattern of relapse was predominantly (77.4%) an isolated organ. Five-year EFS and OS were 57.9% (71.4% for MYCN A) 95% CI = (47.2, 70.9%); and 78.6% (81% for MYCN A) 95% CI = (68.7%, 89.8%), respectively. EFS showed significant differences for patients having received ASCT (p = 0.037) and pre-immunotherapy MRD (p = 0.0011). Cox models showed only MRD as a predictor of EFS. In conclusion, consolidation with naxitamab resulted in reassuring survival rates for HR-NB patients after end-induction CR.

Naxitamab combined with granulocyte-macrophage colony-stimulating factor as consolidation for high-risk neuroblastoma patients in complete remission.

BACKGROUND: Naxitamab is a humanized anti-disialoganglioside (GD2) monoclonal antibody approved for treatment of bone/bone marrow refractory high-risk neuroblastoma (HR-NB). Compassionate use (CU) expanded access program at Hospital Sant Joan de Deu permitted treatment of patients in complete remission (CR). We here report the survival, toxicity, and relapse pattern of patients in first or second CR treated with naxitamab and sargramostim (GM-CSF). PROCEDURE: Seventy-three consecutive patients with HR-NB (stage M at age >18 months or MYCN-amplified stages L1/L2 at any age) were treated in first or second CR. Treatment comprised five cycles of subcutaneous (SC) GM-CSF for 5 days at 250 µg/m2 /day (days -4 to 0), followed by naxitamab + SC GM-CSF for 5 days at 500 µg/m2 /day (days 1-5). Naxitamab was infused over 30 minutes at 3 mg/kg/day, days 1, 3, and 5, outpatient. RESULTS: Fifty-five patients were in first CR and 18 in second CR. Seventeen patients had MYCN-amplified NB and 11 detectable minimal residual disease in the bone marrow. Fifty-eight (79.5%) patients completed therapy. Four (5%) experienced grade 4 toxicities and 10 (14%) early relapse. Three-year event-free survival (EFS) 58.4%, 95% CI = (43.5%, 78.4%) and overall survival (OS) 82.4%, 95% CI = (66.8%, 100%). First CR patients 3-year EFS 74.3%, 95% CI = (62.7%, 88.1%), and OS 91.6%, 95% CI = (82.4%, 100%). EFS is significantly different between first and second CR (p = .0029). The pattern of relapse is predominantly (75%) of an isolated organ, mainly bone (54%). Univariate Cox models show prior history of relapse as the only statistically significant predictor of EFS but not OS. CONCLUSIONS: Consolidation with naxitamab and GM-CSF resulted in excellent survival rates for HR-NB patients in CR.

Clinical and Pathological Evidence of Anti-GD2 Immunotherapy Induced Differentiation in Relapsed/Refractory High-Risk Neuroblastoma.

BACKGROUND: Neuroblastic tumors (NBTs) originate from a block in the process of differentiation. Histologically, NBTs are classified in neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN). Current therapy for high-risk (HR) NB includes chemotherapy, surgery, radiotherapy, and anti-GD2 monoclonal antibodies (mAbs). Anti-GD2 mAbs induce immunological cytoxicity but also direct cell death. METHODS: We report on patients treated with naxitamab for chemorefractory NB showing lesions with long periods of stable disease. Target lesions with persisting 123I-Metaiodobenzylguanidine (MIBG) uptake after 4 cycles of immunotherapy were further evaluated by functional Magnetic Resonance Imaging (MRI) and/or Fluorodeoxyglucose (FDG)-positron emission tomography (PET). MIBG avid lesions that became non-restrictive on MRI (apparent diffusion coefficient (ADC) > 1) and/or FDG-PET negative (SUV < 2) were biopsied. RESULTS: Twenty-seven relapse/refractory (R/R) HR-NB patients were enrolled on protocol Ymabs 201. Two (7.5%) of the 27 showed persistent bone lesions on MIBG, ADC high, and/or FDG-PET negative. Forty-four R/R HR-NB patients received chemo-immunotherapy. Twelve (27%) of the 44 developed persistent MIBG+ but FDG-PET- and/or high ADC lesions. Twelve (86%) of the 14 cases identified were successfully biopsied producing 16 evaluable samples. Histology showed ganglioneuroma maturing subtype in 6 (37.5%); ganglioneuroma mature subtype with no neuroblastic component in 4 (25%); differentiating NB with no Schwannian stroma in 5 (31%); and undifferentiated NB without Schwannian stroma in one (6%). Overall, 10 (62.5%) of the 16 specimens were histopathologically fully mature NBTs. CONCLUSIONS: Our results disclose an undescribed mechanism of action for naxitamab and highlight the limitations of conventional imaging in the evaluation of anti-GD2 immunotherapy clinical efficacy for HR-NB.

The Role of Autologous Stem-Cell Transplantation in High-Risk Neuroblastoma Consolidated by anti-GD2 Immunotherapy. Results of Two Consecutive Studies.

Background: Treatment of HR-NB comprise induction, consolidation with autologous stem cell transplant (ASCT) followed by anti-GD2 immunotherapy and isotretinoin. Childrens Oncology Group and SIOPEN studies used dinutuximab and cytokines to treat patients in complete remission or refractory Bone/Bone marrow (B/BM) disease after ASCT. Methods: HR-NB patients referred to Hospital Sant Joan de Déu for anti-GD2 immunotherapy were eligible for two consecutive studies (dinutuximab for EudraCT 2013-004864-69 and naxitamab for 017-001829-40) and naxitamab/Sargramostim CU with or without prior ASCT. Patients enrolled in first complete remission or with primary refractory B/BM disease. We accrued a study population of two groups whose therapy, aside from ASCT, was similar. This is a retrospective analysis of their outcome calculated from study entry. Results: From December 2014-2019, 67 patients were treated with dinutuximab and cytokines (n = 21) in the Hospital Sant Joan de Déu-HRNB-Ch14.18 study or with naxitamab and Sargramostim either in the Ymabs study 201 (n = 12) or CU (n = 34). 23 patients were treated with primary refractory disease in the B/BM (11 with dinutuximab and 12 with naxitamab), and 44 in first CR (10 with dinutuximab and 34 with naxitamab). Study patients included 13 (19.4%) treated following single ASCT and 54 following conventional chemotherapy. Median follow-up for all patients is 16.2 months. Two-year rates for ASCT and non-ASCT patients were, respectively, EFS 64.1% vs. 54.2% (p = 0.28), and OS 66.7% vs. 84.1% (p = 0.81). For the 44 pts in first CR, 2-years rates for ASCT and non-ASCT patients were, respectively, EFS 65.5% vs. 58.7% (p = 0.48), and OS 71.4% vs. 85.4% (p = 0.63). Conclusions: In this retrospective, single center study, ASCT did not provide survival benefit when anti-GD2 immunotherapy was used after induction chemotherapy.