Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-G_D2immunotherapy and isotretinoin: a prospective Phase II study

Abstract

Relapse of high-risk neuroblastoma (HR-NB) is deemed invariably fatal yet increasing numbers of HR-NB patients achieve a second complete/very good partial remission (CR/VGPR), hence the urgency to find a successful consolidative therapy. Identifying efficacy in patients without assessable disease, however, is problematic. We report the first study providing outcome data for this group of patients with poor prognosis. To prevent another relapse, HR-NB patients in second or later CR/VGPR received the anti-G D2 murine antibody 3F8 plus granulocyte-macrophage colony-stimulating factor plus isotretinoin in a Phase II trial. Upon meeting the target aim for progression-free survival (PFS) in the initial cohort of 33 patients, the trial was amended to allow patients who developed human anti-mouse antibody (HAMA) to receive rituximab to ablate HAMA with or without low-dose maintenance chemotherapy until immunotherapy could resume. For the total of 101 study patients, 5-year PFS and overall survival (OS) rates were 33% § 5% and 48% § 5%, respectively. Among the 33 long-term progression-free survivors, 19 had MYCN amplification, 19 had previously received anti-G D2 immunotherapy plus isotretinoin (as first-line therapy), and 15 never received maintenance chemotherapy. In a multivariate analysis of prognostic factors, only absence of minimal residual disease in bone marrow after 2 cycles of immunotherapy and before initiation of isotretinoin or anti-HAMA therapy was significantly favorable for both PFS and OS. Therefore, long-term PFS is possible for HR-NB patients who achieve at least a second CR/VGPR and receive consolidation that includes anti-G D2 immunotherapy plus isotretinoin, even if the patients received these biological treatments before relapse. Results from this prospective study will aid in the development of future Phase II studies for this growing ultra high-risk patient population.

Neuroblastoma Patients' KIR and KIR-Ligand Genotypes Influence Clinical Outcome for Dinutuximab-based Immunotherapy: A Report from the Children's Oncology Group

“…Human anti-mouse antibody (HAMA) responses against murine mAbs can reduce the efficacy of the antibody immunotherapy by neutralizing the antibody, not allowing for effective recruitment of immune cells to the tumor site. It is possible that the frequent induction of a neutralizing (HAMA) response to 3F8 vs. the infrequent induction of a human anti-chimeric antibody (HACA) response to ch14.18 (23,24), or the use of IL2, may somehow account for the differential association of KIR-ligand missing status with better outcome for anti-GD2 treated patients in the MSKCC regimen but not the COG regimen.…”

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long‐term progression‐free survival of patients with resistant neuroblastoma

“…It might also be considered as treatment after completion of standard therapy for HR‐NB, though perhaps only for MYCN ‐non‐amplified disease, given that to date only preclinical data support perifosine for MYCN ‐amplified disease . The progression‐free survival off all therapy of 9/27 study patients with very long follow‐up (Table ) adds to accumulating evidence that refractory or relapsed HR‐NB can potentially be cured …”

Anti-GD2 immunotherapy for neuroblastoma

“…Of the 33 long-term progression-free survivors, 19 (58%) had previously received m3F8+GMCSF suggesting its effectiveness in eradicating MRD even when used for re-treatment. [48]…”