Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial

Abstract

Summary Background Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. Methods Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either nonpurged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus metaiodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. Findings 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33–46) in the purged group versus 36% (30–42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43–56) in the purged group compared with 51% (44–57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged gr...

Prolonged progression-free survival after consolidating second or later remissions of neuroblastoma with Anti-GD2immunotherapy and isotretinoin: a prospective Phase II study

“…All patients received HR-NB induction regimens. 5,6,30,31 Therapy before relapse included isotretinoin in 85 (84%) patients and anti-G D2 mAb in 51 (50%) patients. Sites of relapse were osteomedullary (BM and/or bone) (nD34), osteomedullary plus soft tissue (n D 31), or soft tissue (n D 36).…”

“…1 Before the routine use of immunotherapy, 3-5 year progression-free survival (PFS) rates in national studies were 20-40%, [2][3][4][5][6] even with inclusion of patients with what is now known to be intermediate-risk NB. 7 The randomized study of the Children's Oncology Group showed significantly better outcome in patients treated post-ASCT with the anti-G D2 chimeric mAb ch14.18 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin-2.…”

Specificities of Autologous Haematopoietic Stem Cell Transplantation in Children: A Single Centre Experience

“…The reason to this was considered to be either incomplete purging or residual tumour in the patient. These findings suggest that non-purged peripheral blood stem cell transplants are acceptable to support myeloablative therapy in highrisk neuroblastoma patients [30,31]. Tumour cell purging also significantly increases the price of the procedure, which further questions its necessity.…”

Not too little, not too much—just right! (Better ways to give high dose melphalan)

“…62 Subsequent studies simplified the intensity of the conditioning; dropping the TBI and using two or three drugs. 63,64 As the importance of the high-dose block of therapy has evolved from a 'kill or cure' approach to a cytoreductive cassette in overall therapy, the TRM has fallen from over 10% in an earlier era to the current 2%. 63 Figure 1.…”

“…63,64 As the importance of the high-dose block of therapy has evolved from a 'kill or cure' approach to a cytoreductive cassette in overall therapy, the TRM has fallen from over 10% in an earlier era to the current 2%. 63 Figure 1. 100-day TRM and year of high-dose procedure for neuroblastoma (with permission, from Ladenstein et al 60 ).…”