Busulfan–melphalan in high-risk neuroblastoma: the 30-year experience of a single institution

Abstract

High-dose chemotherapy (HDC) was investigated in high-risk neuroblastoma (HR-NBL) to reduce the risk of relapse. We report the results of the 30-year experience of a cohort of patients with HR-NBL treated with high-dose (HD) busulfan (Bu)-containing regimens. From 1980From to 2009 patients aged 41 year with stage 4 NBL were treated with HD Bu-containing regimens at Gustave Roussy. These data were prospectively recorded in the Pediatric Transplantation Database. The median age at diagnosis was 40 months (12-218 months). All patients had a stage 4 neuroblastoma. NMYC amplification was displayed in 24% of the tumors. The hematopoietic support consisted of bone marrow or PBSCs in 46% and 49% of patients, respectively. The 5-year eventfree survival and overall survival rates of the whole cohort were 35.1% and 40%, respectively. Age at diagnosis, bone marrow involvement and tumor response after induction chemotherapy were significant prognostic factors. Toxicity was manageable and decreased over time, owing to both PBSC administration and better supportive care. Based on this experience, HD Bu-melphalan (Mel) has been implemented in Europe and compared with Carboplatin-Etoposide-Mel in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized protocol. It has now become the standard HDC in the SIOPEN HR strategy. INTRODUCTIONThe improved survival rates of patients with high-risk (HR) neuroblastoma (NBL) observed during the past decades are related to the intensification of induction therapy, high-dose chemotherapy (HDC) and better supportive care. 1 In the HR-NBL population, a correlation between survival and dose intensity has been reported, and three randomized studies showed that HDC followed by autologous stem cell transplantation (ASCT) or autologous bone marrow transplantation (ABMT) improved survival rates. [2][3][4] As NBL is notoriously radiosensitive, hyperfractionated TBI was incorporated into the conditioning regimen and has yielded encouraging results. 5 Alkylating agents were demonstrated to produce a log-linear dose response against tumor cells in vitro. 6 Since the mid-1980s, HDC with alkylating agents and ASCT has been the treatment strategy used at Gustave Roussy. HD busulfan (Bu) was selected because of its specific cytotoxicity against quiescent cells, 7 as an alternative to TBI in HR-NBL patients to avoid its side-effects, 8 especially in this very young population, and to achieve better survival rates.We report here the results of our 30-year experience on patients with HR-NBL treated with HD Bu-containing regimens. Bu was combined with melphalan (Mel) or Mel plus cyclophosphamide, and HDC was followed by stem cell (SC) or bone marrow (BM) transplantation. These results provided the rationale to widely implement the use of HD Bu-Mel, which was then compared with Carboplatin-Etoposide-Mel (CEM) in the European SIOP Neuroblastoma (SIOPEN)/HR-NBL randomized trial. HD Bu-Mel has now become the standard HD regimen in the SIOPEN HR strategy.

Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony–Stimulating Factor, Interleukin-2, and Haploidentical Natural Killer Cells

“…In these 30 patients, 8 developed VOD, 3 of which had mild MOD. The incidence of other toxicities (Table II) were similar to those previously reported for AHCT using a Bu/Mel conditioning regimens 27–33 . We did not appreciate any difference in toxicities between those patients that did and did not receive NKs.…”

Incorporation ofGSTA1genetic variations into a population pharmacokinetic model for IV busulfan in paediatric hematopoietic stem cell transplantation

“…In children, it has been used as an alternative to total body irradiation (TBI) with comparable event‐free survival (EFS) in patients with acute myeloblastic leukaemia (AML) and less developmental and cognitive impacts in long‐term survivors . Bu is also included in conditioning regimens before allogeneic SCT for acute lymphoblastic leukaemia and non‐malignant diseases as well as in autologous transplantation regimens for high‐risk neuroblastoma and relapsed/refractory Hodgkin lymphoma .…”

Neuroblastoma de Alto Riesgo en Uruguay. ¿Dónde estamos?

“…la localización fue abdominal en todos los pacientes, excepto en uno en el que el sitio del tumor primario fue desconocido. en otros estudios que incluyen mayor cantidad de pacientes, se identifican pacientes con estadios menores y enfermedad de alto riesgo que presentan una mejor sobrevida con respecto a los que debutan con enfermedad avanzada 11 .…”

“…el beneficio del tPH se mantiene en la sle, no teniendo tanta incidencia en la sG 15 . el tPH se realizó en 33 pacientes, la mortalidad relacionada al trasplante fue mayor que la reportada en otras series 11,12,21 .…”

“…los pacientes con estadios localizados, menores de 1 año, siempre se consideran de riesgo bajo 7,8 . la estrategia terapéutica en estos tumores de alto riesgo se divide en tres fases: inducción de la remisión con quimioterapia seguida de cirugía del tumor primario, consolidación con quimioterapia a altas dosis y rescate con trasplante autólogo de progenitores hematopoyéticos (tPH) y radioterapia, y tratamiento de la enfermedad residual con ácido 13-cis retinoico 5,9,10 . Hay una correlación entre sobrevida e intensidad de tratamiento, lo que ha sido la base para la consolidación con quimioterapia mieloablativa y rescate con tPH autólogo 11,12 . a su vez, la respuesta al tratamiento de inducción tiene implicancias pronósticas 13 .…”