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Intensive treatments including high-dose chemotherapy (HDC) with autologous stem cell rescue have improved high-risk neuroblastoma (HRNB) survival. We report the long-term health status of 145 HRNB survivors, alive and disease-free 5 years post HDC. Median follow-up was 15 years (range = 5-34). Six patients experienced late relapses, 11 developed second malignant neoplasms (SMNs), and 9 died. Event-free and overall survivals 20 years post HDC were 82% (95% CI = 70%-90%) and 89% (78%-95%), respectively. Compared with the French general population, the standardized mortality ratio was 19 (95% CI = 8.7-36.1; p < 0.0001) and the absolute excess risk was 37.6 (19.2-73.5). Late effects were observed in 135/145 patients (median = 3 events/patient); 103 had at least one severe event. SMNs arose at a median of 20 years post HDC and included carcinoma (n = 5), sarcoma (2), acute myeloid leukemia (2), melanoma (1), and malignant glioma (1). Non-oncologic health events included dental maldevelopment (60%), severe hearing loss (20% cumulative probability at 15 years), hepatic focal nodular hyperplasia (14%), thyroid (11%), cardiac (8%), and renal (7%) diseases and growth retardation (height-for-age z-score ≤ -2 for 21%). Gonadal insufficiency was near-universal after busulfan (40/43 females, 33/35 males). Severe late effects are frequent and progressive in HRNB survivors needing systematic very long-term follow-up., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

High-risk neuroblastoma is characterized by poor long-term survival, especially for very high-risk (VHR) patients (poor response of metastases after induction therapy). The benefits of a tandem high-dose therapy and hematologic stem cell reinfusion (HSCR) have been shown in these patients. Further dose escalation will be limited by toxicity. It is thus important to evaluate the efficacy and tolerability of the addition of new agents such as I-MIBG (131Iode metaiodobenzylguanidine) to be combined with high-dose therapy in the consolidation phase. We report the feasibility of busulfan/melphalan (BuMel) after I-MIBG therapy with HSCR in patients with refractory or relapsed metastatic neuroblastoma. From November 2008 to March 2015, 9 patients received BuMel after I-MIBG therapy and topotecan. The main toxicity was digestive with only 1 patient developing grade 4 sinusoidal obstructive syndrome. Seven patients are alive at a median follow-up of 25 months. Among them, 2 are in ongoing complete remission and 1 in ongoing stable disease. These results suggest that BuMel with HSCR can be administered safely 2 months after I-MIBG therapy associated with topotecan for VHR patients. This strategy will be compared with tandem high-dose chemotherapy (thiotepa and busulfan-melphalan), followed by HSCR in the upcoming SIOPEN VHR Neuroblastoma Protocol.

Background: Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce the incidence of veno-occlusive disease in this setting., Methods: In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov, number NCT00272948., Findings: Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference -7·7%, 95% CI -15·3 to -0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls., Interpretation: Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT., Funding: Gentium SpA, European Group for Blood and Marrow Transplantation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children., Procedure: IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata., Results: The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 µM · min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group., Conclusion: The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome., (Copyright © 2011 Wiley Periodicals, Inc.)

Hepatic veno-occlusive disease (HVOD) is a frequent complication during hematopoietic stem-cell transplantation (HSCT). A strong relationship has been demonstrated between busulfan exposure and HVOD for busulfan-cyclophosphamide and allogeneic HSCT in adults. Busulfan disposition after the first intake was studied in 77 children treated for solid malignancies with high-dose busulfan-containing regimens and autologous HSCT. Busulfan was combined with cyclophosphamide and melphalan (n=30), melphalan (n=27), and thiotepa (n=20). No relationship was observed between busulfan exposure and HVOD. In contrast, plasma ferritin at baseline was higher in patients with HVOD (750 ng/ml (20-3,110)) compared with those without HVOD (189 ng/ml (8-3,967), P=0.012). Multivariate analysis showed that a ferritin level exceeding 300 ng/ml was the only risk factor for HVOD with an odds ratio of 4.0 (confidence interval 95% (1.5-11.2), P=0.0071). A high ferritin level at baseline was explained by the diagnosis of neuroblastoma, related treatments and transfusions.

Background: Invasive aspergillosis (IA) is a major cause of death after hematopoietic stem cell transplantation (HSCT). The goal of this retrospective and consecutive survey was to assess prognostic factors of death due to IA after HSCT at the time of diagnosis of IA., Methods: All 64 health care centers affiliated with the Société Française de Greffe de Moelle et de Thérapie Cellulaire were contacted to participate in this study of all proven or probable cases of IA that occurred among HSCT recipients in 2002. Data for 51 cases (41 involving allogeneic HSCT and 10 involving autologous HSCT) were collected from patient records and included diagnostic and therapeutic features of IA, outcome, presence of hematological disease, and transplantation data. Cox models were applied to risk factors for death attributed to IA that were initially identified using the usual tests., Results: The proportion of deaths attributed to IA within 4 months after diagnosis was 0.62 (95% confidence interval, 0.47-0.76). Seven factors assessed at diagnosis were determined to be strongly related to death due to IA: age of 12-35 years, dissemination of IA, presence of a pleural effusion, monocyte count of <120 cells/mm3, prolonged administration of steroids within the previous 2 months, receipt of a dose > or =2 mg/kg at the time of diagnosis, and uncontrolled graft-versus-host disease.Conclusions. Our study explored potential risk factors for death due to IA among HSCT recipients as a reference for investigation in larger future studies. These factors should help to identify HSCT recipients who would benefit from more-aggressive antifungal therapies.

We previously demonstrated that Busulfan-Thiotepa (Bu-Thio) and ASCT effectively treated patients with locally relapsed medulloblastoma after surgery and conventional chemotherapy. We thus evaluated the administration of Bu-Thio in patients relapsing after conventional CNS irradiation. Patients were scheduled to receive Busulfan (600 mg/m(2)) and Thiotepa (900 mg/m(2)) and ASCT. Resection of residual tumour and additional irradiation were performed if necessary and feasible after Bu-Thio. Toxicity was compared to that observed in 35 patients treated without previous CNS irradiation. From 5/88 to 3/02, 15 patients were treated according to this strategy. Toxicity was significantly higher than that observed in unirradiated patients: thrombocytopenia <50,000/mm(3) lasting 56 days (13-732) (P=0.02) and 30 days (4-124), respectively, HVOD (10/15 and 12/35 patients, respectively) (P=0.06), neurological toxicity (8/15 vs 3/35 patients) (P=0.01). Tumour response was assessable in seven patients and consisted in two CR, three PR and two NR. Currently, two of 15 patients are alive with no evidence of disease. In conclusion, the toxicity of Bu-Thio was significantly more severe in previously irradiated patients. In spite of a high response rate, this strategy failed to improve the prognosis of previously irradiated patients with a relapse from a medulloblastoma.

Background: Central nervous system (CNS) metastases rarely occur in patients with neuroblastoma, although recent reports suggest an increase in the rate. CNS recurrence may represent a different mechanism of spread than bone and bone marrow metastases and may be associated with unique genetic determinants. Further definition of the radiologic, clinical, and biologic features may provide clues to the predisposing factors and mechanisms of CNS dissemination., Methods: A retrospective analysis of all children ages 0-21 years with Stage IV neuroblastoma who were diagnosed at the Institut Curie and the Institut Gustave-Roussy between 1985 and 2000 was performed with direct review of medical records and magnetic resonance images, computed tomography scans, and iodine-123 or iodine-131 metaiodobenzylguanidine scintiscans (MIBG scans). When tumor tissue was available, genetic analysis was performed using comparative genomic hybridization (CGH)., Results: Of 434 patients with Stage 4 disease, 23 children had the CNS as their site of first recurrence. The estimated risk of CNS recurrence was 8.0% at 3 years, with no significant change in risk over the 15-year period. Eleven patients had isolated CNS recurrences, and the remaining patients developed recurrences concomitantly in other sites. The sites of recurrences were parenchymal (n = 8 patients), parenchymal with meningeal (n = 7 patients), and meningeal alone (n = 8 patients). MIBG scans detected CNS lesions in only 43% of patients. Significant risk factors for CNS recurrence included lumbar puncture at diagnosis, ages 2-3 years, and MYCN gene amplification. Abnormalities that were identified using CGH, in addition to 2p24 amplification in 5/7, included gains of 17q and 18q and losses of 1p, 3p, 10q25-26, and 11q., Conclusions: The risk of CNS recurrence in patients with neuroblastoma is 8% at 3 years after diagnosis and has not increased in the last 15 years. Because the CNS often is the sole site of recurrence, either it may be a sanctuary site, or the biologic determinants of CNS metastasis may be unique. Elucidation of risk factors and pathogenesis may allow prevention of this fatal event. Cancer 2003;98:155-65., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11448)

Background: Currently, the severity of veno-occlusive disease (VOD) is graded retrospectively on the basis of the evolution of clinical and biological criteria. The objective of this study was to describe a noninvasive method capable of predicting the severity of this disease at the time of the diagnosis., Methods: Seventy-one children who developed VOD after intensive myeloablative therapy with busulfan before hematopoietic stem cell transplantation were included in this study. Sixty-four patients underwent baseline ultrasonography (US) and Doppler examination before transplantation. All patients had posttransplantation US and Doppler examinations at the time of the clinical and biological diagnosis of VOD. Seven US morphological criteria and seven Doppler criteria were studied that yielded three individual scores: a US score, a Doppler score, and a total Doppler ultrasonography (DUS) score., Results: In the univariate analysis, three of 7 US criteria, three of 7 Doppler criteria, and the three scores were correlated with the severity of VOD after transplantation and at the time of the diagnosis. In the multivariate analysis, two US criteria (splenomegaly and ascites) and one Doppler criterion (flow recorded in para-umbilical vein) were correlated with the severity of VOD. The multivariate analysis of the pooled US and Doppler criteria showed that the flow recorded in the para-umbilical vein was the only criterion significantly associated with the grade of VOD (P=0.0001). All patients with a US-Doppler score >9 developed grade 2 or 3 VOD., Conclusion: Postgraft US and Doppler examinations have a prognostic significance according to the grade of VOD.

Our objective was to understand the parents' perception of children treated in an ASCT unit. Parents (40) of children and adolescents were interviewed by the department psychiatrist-psychoanalyst, over 9 months. They expressed great distress (22), considerable difficulty in assuming their parental role (with feelings of helplessness and guilt), and had distorted relations with the child whose behavior was unusual and incomprehensible (22). The relation with care providers, who should be 'all-powerful' and harmless, was ambivalent (15). They found it difficult to think or refused to do so, because their 'thoughts are terrifying', and they wanted to forget everything (11). The couple was going through a crisis (9). Temporal landmarks were disturbed (8); ASCT was experienced as a threatening discontinuity in the course of treatment (parents were unable to think of the past, the future, or the present); social landmarks were disturbed (6) with loss of social and professional relations. We concluded that parents may experience intense distress and disorientation. Trained to understand the parents' and their children's thoughts and behavior, the medical team, which includes a psycho-oncologist, can better help them to understand and support the children, to strike a balance between their parental role and other responsibilities, and prevent conflicts.

Repeated high-dose (HD) chemotherapy with peripheral blood stem cell (PBSC) transplantation is a new modality aimed at increasing both the dose and its intensity in the treatment of chemosensitive tumours. The aim of this study was to evaluate the tolerance, pharmacokinetics (PK) and pharmacodynamics (PD) of HD single-agent melphalan administered over two consecutive courses (C1 and C2) in children. Twenty-one patients (10 girls) with a median age of 4.1 years (range 8 months-14 years) were entered into this study. Five had metastatic neuroblastoma (NB) and 16 a cerebral primitive neuroectodermal tumour (PNET). Melphalan was given at a dose of 100 mg/m(2) every 21 days. PBSCs were infused at a median number of 2.98 x 10(6) CD34(+) cells/kg. Forty courses, ie 21 C1 and 19 C2, were administered. Both courses were well tolerated. The median duration of ANC < 500/microl was 7 and 6 days after C1 and C2, respectively. Platelet recovery (not mandatory to continue the HD strategy) was achieved in 52% of courses. GI toxicity was mild to moderate. The melphalan AUC ranged from 177 to 475 microg small middle dotmin/ml (no difference between C1 and C2). Prolonged neutropenia was associated with a young age (P < 0.001) and a low amount of CFU-GM (P = 0.002). A long time to platelet recovery was associated with a high AUC (P = 0.004) and a young age (P = 0.02). Grade 1 or 2 GI toxicity was associated with a high AUC (P = 0.015). Partial remission was observed in 11/14 patients with measurable cerebral PNET. In conclusion, tandem HD melphalan is feasible and safe in children, and achieved a high response rate in cerebral PNET. The observed PK-PD relationships may help us design PK-guided outpatient treatment.

Introduction: The ex vivo expansion of hematopoietic grafts could be an important therapeutic tool for accelerating hematopoietic recovery after administration of high-dose chemotherapy regimens. The fate of the long-term repopulating cells during the ex vivo manipulation of grafts is a critical issue and will ultimately define the clinical applicability of this technology to hematopoietic transplantation., Materials and Methods: To study the effects of a clinically applicable ex vivo expansion protocol in the proliferative potential of the most primitive human hematopoietic cells, both LTC-IC and NOD/SCID-RC assays were used to determine LTC-IC and NOD/SCID-RC contents of hematopoietic grafts, both before and after expansion (SCF, IL-3, PEG-MGDF Flt3-L and 5% AB serum), in four children with non-hematological malignancies., Results: The mean percentage of CD34+ cells after expansion was 16%. The numbers of nucleated cells increased 20-fold with a mean three-fold increase in the numbers of CD34+ cells during the expansion period. The CFC content of the samples showed a mean 11-fold increase (range: 5-17) after ex vivo expansion. The primitive hematopoietic stem cell content of the expanded cell fraction evaluated by LTC-IC assays was found to be increased in two patients out of three, with maintenance of the LTC-IC frequency in the third patient. The NOD/SCID-RC potential, evaluated in five experiments from four patients using 109 mice injected 5-6 weeks earlier with human hematopoietic cells, increased from a mean percentage of 36% (range: 7-75%) before expansion, to a mean percentage of 70% (range: 37-100%) after expansion (P < 0.00001). The frequency of NOD/SCID-RC calculated with pooled data from all patients was 1/80,000 at day 0 and 1/40,000 after seven days of culture. The full phenotypic analysis of human hematopoietic cells obtained in NOD/SCID mice injected with expanded cells showed the presence of significant numbers of CD34+, CD19+ and CD15+ cells, suggesting the persistent lympho-myeloid potential of the expanded hematopoietic cells., Conclusion: Our results suggest that efficient expansion of NOD/SCID-RC with lympho-myeloid potential can be achieved not only in cord blood or normal marrow as previously reported, but also in hematopoietic grafts obtained from children exposed to high-dose chemotherapy.

Although infants with stage 4 neuroblastoma (NB) usually have a good prognosis, metastatic relapses after 1 year of age and amplification of the N-myc oncogene are established poor prognostic factors. In order to improve the survival of patients with such high-risk factors, we performed consolidation with a busulfan (600 mg/m2)-melphalan (140 mg/m2)-containing regimen followed by autologous stem cell transplantation (SCT). From 1986 to 1998, 12 patients were treated according to this strategy. Their median age at diagnosis was 9 months (1-11). Consolidation was performed after a metastatic relapse in five children, because of persistent bone metastases in one and as first-line consolidation in six patients whose tumor exhibited N-myc amplification. The 5-year EFS rate is 64. 5% (36-85%) with a median follow-up of 92 months (20-126). One toxicity-related death occurred in a very heavily pretreated patient. Hepatic veno-occlusive disease was the major side-effect that occurred in nine of 12 children. This busulfan-melphalan combination appears to dramatically improve the prognosis of these high-risk infants with metastatic NB. Given its high toxicity, indications for this consolidation must be restricted to high-risk infants and a lower dose of busulfan (480 mg/m2) is recommended in children weighing less than 10 kg. Bone Marrow Transplantation (2000) 25, 937-942.

The purpose of this paper is to study prognostic factors in neuroblastoma patients treated with high-dose chemotherapy and hematopoietic stem cell transplantation. Two hundred and eighteen children over 1 year of age and treated for stage 4 neuroblastoma were enrolled in this study. The median age at diagnosis was 39 months, the sex ratio 1.5 and 84% of patients had an abdominal primary tumor. Skeletal disease was detected in 79% of cases and bone marrow involvement in 93%. N-myc oncogene amplification was present in 27% of the patients studied. The probability of event-free survival at 5 years post-diagnosis was 29% in this series. Three major favorable prognostic factors were significant and independent in the multivariate analysis: age under 2 years at diagnosis (P<0.01), absence of bone marrow metastases at diagnosis (P<0.04) and the high-dose conditioning regimen containing busulfanmelphalan combination (P = 0.001). The quality of response to conventional primary chemotherapy was close to significance (P = 0.053). We conclude that factors related to the patient (age) and extent of disease are predictive of outcome in patients with neuroblastoma treated with conventional chemotherapy followed by surgical excision of the primary and consolidation with high-dose chemotherapy. They should be taken into account in future prospective studies. Moreover, the type of conditioning regimen appears to be the most important prognostic factor. This should encourage new investigations into innovative drug combinations.

Purpose: The three-drug combination of melphalan (M), etoposide (E), and carboplatin (C) followed by autologous stem-cell (ASC) rescue has been evaluated prospectively by the French Society of Pediatric Oncology (SFOP) in pediatric high-risk recurrent (HRR) Wilms' tumor (WT) patients with chemotherapy-responsive disease., Patients and Methods: From October 1988 to October 1994, 29 patients with HRR WT were treated in nine SFOP centers. Two additional patients with stage IV anaplastic WT were consolidated in first complete response (CR) with the same regimen and have been studied separately. The regimen consisted of M 180 mg/m2 for 1 day, E 200 mg/m2/d for 5 days, and C at a daily targeted area under the concentration-time curve (AUC) of 4 mg x min/mL for 5 days. ASCs were reinfused 48 hours after M., Results: Twelve of 28 assessable patients with HRR WT are still in continuous CR at a median of 48.5 months (range, 36 to 96) after consolidation. Disease-free survival (DFS) and overall survival (OS) estimated by the Kaplan-Meier method at 3 years were 50%+/-17% and 60%+/-18%, respectively. Sixteen patients relapsed at a median of 8.5 months (range, 3 to 53) after consolidation. Toxicity data are available in 31 grafted patients. Grade III and IV toxicities included hematologic side effects (n=31), hemorrhage (n=8), mucositis (n=24), diarrhea (n=12), renal disorders (n=8), and pneumonitis (n=3)., Conclusion: The adverse prognostic factors (APF) used to select patients for this dose-intensive chemotherapy define children with very-poor-risk recurrent WT. Despite high treatment-related toxicity, about half of these patients remain disease-free at 3 years. Patient outcome is statistically better when high-dose chemotherapy (HDCT) is performed as early as the second CR or partial response (PR). Novel therapeutic approaches with innovative preparative regimens are warranted for the remaining high-risk patients.

From 1987 to 1995, 22 children with refractory solid tumors entered a phase II study of high-dose thiotepa (HDT) (900 mg/m2) followed by stem cell transplantation (SCT) in the Pediatrics Department of the Institut Gustave Roussy. Tumor types were rhabdomyosarcoma (eight), osteosarcoma (seven), neuroblastoma (three), Ewing's sarcoma (three) and Burkitt's lymphoma (one). Before HDT, all had been extensively treated with conventional chemotherapy, surgical resection of the primary tumor (13/22) and of metastases (6/22), and radiotherapy of the primary tumor in three patients. All had measurable disease, at the site of the primary tumor (3 patients), of the metastases (9 patients) or both (10 patients). Toxicity from the HDT was severe but acceptable. No toxicity-related death occurred. The median duration of neutropenia and thrombocytopenia was 18 days (5-37) and 30 days (7-377), respectively. Septicemia was documented in four patients. Severe diarrhea was observed in seven patients. Mild hepatic toxicity occurred 18 times. No CR and 11/22 PR were documented: osteosarcoma 4/7, rhabdomyosarcoma 4/8, Ewing's sarcoma 2/3; 1/1 Burkitt's lymphoma progressed. We conclude that at a dose of 900 mg/m2 followed by SCT support in these heavily pretreated children, the main toxicity induced by thiotepa was digestive. The response rate observed, especially in sarcoma, is particularly encouraging. Thiotepa should be further evaluated in HDC regimens either in combination with other alkylating agents or in rapidly cycled courses of HDC with SCT.

Purpose: To determine the value of gray-scale ultrasonography (US) and Doppler US in the prediction, diagnosis, and prognostic assessment of hepatic veno-occlusive disease (HVOD)., Materials and Methods: One hundred patients (median age, 22 years; range, 18 months to 59 years) receiving total body irradiation or busulfan therapy as intensive treatment before hematopoietic stem cell transplantation were studied prospectively. Each patient underwent gray-scale and Doppler US examination before transplantation and weekly thereafter while hospitalized (about four examinations per patient). Seven gray-scale morphologic criteria and seven Doppler criteria were studied, yielding three individual scores: gray-scale score, Doppler score, and total score., Results: Twenty-five patients developed HVOD; nine of these patients died. Positive predictive values of the 14 criteria were 31%-95%, and negative predictive values were 85%-96%. The three scores correlated with the clinical diagnosis of HVOD. Depending on the cutoff value, the positive predictive value of the total score was 44%-89% and the negative predictive value was 91%-98%. The gray-scale and Doppler criteria differed significantly between patients with HVOD and those with graft-versus-host disease of the liver (P = 10(-4))., Conclusion: Even if there is overlap in findings between patients with and those without HVOD, gray-scale and Doppler US are valid for positive and differential diagnosis and have predictive and prognostic relevance.