High-dose busulfan/melphalan as conditioning for autologous PBPC transplantation in pediatric patients with solid tumors

Abstract

Summary:We conducted a prospective pilot study to assess the feasibility and safety of high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC transplantation in pediatric patients with high-risk solid tumors. From January 1995 to January 1999, 30 patients aged 2-21 years (median 8) were entered into the study. There were 14 females and 16 males. Diagnoses included neuroblastoma in 10 patients; Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) in 15 patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan 16 mg/kg, orally over 4 days (from days ؊5 to ؊2) in 6 hourly divided doses, and melphalan at a dose of 140 mg/m 2 given by intravenous infusion over 5 min on day ؊1. G-CSF mobilized PBPC were used as autologous stemcell rescue. One patient developed a single generalized convulsion during busulfan therapy. The most relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2-3 mucositis and diarrhea in 12 patients. Two patients died of procedure-related complications, one from veno-occlusive disease of liver and multiorgan failure and the other from adult respiratory distress syndrome. Probability of treatment-related mortality was 6.6 ؎ 4.5%. With a median follow-up of 18 months (range, 1-48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being 55 ؎ 12% for the whole group. We conclude that high-dose busulfan/melphalan for autologous transplantation in children with solid tumors is feasible even in small patients. It is well-tolerated, with an acceptable transplant-related mortality and has proven antitumor activity. Keywords: busulfan/melphalan; solid tumors; PBPC transplantation; children Children with advanced or recurrent solid tumor have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic cell rescue has improved this situation. 1 introduced as consolidation for pediatric patients with highrisk relapsed solid tumors. 2 However, the best conditioning regimen has not yet been established. High-dose chemotherapy regimens should consist of one or several agents that have dose-response-related anti-cancer activity and do not have overlapping extra-hematological toxicities. Busulfan is currently used at high doses in preparative regimens for hematopoietic transplantation. Liver toxicity is doselimiting for busulfan as a single agent. 3 Melphalan has demonstrated activity in high doses for relapsed or refractory solid tumors in children and its primary toxicity is myelosuppression. 4-5 A preparative regimen based on highdose busulphan and melphalan has been used for transplantation in patients with hematological malignancies in adults with low toxicity. 6-8 Based on previous experience, we conducted a pilot study to assess the feasibility and safety of high-dose busulfan and melphalan as conditioning therapy followed by mobilized peripheral blood progenitor cell (PBPC) support in pediatric patients with high-risk solid tumors. Patients and methods Patients

High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors

“…The pediatric BM transplant team from the University of Madrid reported an EFS rate of 55% at 4 years in a group of children and young adults with highrisk solid tumors that included 15 patients with EFT treated with BU at a dose of 16 mg/kg and Mel at a dose of 140 mg/m 2 followed by HSCT. 30 Similarly, the pediatric oncology group from the Royal Marsden Hospital in the United Kingdom used high-dose BU and Mel to treat a group of 18 patients with high-risk ES (including 11 patients with metastatic disease at presentation) and reported 13 out of 18 patients alive and disease free after a median follow-up of 2 years. 23 The decision to change our HDT regimen to Mel/BU was based on these studies.…”

Nucleophosmin as a Candidate Prognostic Biomarker of Ewing's Sarcoma Revealed by Proteomics

“…Despite significant progress regarding intensive chemotherapy protocols and local control measures, 30% to 40% of patients with localized Ewing's sarcoma and 80% of patients with metastatic Ewing's sarcoma at diagnosis die due to disease progression within 5 years (1). More intensified first-line chemotherapy regimens or combinations of chemotherapeutic agents improve clinical outcome compared with conventional chemotherapy (2,3). However, such therapies may result in serious toxicity, including fatal gastrointestinal toxicity, grade 3 or 4 infections, and severe myelosuppression (4 -6).…”

High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma

“…7,8 In other studies describing treatment of refractory malignancies, combinations of high-dose alkylating agents were reported as being effective. 9,10 Until now, however, there has been no established protocol for high-dose chemotherapy in osteosarcoma. All published studies have included only small patient numbers and heterogeneous treatment regimens.…”