8534 Background: Autologous HSCT is curative for some children with high-risk solid tumors and lymphomas; however, no conditioning regimen has proven superior. In this phase II trial, we studied the antitumor response of the novel combination of cyclophosphamide and targeted-dose topotecan with stem cell support. Methods: Patients less than 25 years of age with a chemosensitive solid tumor or lymphoma at high risk of relapse or progression were eligible. Topotecan was administered intravenously once daily for 10 days at an initial dose of 3 mg/m2 with subsequent doses adjusted to achieve an AUC of 100 ± 20 ng-hr/ml. During the last 5 days, cyclophosphamide with mesna uroprotection was administered following the topotecan. At level 1, the cyclophosphamide dose was 750 mg/m2/day; at level 2 the dose was 1000 mg/m2/day. Results: Between November 1998 and October 2002, 56 patients with a median age of 5.7 years (1.2–21.3) were enrolled. Diagnoses included neuroblastoma (46.4%), sarcoma (21.4%), lymphoma (16.1%), brain tumor (8.9%), Wilms' tumor (5.4%), and retinoblastoma (1.8%). 24 were in remission at HSCT (43%); 32 had persistent disease (57%). 35 patients received a bone marrow graft; 21 received peripheral blood stem cells. The median time to neutrophil engraftment was 14 days; the median time to platelet engraftment was 23 days. 43 patients (77%) remain alive. 13 have died: 11 of disease recurrence and 2 of regimen-related toxicities. With a median follow-up of 20.1 months (0.7–59.4), 2 year overall survival was 93% for neuroblastoma, 78% for lymphomas 68% for sarcomas, and 22% for other tumors. 2 year disease-free survival (DFS) was 41% for neuroblastoma, 67% for lymphoma, 51% for sarcomas, and 33% for other tumors. The 2 year overall DFS was 50% for the entire cohort. The median time to recurrence was 5.8 months (1.2–15.2). Patients with residual disease at transplant had similar DFS as those in remission (51% vs. 49%). Conclusions: The combination of cyclophosphamide and targeted topotecan with autologous HSCT yields favorable outcomes for children with high-risk solid tumors and lymphomas, particularly sarcomas. Additional investigation is warranted. No significant financial relationships to disclose.