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Camptothecin Analogs (Irinotecan or Topotecan) plus High-Dose Cyclophosphamide as Preparative Regimens for Antibody-Based Immunotherapy in Resistant Neuroblastoma

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York

Purpose: We used high-dose cyclophosphamide plus topotecan/vincristine (CTV) or irinotecan (C/I) in patients with resistant neuroblastoma. The aim was to use a regimen with little risk to major organs to (a) achieve or consolidate remission in heavily treated patients and to (b) induce an immunological state conducive to passive immunotherapy with the murine 3F8 antibody.

Experimental Design: CTV and C/I included cyclophosphamide 140 mg/kg (4200 mg/m²). With CTV, topotecan 2 mg/m² was infused i.v. (30 min) on days 1–4 (total, 8 mg/m²), and vincristine 0.067 mg/kg was injected on day 1. With C/I, irinotecan, 50 mg/m² was infused i.v. (1 h) on days 1–5 (total, 250 mg/m²). Mesna and granulocyte colony-stimulating factor were used.

Results: Twenty-nine patients received 38 courses of CTV, and 26 patients received 38 courses of C/I. All patients had previously received topotecan, a hemopoietic stem-cell transplant, and/or high-dose cyclophosphamide. CTV and C/I caused myelosuppression of comparably prolonged duration as follows: absolute neutrophil counts <500/µl lasted 5–12 days in patients who had not previously received transplant and 7–21 days in patients who were post-transplant. Other significant toxicities included typhlitis (two CTV-treated patients, one C/I-treated patient) and hemorrhagic cystitis (one C/I-treated patient). Major responses were seen in 4 (15%) of 26 CTV and 4 (17%) of 24 C/I-treated patients with assessable disease. Bone marrow disease resolved in 5 (28%) of 18 CTV-treated patients and in 4 (27%) of 15 C/I-treated patients. 3F8 after CTV or C/I was not blocked by neutralizing antibodies, consistent with the desired immunosuppressive effect of high-dose cyclophosphamide.

Conclusions: CTV and C/I require transfusional and antibiotic support but otherwise entail tolerable morbidity. They have modest antineuroblastoma activity in heavily treated patients and are good preparative regimens for passive immunotherapy with monoclonal antibodies.

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