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Pilot study of intravenous melphalan combined with continuous infusion L‐ S,R ‐buthionine sulfoximine for children with recurrent neuroblastoma
Author(s) -
Anderson Clarke P.,
Matthay Katherine K.,
Perentesis John P.,
Neglia Joseph P.,
Bailey Howard H.,
Villablanca Judith G.,
Groshen Susan,
Hasenauer Beth,
Maris John M.,
Seeger Robert C.,
Reynolds C. Patrick
Publication year - 2015
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.25594
Subject(s) - medicine , melphalan , buthionine sulfoximine , bolus (digestion) , gastroenterology , leukopenia , toxicity , urology , chemotherapy , pharmacology , glutathione , chemistry , enzyme , biochemistry
Purpose To evaluate BSO‐mediated glutathione (GSH) depletion in combination with L‐PAM for children with recurrent or refractory high‐risk neuroblastoma (NB) as a means to enhance alkylator sensitivity. Procedure This pilot study (NCI #T95‐0092) administered L‐S,R‐buthionine sulfoximine (BSO) as a bolus followed by 72 hr continuous infusion of either 0.75 g/m 2 /hr (level 1) or 1.0 g/m 2 /hr (level 2) and melphalan (L‐PAM) (15 mg/m 2 bolus at hour 48 of BSO infusion). GSH in blood mononuclear cells and bone marrow was measured by enzymatic assay, BSO in plasma by HPLC. Results Thirty two patients received 58 courses of therapy (median 1, range 1–4 courses). Blood mononuclear cell GSH decreased (48 hr) to 47% ± 15.7%. Level 2 mean steady‐state concentration (Css) for BSO = 524 ± 207 μM and peak L‐PAM concentration = 3.32 ± 1.2 μM. Grade 3–4 leukopenia and thrombocytopenia were common. There were two deaths from CNS toxicity and acute tubular necrosis; one had a large, intracranial mass, both were receiving cephalosporin antibiotics. No other significant toxicities were seen. There were six responses (five partial and, one mixed) representing an 18% response rate; four/six responses occurred in patients that relapsed following myeloablative therapy and included a 98% reduction in volume (cm 3 ) of a pelvic mass, and three/five patients with >3 log reduction of tumor in marrow as measured by immunocytology (sensitivity 1/10 5 ). Conclusions BSO/L‐PAM has activity against recurrent high‐risk NB. Exclusion of cephalosporin antibiotics in future clinical trials of BSO may diminish the potential for serious renal and CNS toxicity. Pediatr Blood Cancer 2015;62:1739–1746. © 2015 Wiley Periodicals, Inc.