title: Amifostine (WR-2721) shortens the engraftment period of 4-hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support.
abstract: 4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty-three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high-dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.
authors.affiliation: Bone Marrow Transplant Program, University of Colorado, Denver, CO 80262.
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: S M
authors.initials: SM
authors.lastname: Stemmer
authors.forename: L
authors.initials: L
authors.lastname: Hami
authors.forename: W A
authors.initials: WA
authors.lastname: Franklin
authors.forename: L
authors.initials: L
authors.lastname: Shaw
authors.forename: H S
authors.initials: HS
authors.lastname: Bonner
authors.forename: S I
authors.initials: SI
authors.lastname: Bearman
authors.forename: W P
authors.initials: WP
authors.lastname: Peters
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
authors.forename: W
authors.initials: W
authors.lastname: McCulloch
mesh_terms: D000328:Adult; D004999:Amifostine / Q000494:pharmacology*; D016465:Bone Marrow Purging; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006412:Hematopoietic Stem Cells; D006801:Humans; D014182:Transplantation, Autologous
chemical_list: D003520:Cyclophosphamide; D004999:Amifostine; C011272:perfosfamide