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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
EJ Shpall, SM Stemmer, L Hami, WA Franklin, L Shaw, HS Bonner, SI Bearman, WP Peters, RC Bast and W McCulloch
Bone Marrow Transplant Program, University of Colorado, Denver, CO 80262.
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.
Volume 83,
Issue 11,
pp. 3132-3137,
06/01/1994
Copyright © 1994 by The American Society of Hematology
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