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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1224-1232
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Phase 3 study of the multidrug resistance modulator PSC-833 in
previously untreated patients 60 years of age and older with acute
myeloid leukemia: Cancer and Leukemia Group B Study 9720
Maria R. Baer,
Stephen L. George,
Richard K. Dodge,
Kieran L. O'Loughlin,
Hans Minderman,
Michael A. Caligiuri,
John Anastasi,
Bayard L. Powell,
Jonathan E. Kolitz,
Charles A. Schiffer,
Clara D. Bloomfield, and
Richard A. Larson
From the Roswell Park Cancer Institute, Buffalo, NY;
CALGB Statistical Center, Durham, NC; Ohio State University Medical
Center, Columbus; University of Chicago, IL; Wake Forest University
School of Medicine, Winston-Salem, NC; North Shore University Hospital,
Manhasset, NY; and Wayne State University School of Medicine, Detroit,
MI. Participating institutions and principal investigators are listed
in the "appendix."
The Cancer and Leukemia Group B conducted a phase 3 trial of the
P-glycoprotein modulator PSC-833 in untreated acute myeloid leukemia
patients aged 60 years and older. Patients were randomized to 1 of 2 regimens, with doses determined in a prior phase 1 study, consisting of
cytarabine 100 mg/m2/d by 7-day infusion, with daunorubicin
60 mg/m2 and etoposide 100 mg/m2 daily for 3 days (ADE), or daunorubicin 40 mg/m2 and etoposide 60 mg/m2 for 3 days with PSC-833, 2.8 mg/kg over 2 hours, and
then 10 mg/kg/d by 3-day infusion (ADEP). The ADEP arm was closed after randomization of 120 patients (61 to ADE and 59 to ADEP) because of
excessive early mortality. Rates of complete remission, nonresponse, and death were 46%, 34%, and 20% for ADE, versus 39%, 17%, and 44% for ADEP (P = .008). Nevertheless, disease-free
survival (median 7 vs 8 months; P = .38) and overall
survival (approximately 33% alive at 1 year) did not differ and were
similar to historical results. Although the number of patients was
limited, ADE patients whose pretreatment cells exhibited
PSC-833-modulated dye efflux in vitro (n = 22) had worse outcomes
than those without efflux (n = 11) (complete remission, nonresponse,
and death rates of 41%, 41%, and 18%, compared with 91%, 9%, and
0%; P = .03), but with ADEP outcomes were nearly
identical. Moreover, for patients with PSC-833-modulated efflux,
median disease-free survival was 5 months with ADE and 14 months with
ADEP (P = .07). Further modulation trials in older
patients must await the design of less-toxic regimens.
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