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Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 787-795
Treatment of Refractory and Relapsed Acute Myelogenous Leukemia
With Combination Chemotherapy Plus the Multidrug Resistance
Modulator PSC 833 (Valspodar)
Ranjana Advani,
Hussain I. Saba,
Martin S. Tallman,
Jacob M. Rowe,
Peter H. Wiernik,
Joseph Ramek,
Kathleen Dugan,
Bert Lum,
Jenny Villena,
Eric Davis,
Elisabeth Paietta,
Manuel Litchman,
Branimir
I. Sikic, and
Peter L. Greenberg
From Stanford University Medical Center, Stanford, CA; VA Medical
Center, Palo Alto, CA; Moffitt Cancer Center, Tampa, FL; Northwestern
University Medical Center, Chicago, IL; University of Rochester School
of Medicine and Dentistry, Rochester, NY; Albert Einstein Cancer
Center, Bronx, NY; and Novartis Pharmaceuticals, E Hanover, NJ.
A potential mechanism of chemotherapy resistance in acute myeloid
leukemia (AML) is the multidrug resistance (MDR-1) gene product
P-glycoprotein (P-gp), which is often overexpressed in myeloblasts from
refractory or relapsed AML. In a multicenter phase II clinical trial,
37 patients with these poor risk forms of AML were treated with PSC 833 (Valspodar; Novartis Pharmaceutical Corporation, East Hanover, NJ), a
potent inhibitor of the MDR-1 efflux pump, plus mitoxantrone,
etoposide, and cytarabine (PSC-MEC). Pharmacokinetic (PK) interactions
of etoposide and mitoxantrone with PSC were anticipated, measured in
comparison with historical controls without PSC, and showed a 57%
decrease in etoposide clearance (P = .001) and a 1.8-fold
longer beta half-life for mitoxantrone in plasma (P < .05).
The doses of mitoxantrone and etoposide were substantially reduced to
compensate for these interactions and clinical toxicity and in Cohort
II were well tolerated at dose levels of 4 mg/m2
mitoxantrone, 40 mg/m2 etoposide, and 1 g/m2 C
daily for 5 days. Overall, postchemotherapy marrow hypoplasia was
achieved in 33 patients. Twelve patients (32%) achieved complete remission, four achieved partial remission, and 21 failed therapy. The
PK observations correlated with enhanced toxicity. The probability of
an infectious early death was 36% (4 of 11) in patients with high PK
parameters for either drug versus 5% (1 of 20) in those with lower PK
parameters (P = .04). P-gp function was assessed in 19 patients using rhodamine-123 efflux and its inhibition by PSC. The
median percentage of blasts expressing P-gp was increased (49%) for
leukemic cells with PSC-inhibitable rhodamine efflux compared with 17%
in cases lacking PSC-inhibitable efflux (P = .004). PSC-MEC
was relatively well tolerated in these patients with poor-risk AML, and
had encouraging antileukemic effects. The Eastern Cooperative Oncology
Group is currently testing this regimen versus standard MEC
chemotherapy in a phase III trial, E2995, in a similar patient population.
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