| | |  | | | | Record from Web of Science® | | | | | | |
| Treatment of refractory and relapsed acute myelogenous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC833 (Valspodar) |
|
|
| Author(s): Advani R, Saba HI, Tallman MS, Rowe JM, Wiernik PH, Ramek J, Dugan K, Lum B, Villena J, Davis E, Paietta E, Litchman M, Sikic BI, Greenberg PL |
| Source: BLOOD Volume: 93 Issue: 3 Pages: 787-795 Published: FEB 1 1999 |
| Times Cited: 109 References: 74 |
| Abstract: 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, pins 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 tb compensate for these interactions and clinical toxicity and in Cohort II were well tolerated at dose levels of 4 mg/m(2) mitoxantrone, 40 mg/m(2) etoposide, and 1 g/m(2) 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. (C) 1999 by The American Society of Hematology. |
| Document Type: Proceedings Paper |
| Language: English |
| Reprint Address: Greenberg, PL (reprint author), Stanford Univ, Med Ctr, Div Hematol, Room S-161, Stanford, CA 94305 USA |
Addresses:
1. Stanford Univ, Med Ctr, Div Hematol, Stanford, CA 94305 USA
2. Vet Affairs Med Ctr, Palo Alto, CA 94304 USA
3. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA
4. Northwestern Univ, Med Ctr, Chicago, IL 60611 USA
5. Univ Rochester, Sch Med & Dent, Rochester, NY USA
6. Albert Einstein Canc Ctr, Bronx, NY 10461 USA
7. Novartis Pharmaceut, E Hanover, NJ USA |
| Publisher: AMER SOC HEMATOLOGY, 1200 19TH ST, NW, STE 300, WASHINGTON, DC 20036-2422 USA |
| Subject Category: Hematology |
| IDS Number: 161YX |
| ISSN: 0006-4971 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |