Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.

2.50
Hdl Handle:
http://hdl.handle.net/10541/84120
Title:
Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.
Authors:
Visani, G; Milligan, Donald W; Leoni, F; Chang, James; Kelsey, S; Marcus, R; Powles, R; Schey, S; Covelli, A; Isidori, A; Litchman, M; Piccaluga, P P; Mayer, H; Malagola, M; Pfister, C
Abstract:
PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.
Affiliation:
Istituto di Ematologia e Oncologia Medica L & A Seragnoli, Università degli Studi di Bologna, Azienda Ospedaliera Policlinico Sant'Orsola-Malpighi, Italy.
Citation:
Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia. 2001, 15 (5):764-71 Leukemia
Journal:
Leukemia
Issue Date:
May-2001
URI:
http://hdl.handle.net/10541/84120
PubMed ID:
11368437
Type:
Article
Language:
en
ISSN:
0887-6924
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorVisani, Gen
dc.contributor.authorMilligan, Donald Wen
dc.contributor.authorLeoni, Fen
dc.contributor.authorChang, Jamesen
dc.contributor.authorKelsey, Sen
dc.contributor.authorMarcus, Ren
dc.contributor.authorPowles, Ren
dc.contributor.authorSchey, Sen
dc.contributor.authorCovelli, Aen
dc.contributor.authorIsidori, Aen
dc.contributor.authorLitchman, Men
dc.contributor.authorPiccaluga, P Pen
dc.contributor.authorMayer, Hen
dc.contributor.authorMalagola, Men
dc.contributor.authorPfister, Cen
dc.date.accessioned2009-10-13T08:54:58Z-
dc.date.available2009-10-13T08:54:58Z-
dc.date.issued2001-05-
dc.identifier.citationCombined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia. 2001, 15 (5):764-71 Leukemiaen
dc.identifier.issn0887-6924-
dc.identifier.pmid11368437-
dc.identifier.urihttp://hdl.handle.net/10541/84120-
dc.description.abstractPSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.en
dc.language.isoenen
dc.subjectAcute Myeloid Leukaemiaen
dc.subject.meshAdolescent-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshCyclosporins-
dc.subject.meshCytarabine-
dc.subject.meshDrug Resistance, Multiple-
dc.subject.meshEtoposide-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshLeukemia, Myeloid, Acute-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshMitoxantrone-
dc.subject.meshP-Glycoprotein-
dc.titleCombined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia.en
dc.typeArticleen
dc.contributor.departmentIstituto di Ematologia e Oncologia Medica L & A Seragnoli, Università degli Studi di Bologna, Azienda Ospedaliera Policlinico Sant'Orsola-Malpighi, Italy.en
dc.identifier.journalLeukemiaen

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