title: A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia.
abstract: The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate.Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10 mg/kg per 24 h in combination with daunorubicin 45 mg/m(2) for 3 days and cytarabine 1 g/m(2) twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients.
authors.affiliation: Department of Hematology, Karolinska Hospital, SE-17176 Stockholm, Sweden. astrid.gruber@ks.se
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Magnus
authors.initials: M
authors.lastname: Björkholm
authors.forename: Lorentz
authors.initials: L
authors.lastname: Brinch
authors.forename: Stein
authors.initials: S
authors.lastname: Evensen
authors.forename: Bengt
authors.initials: B
authors.lastname: Gustavsson
authors.forename: Michael
authors.initials: M
authors.lastname: Hedenus
authors.forename: Gunnar
authors.initials: G
authors.lastname: Juliusson
authors.forename: Eva
authors.initials: E
authors.lastname: Löfvenberg
authors.forename: Ingerid
authors.initials: I
authors.lastname: Nesthus
authors.forename: Bengt
authors.initials: B
authors.lastname: Simonsson
authors.forename: Malvin
authors.initials: M
authors.lastname: Sjo
authors.forename: Leif
authors.initials: L
authors.lastname: Stenke
authors.forename: Jon Magnus
authors.initials: JM
authors.lastname: Tangen
authors.forename: Ulf
authors.initials: U
authors.lastname: Tidefelt
authors.forename: Ann-Mari
authors.initials: AM
authors.lastname: Udén
authors.forename: Christer
authors.initials: C
authors.lastname: Paul
authors.forename: Jan
authors.initials: J
authors.lastname: Liliemark
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D019540:Area Under Curve; D002423:Cause of Death; D003524:Cyclosporins / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D006801:Humans; D007951:Leukemia, Myeloid / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy; D016896:Treatment Outcome
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D003561:Cytarabine; C070272:valspodar; D003630:Daunorubicin