title: Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia.
abstract: OBJECTIVE
  Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed.
  
  
  METHODS
  Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0.
  
  
  RESULTS
  Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum.
  
  
  CONCLUSIONS
  We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.
authors.affiliation: Section of Molecular Hematology and Therapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. smk@odin.mdacc.tmc.edu
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
authors.forename: E
authors.initials: E
authors.lastname: Estey
authors.forename: T
authors.initials: T
authors.lastname: Madden
authors.forename: H T
authors.initials: HT
authors.lastname: Tran
authors.forename: S
authors.initials: S
authors.lastname: Zhao
authors.forename: U
authors.initials: U
authors.lastname: Consoli
authors.forename: V
authors.initials: V
authors.lastname: Snell
authors.forename: G
authors.initials: G
authors.lastname: Sanchez-Williams
authors.forename: H
authors.initials: H
authors.lastname: Kantarjian
authors.forename: M
authors.initials: M
authors.lastname: Keating
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D019450:Genes, MDR; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D012008:Recurrence
chemical_list: D003524:Cyclosporins; D005047:Etoposide; D008942:Mitoxantrone; C070272:valspodar