title: A Phase II trial of gemcitabine and mitoxantrone for patients with acute myeloid leukemia in first relapse.
abstract: BACKGROUND
  We evaluated the complete remission (CR) rate in patients with acute myeloid leukemia (AML) in first relapse treated with fixed-dose-rate gemcitabine and mitoxantrone. In addition, we measured multidrug resistance (MDR) proteins on pretreatment bone marrows and correlated expression with outcome.
  
  
  METHODS
  The study was performed in a 2-stage design. Pretreatment bone marrows were assayed for the MDR proteins (LRP, MDR1, MRP1, SLC28-29A1/A2, ABCC4/C5, and GSTP1) by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Only 5 of the first 24 patients (21%) achieved CR; therefore, the study was terminated. Eleven patients (46%) had poor-risk cytogenetics and the median duration of first CR was 7.3 months. Patients had significant expression of the various MDR genes, with 70% of patients expressing moderate to high levels of GSTP1 by immunohistochemistry. Higher sum total of ABCC4 and SLC29A2 expression measured by RT-PCR was associated with not achieving CR (20.6 vs. 12.1; P = .006). In addition, there was a trend for higher expression of the sum total of the 10 MDR genes (measured by RT-PCR) and not achieving CR (P = .06).
  
  
  CONCLUSIONS
  The CR rate in this study was comparable to other regimens used in poor-risk patients. Of interest, ABCC4 and SLC29A2 expression were predictive of achieving CR. The high expression of GSTP1 suggests that this may be a therapeutic target for relapsed AML. Finally, the rapidity and ease of using RT-PCR to quantify MDR in this study may have clinical utility in future trials.
authors.affiliation: Hematologic Oncology and Blood Disorders, Taussig Cancer Center, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. advania@ccf.org
authors.forename: Anjali S
authors.initials: AS
authors.lastname: Advani
authors.forename: Mazyar
authors.initials: M
authors.lastname: Shadman
authors.forename: Francis
authors.initials: F
authors.lastname: Ali-Osman
authors.forename: Andrew
authors.initials: A
authors.lastname: Barker
authors.forename: Lisa
authors.initials: L
authors.lastname: Rybicki
authors.forename: Matt
authors.initials: M
authors.lastname: Kalaycio
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Carlos M
authors.initials: CM
authors.lastname: de Castro
authors.forename: Louis F
authors.initials: LF
authors.lastname: Diehl
authors.forename: Joseph O
authors.initials: JO
authors.lastname: Moore
authors.forename: Anne
authors.initials: A
authors.lastname: Beaven
authors.forename: Ed
authors.initials: E
authors.lastname: Copelan
authors.forename: Ronald
authors.initials: R
authors.lastname: Sobecks
authors.forename: Parisa
authors.initials: P
authors.lastname: Talea
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018432:Drug Resistance, Multiple / Q000235:genetics; D033722:Equilibrative-Nucleoside Transporter 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005334:Fever / Q000139:chemically induced; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D020298:U937 Cells; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D033722:Equilibrative-Nucleoside Transporter 2; D051549:Glutathione S-Transferase pi; D008942:Mitoxantrone; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000093542:Gemcitabine; C073492:ABCC4 protein, human; C496556:GSTP1 protein, human