title: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995).
abstract: OBJECTIVE
  To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
  
  
  METHODS
  A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS.
  
  
  RESULTS
  For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents.
  
  
  CONCLUSIONS
  CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.
authors.affiliation: Hematology Division, Stanford University Medical Center, 703 Welch Rd, Suite G-1, Stanford, CA 94305, USA. peterg@stanford.edu
authors.forename: Peter L
authors.initials: PL
authors.lastname: Greenberg
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
authors.forename: Louis
authors.initials: L
authors.lastname: Letendre
authors.forename: Kathleen
authors.initials: K
authors.lastname: Dugan
authors.forename: Bert
authors.initials: B
authors.lastname: Lum
authors.forename: David L
authors.initials: DL
authors.lastname: Chin
authors.forename: Gordon
authors.initials: G
authors.lastname: Dewald
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: John M
authors.initials: JM
authors.lastname: Bennett
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003524:Cyclosporins / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D019450:Genes, MDR; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics; D016019:Survival Analysis; D014481:United States
chemical_list: D003524:Cyclosporins; D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone; C070272:valspodar