title: Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia.
abstract: OBJECTIVE
  Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted.
  
  
  METHODS
  In all, 1,014 newly diagnosed CP-CML patients were randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months.
  
  
  RESULTS
  A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% [95% CI, 53% to 65%] v 44% [95% CI, 37% to 50%]; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% [95% CI, 40% to 52%]; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission.
  
  
  CONCLUSIONS
  Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
authors.affiliation: Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Pettenkoferstr. 22, 68169 Mannheim, Germany. r.hehlmann@urz.uni-heidelberg.de
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Michael
authors.initials: M
authors.lastname: Lauseker
authors.forename: Susanne
authors.initials: S
authors.lastname: Jung-Munkwitz
authors.forename: Armin
authors.initials: A
authors.lastname: Leitner
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Nadine
authors.initials: N
authors.lastname: Pletsch
authors.forename: Ulrike
authors.initials: U
authors.lastname: Proetel
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Leopold
authors.initials: L
authors.lastname: Balleisen
authors.forename: Mathias
authors.initials: M
authors.lastname: Hänel
authors.forename: Markus
authors.initials: M
authors.lastname: Pfirrmann
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Krause
authors.forename: Christoph
authors.initials: C
authors.lastname: Nerl
authors.forename: Hans
authors.initials: H
authors.lastname: Pralle
authors.forename: Alois
authors.initials: A
authors.lastname: Gratwohl
authors.forename: Dieter K
authors.initials: DK
authors.lastname: Hossfeld
authors.forename: Joerg
authors.initials: J
authors.lastname: Hasford
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Susanne
authors.initials: S
authors.lastname: Saussele
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D016009:Chi-Square Distribution; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005858:Germany; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D012074:Remission Induction; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate