title: Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV.
abstract: OBJECTIVE
  Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.
  
  
  METHODS
  Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.
  
  
  RESULTS
  Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.
  
  
  CONCLUSIONS
  MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
authors.affiliation: Rüdiger Hehlmann, Martin C. Müller, Benjamin Hanfstein, Alice Fabarius, Annette Schreiber, Ulrike Proetel, Nadine Pletsch, Susanne Saußele, Universitätsmedizin Mannheim Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim; Jolanta Dengler Universitätsklinikum Heidelberg, Heidelberg; Michael Lauseker, Markus Pfirrmann, Joerg Hasford, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität; Christoph Nerl, Städtisches Klinikum Munchen Schwabing; Hans-Jochem Kolb, Klinikum rechts der Isar, Technische Universität München; Karsten Spiekermann, Universitätsklinikum, Ludwig-Maximilians Universität München; Claudia Haferlach, Susanne Schnittger, MLL Münchner Leukämielabor, Munich; Hermann Einsele, Universitätsklinikum Würzburg, Würzburg; Christiane Falge, Klinikum Nürnberg Nord, Nuremberg; Lothar Kanz, Universitätsklinikum Tübingen, Tübingen; Andreas Neubauer, Universitätsklinikum Gießen und Marburg, Marburg; Michael Kneba, Universitätsklinikum Schleswig-Holstein, Kiel; Frank Stegelmann, Hermann Heimpel, Universitätsklinikum Ulm, Ulm; Michael Pfreundschuh, Universitätsklinikum des Saarlandes, Homburg/Saar; Cornelius F. Waller, Universitätsklinikum Freiburg, Freiburg; Gerhard Ehninger, Universitätsklinikum Carl Gustav Carus, Dresden; Stefan W. Krause, Universitätsklinikum Erlangen, Erlangen; Dieter K. Hossfeld, Universitätsklinikum Eppendorf, Hamburg; Andreas Hochhaus, Universitätsklinikum Jena, Jena, Germany; Gabriela M. Baerlocher, Inselspital Bern, Bern; Dominik Heim, Universitätsspital Basel, Basel, Switzerland.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Martin C
authors.initials: MC
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Lauseker
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hanfstein
authors.forename: Alice
authors.initials: A
authors.lastname: Fabarius
authors.forename: Annette
authors.initials: A
authors.lastname: Schreiber
authors.forename: Ulrike
authors.initials: U
authors.lastname: Proetel
authors.forename: Nadine
authors.initials: N
authors.lastname: Pletsch
authors.forename: Markus
authors.initials: M
authors.lastname: Pfirrmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Jolanta
authors.initials: J
authors.lastname: Dengler
authors.forename: Christiane
authors.initials: C
authors.lastname: Falge
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Frank
authors.initials: F
authors.lastname: Stegelmann
authors.forename: Michael
authors.initials: M
authors.lastname: Pfreundschuh
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Waller
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Baerlocher
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Dominik
authors.initials: D
authors.lastname: Heim
authors.forename: Hermann
authors.initials: H
authors.lastname: Heimpel
authors.forename: Christoph
authors.initials: C
authors.lastname: Nerl
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Krause
authors.forename: Dieter K
authors.initials: DK
authors.lastname: Hossfeld
authors.forename: Hans-Jochem
authors.initials: HJ
authors.lastname: Kolb
authors.forename: Joerg
authors.initials: J
authors.lastname: Hasford
authors.forename: Susanne
authors.initials: S
authors.lastname: Saußele
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
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 / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000008:administration & dosage; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C581634:BCR-ABL1 fusion protein, human; D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D003561:Cytarabine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl