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

J Clin Oncol. 2014 Feb 10;32(5):415-23. doi: 10.1200/JCO.2013.49.9020. Epub 2013 Dec 2.


Purpose: 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.

Patients and 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.

Conclusion: 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.

Trial registration: NCT00055874.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Cytarabine / administration & dosage
  • Disease Progression
  • Disease-Free Survival
  • Female
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imatinib Mesylate
  • Interferon-alpha / administration & dosage
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / mortality
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Piperazines / administration & dosage*
  • Piperazines / adverse effects
  • Proportional Hazards Models
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Remission Induction
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • BCR-ABL1 fusion protein, human
  • Benzamides
  • Interferon-alpha
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Cytarabine
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl

Associated data