1. 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.
- Author
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Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saußele S, and Hochhaus A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, 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 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 adverse effects, Proportional Hazards Models, Protein Kinase Inhibitors adverse effects, Pyrimidines adverse effects, Remission Induction, Risk Factors, Time Factors, Treatment Outcome, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Benzamides administration & dosage, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Piperazines administration & dosage, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage
- Abstract
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.
- Published
- 2014
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