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

TY - JOUR

T1 - 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

AU - Hehlmann, Rüdiger

AU - Müller, Martin C

AU - Lauseker, Michael

AU - Hanfstein, Benjamin

AU - Fabarius, Alice

AU - Schreiber, Annette

AU - Proetel, Ulrike

AU - Pletsch, Nadine

AU - Pfirrmann, Markus

AU - Haferlach, Claudia

AU - Schnittger, Susanne

AU - Einsele, Hermann

AU - Dengler, Jolanta

AU - Falge, Christiane

AU - Kanz, Lothar

AU - Neubauer, Andreas

AU - Kneba, Michael

AU - Stegelmann, Frank

AU - Pfreundschuh, Michael

AU - Waller, Cornelius F

AU - Spiekermann, Karsten

AU - Baerlocher, Gabriela M

AU - Ehninger, Gerhard

AU - Heim, Dominik

AU - Heimpel, Hermann

AU - Nerl, Christoph

AU - Krause, Stefan W

AU - Hossfeld, Dieter K

AU - Kolb, Hans-Jochem

AU - Hasford, Joerg

AU - Saußele, Susanne

AU - Hochhaus, Andreas

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Benzamides

KW - Cytarabine

KW - Disease Progression

KW - Disease-Free Survival

KW - Female

KW - Fusion Proteins, bcr-abl

KW - Humans

KW - Interferon-alpha

KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Piperazines

KW - Proportional Hazards Models

KW - Protein Kinase Inhibitors

KW - Pyrimidines

KW - Remission Induction

KW - Risk Factors

KW - Time Factors

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1200/JCO.2013.49.9020

DO - 10.1200/JCO.2013.49.9020

M3 - SCORING: Journal article

C2 - 24297946

VL - 32

SP - 415

EP - 423

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 5

ER -