TY  - JOUR
A1  - Saussele, Susanne
A1  - Hehlmann, Ruediger
A1  - Fabarius, Alice
A1  - Jeromin, Sabine
A1  - Proetel, Ulrike
A1  - Rinaldetti, Sebastien
A1  - Kohlbrenner, Katharina
A1  - Einsele, Hermann
A1  - Falge, Christine
A1  - Kanz, Lothar
A1  - Neubauer, Andreas
A1  - Kneba, Michael
A1  - Stegelmann, Frank
A1  - Pfreundschuh, Michael
A1  - Waller, Cornelius F.
A1  - Oppliger Leibundgut, Elisabeth
A1  - Heim, Dominik
A1  - Krause, Stefan W.
A1  - Hofmann, Wolf-Karsten
A1  - Hasford, Joerg
A1  - Pfirrmann, Markus
A1  - Müller, Martin C.
A1  - Hochhaus, Andreas
A1  - Lauseker, Michael
T1  - Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV
JF  - Leukemia
N2  - Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.
KW  - Chronic myeloid leukaemia
KW  - Molecularly targeted therapy
KW  - Risk factors
KW  - Risk factors
KW  - Translational research
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227528
VL  - 32
IS  - 5
ER  - 
TY  - JOUR
A1  - Rinaldetti, Sébastien
A1  - Pfirrmann, Markus
A1  - Manz, Kirsi
A1  - Guilhot, Joelle
A1  - Dietz, Christian
A1  - Panagiotidis, Panayiotidis
A1  - Spiess, Birgit
A1  - Seifarth, Wolfgang
A1  - Fabarius, Alice
A1  - Müller, Martin
A1  - Pagoni, Maria
A1  - Dimou, Maria
A1  - Dengler, Jolanta
A1  - Waller, Cornelius F.
A1  - Brümmendorf, Tim H.
A1  - Herbst, Regina
A1  - Burchert, Andreas
A1  - Janßen, Carsten
A1  - Goebeler, Maria Elisabeth
A1  - Jost, Philipp J.
A1  - Hanzel, Stefan
A1  - Schafhausen, Philippe
A1  - Prange-Krex, Gabriele
A1  - Illmer, Thomas
A1  - Janzen, Viktor
A1  - Klausmann, Martine
A1  - Eckert, Robert
A1  - Büschel, Gerd
A1  - Kiani, Alexander
A1  - Hofmann, Wolf-Karsten
A1  - Mahon, François-Xavier
A1  - Saussele, Susanne
T1  - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial
JF  - Clinical Lymphoma, Myeloma & Leukemia
N2  - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.
KW  - ABCG2
KW  - Biomarker
KW  - CML
KW  - Imatinib
KW  - Prediction
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281
VL  - 18
IS  - 4
ER  -