Page 96 - Haematologica3

Correspondence:
tobias.herold@med.uni-muenchen.de
Received: August 15, 2017. Accepted: December 7, 2017. Pre-published: December 14, 2017.
doi:10.3324/haematol.2017.178442
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/2/xxx
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Haematologica 2018 Volume 103(3):456-465
Ferrata Storti Foundation
Acute Myeloid Leukemia
A 29-gene and cytogenetic score for the prediction of resistance to induction treatment in acute myeloid leukemia
Tobias Herold,1,2,3 Vindi Jurinovic,4 Aarif M. N. Batcha,2,3,4
Stefanos A. Bamopoulos,1 Maja Rothenberg-Thurley,1 Bianka Ksienzyk,1 Luise Hartmann,1,2,3 Philipp A. Greif,1,2,3 Julia Phillippou-Massier,5
Stefan Krebs,5 Helmut Blum,5 Susanne Amler,3 Stephanie Schneider,1 Nikola Konstandin,1 Maria Cristina Sauerland,6 Dennis Görlich,6 Wolfgang E. Berdel,7 Bernhard J. Wörmann,8 Johanna Tischer,1
Marion Subklewe,1 Stefan K. Bohlander,9 Jan Braess,10
Wolfgang Hiddemann,1,2,3 Klaus H. Metzeler,1,2,3 Ulrich Mansmann2,3,4* and Karsten Spiekermann1,2,3*
1Department of Internal Medicine III, University of Munich, Germany; 2German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany; 3German Cancer Research Center (DKFZ), Heidelberg, Germany; 4Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Germany; 5Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, Germany; 6Institute of Biostatistics and Clinical Research, University of Munich, Germany; 7Department of Medicine, Hematology and Oncology, University of Münster, Germany; 8German Society of Hematology and Oncology, Berlin, Germany; 9Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand and 10Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany
*UM and KS contributed equally to this work.
ABSTRACT
Primary therapy resistance is a major problem in acute myeloid leukemia treatment. We set out to develop a powerful and robust predictor for therapy resistance for intensively treated adult patients. We used two large gene expression data sets (n=856) to develop a predictor of therapy resistance, which was validated in an independent cohort analyzed by RNA sequencing (n=250). In addition to gene expres- sion markers, standard clinical and laboratory variables as well as the mutation status of 68 genes were considered during construction of the model. The final predictor (PS29MRC) consisted of 29 gene expression markers and a cytogenetic risk classification. A continuous predictor is calculated as a weighted linear sum of the individual variables. In addi- tion, a cut off was defined to divide patients into a high-risk and a low- risk group for resistant disease. PS29MRC was highly significant in the validation set, both as a continuous score (OR=2.39, P=8.63·10-9, AUC=0.76) and as a dichotomous classifier (OR=8.03, P=4.29·10-9); accuracy was 77%. In multivariable models, only TP53 mutation, age and PS29MRC (continuous: OR=1.75, P=0.0011; dichotomous: OR=4.44, P=0.00021) were left as significant variables. PS29MRC dom- inated all models when compared with currently used predictors, and also predicted overall survival independently of established markers. When integrated into the European LeukemiaNet (ELN) 2017 genetic risk stratification, four groups (median survival of 8, 18, 41 months, and not reached) could be defined (P=4.01·10-10). PS29MRC will make it pos- sible to design trials which stratify induction treatment according to the probability of response, and refines the ELN 2017 classification.
Introduction
Approximately 20-30% of younger adult patients with acute myeloid leukemia (AML) and up to 50% of older adults are refractory to induction treatment.1 There are several definitions of treatment failure due to resistant disease (RD) or primary refractory AML.1-5 One of the earliest consensus definitions classified RD as the persistence of leukemic blasts in either the peripheral blood or the bone marrow in a patient alive at least seven days following treatment, excluding patients with
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