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Acute Myeloid Leukemia
Genetics of acute myeloid leukemia in
the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older
Ferrata Storti Foundation
Victoria V. Prassek,1 Maja Rothenberg-Thurley,1 Maria C. Sauerland,2
Tobias Herold,1,3,4 Hanna Janke,1 Bianka Ksienzyk,1 Nikola P. Konstandin,1 Dennis Goerlich,2 Utz Krug,5 Andreas Faldum,2 Wolfgang E. Berdel,2 Bernhard Wörmann,6 Jan Braess,7 Stephanie Schneider,1 Marion Subklewe,1 Stefan K. Bohlander,8 Wolfgang Hiddemann,1,3,4 Karsten Spiekermann1,3,4 and Klaus H. Metzeler1,3,4
Haematologica 2018 Volume 103(11):1853-1861
1Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Germany; 2Institute of Biostatistics and Clinical Research, University of Münster, Germany; 3German Cancer Consortium (DKTK), Partner Site Munich, Germany; 4German Cancer Research Center (DKFZ), Heidelberg, Germany; 5Hospital Leverkusen, Germany; 6Charité – University Hospital Berlin, Germany; 7Department of Oncology and Hematology, Hospital Barmherzige Brüder, Regensburg, Germany and 8Department of Molecular Medicine and Pathology, University of Auckland, New Zealand
ABSTRACT
Acute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65-70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classification sys- tems and identify additional factors associated with outcomes in inten- sively treated patients aged ≥75 years. In 151 patients who received induction chemotherapy in the AMLCG-1999 trial, we investigated recurrently mutated genes using a targeted sequencing assay covering 64 genes. The median number of mutated genes per patient was four. The most commonly mutated genes were TET2 (42%), DNMT3A (35%), NPM1 (32%), SRSF2 (25%) and ASXL1 (21%). The complete remission rate was 44% and the 3-year survival was 21% for the entire cohort. While adverse-risk cytogenetics (MRC classification) were associated with shorter overall survival (P=0.001), NPM1 and FLT3-ITD mutations (present in 18%) did not have a significant impact on overall survival. Notably, none of the 13 IDH1-mutated patients (9%) reached complete remission. Consequently, the overall survival of this subgroup was sig- nificantly shorter than that of IDH1-wildtype patients (P<0.001). In sum- mary, even among very old, intensively treated, acute myeloid leukemia patients, adverse-risk cytogenetics predict inferior survival. The spec- trum and relevance of driver gene mutations in elderly patients differs from that in younger patients. Our data implicate IDH1 mutations as a novel marker for chemorefractory disease and inferior prognosis. (AMLCG-1999 trial: clinicaltrials.gov identifier, NCT00266136)
Introduction
The incidence of acute myeloid leukemia (AML) is highest among the elderly, with the median age at diagnosis being around 70 years.1 The prognosis of older AML patients is generally considered poor. In this age group, comorbidities, poor performance status and a reluctance of physicians and patients to use treatment regimens perceived as toxic often lead to the decision to avoid induction chemotherapy in favor of less intensive therapies.2-6 On the other hand, data from patient registries and randomized trials suggest that intensive induction therapy
Correspondence:
klaus.metzeler@med.uni-muenchen.de
Received: February 22, 2018. Accepted: June 11, 2018. Pre-published: June 14, 2018.
doi:10.3324/haematol.2018.191536
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1853
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haematologica | 2018; 103(11)
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