Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy
| Autor: | Hartmut Döhner, Eugen Tausch, Stephan Stilgenbauer, Giuliano Crispatzu, Anja Engelke, Joanna Schiller, Marion Klaumünzer, Peter Nürnberg, Michael Hallek, Carmen D. Herling, Cristiano Krings Rocha, Kirsten Fischer, Hans Christian Reinhardt, Sandra Kluth, Janine Altmüller, Karl Anton Kreuzer, Marco Herling, Holger Thiele, Jasmin Bahlo, Valentin Goede |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology medicine.medical_specialty Chronic lymphocytic leukemia Immunology Nonsense mutation medicine.disease_cause Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Chemoimmunotherapy Obinutuzumab Internal medicine Complex Karyotype Medicine Chlorambucil business.industry Cell Biology Hematology medicine.disease 030104 developmental biology chemistry 030220 oncology & carcinogenesis KRAS IGHV@ business medicine.drug |
| Zdroj: | Blood. 128:395-404 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2016-01-691550 |
| Popis: | Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity. Chromosomal aberrations as assessed by karyotyping were observed in 68.8% of 154 patients, 31.2% carried translocations, and 19.5% showed complex karyotypes. NGS revealed 198 missense/nonsense mutations and 76 small indels in 76.4% of patients. The most frequently mutated genes were NOTCH1 , SF3B1 , ATM , TP53 , BIRC3, POT1, XPO1, and KRAS . Sole chemotherapy, treatment with Clb-R, or genetic lesions in TP53 (9.9% of patients) and KRAS (6.2% of patients) were significantly associated with nonresponse to study therapy. In multivariate models, complex karyotypes and POT1 mutations (8.1% of patients) represented significant prognostic factors for an unfavorable survival, independently of IGHV mutation status, Binet stage, and serum β-2-microglobuline. Patients with the copresence of complex karyotypes and deletions/mutations involving TP53 demonstrated a particularly short survival. In summary, this is the first prospective, controlled study in CLL patients that shows a role of complex karyotype aberrations as an independent prognostic factor for survival after front-line therapy. Moreover, the study identifies mutations in KRAS and POT1 as novel determinants of outcome after chemoimmunotherapy using chlorambucil and anti-CD20 treatment. |
| Databáze: | OpenAIRE |
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