Universität zu Köln

Herling, Carmen Diana, Klaumuenzer, Marion, Rocha, Cristiano Krings, Altmueller, Janine, Thiele, Holger, Bahlo, Jasmin, Kluth, Sandra, Crispatzu, Giuliano, Herling, Marco, Schiller, Joanna, Engelke, Anja, Tausch, Eugen, Doehner, Hartmut, Fischer, Kirsten, Goede, Valentin, Nuernberg, Peter, Reinhardt, Hans Christian, Stilgenbauer, Stephan, Hallek, Michael and Kreuzer, Karl-Anton (2016). Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy. Blood, 128 (3). S. 395 - 405. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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Abstract

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 beta-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Herling, Carmen Diana UNSPECIFIED UNSPECIFIED UNSPECIFIED Klaumuenzer, Marion UNSPECIFIED UNSPECIFIED UNSPECIFIED Rocha, Cristiano Krings UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahlo, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Kluth, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, Giuliano UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Schiller, Joanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Engelke, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Tausch, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Doehner, Hartmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Goede, Valentin UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreuzer, Karl-Anton UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-269696
DOI:	10.1182/blood-2016-01-691550
Journal or Publication Title:	Blood
Volume:	128
Number:	3
Page Range:	S. 395 - 405
Date:	2016
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	1528-0020
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CHRONIC LYMPHOCYTIC-LEUKEMIA; IDENTIFIES RECURRENT MUTATIONS; CHROMOSOMAL TRANSLOCATIONS; GENETIC-CHARACTERIZATION; METAPHASE CYTOGENETICS; INDEPENDENT PREDICTOR; GENOMIC ABERRATIONS; TELOMERE LENGTH; SPLICING FACTOR; POOR-PROGNOSIS Multiple languages Hematology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26969