Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy

Item Type:	Article
Title:	Complex karyotypes and KRAS and POT1 mutations impact outcome in CLL after chlorambucil-based chemotherapy or chemoimmunotherapy
Creators Name:	Herling, C.D. and Klaumünzer, M. and Rocha, C.K. and Altmüller, J. and Thiele, H. and Bahlo, J. and Kluth, S. and Crispatzu, G. and Herling, M. and Schiller, J. and Engelke, A. and Tausch, E. and Döhner, H. and Fischer, K. and Goede, V. and Nürnberg, P. and Reinhardt, H.C. and Stilgenbauer, S. and Hallek, M. and Kreuzer, K.A.
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 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.
Keywords:	Abnormal Karyotype, B-Cell Chronic Lymphocytic Leukemia, Chlorambucil, Proto-Oncogene Proteins p21(ras), Rituximab, Shelterin Complex, Telomere-Binding Proteins
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	128
Number:	3
Page Range:	395-404
Date:	21 July 2016
Official Publication:	https://doi.org/10.1182/blood-2016-01-691550
PubMed:	View item in PubMed

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