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

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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., Klaumünzer, M., Rocha, C.K., Altmüller, J., Thiele, H., Bahlo, J., Kluth, S., Crispatzu, G., Herling, M., Schiller, J., Engelke, A., Tausch, E., Döhner, H., Fischer, K., Goede, V., Nürnberg, P., Reinhardt, H.C., Stilgenbauer, S., 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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