Journal
BLOOD
Volume 128, Issue 3, Pages 395-404Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2016-01-691550
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Funding
- Volkswagenstiftung (Lichtenberg Program)
- Deutsche Forschungsgemeinschaft [KFO-286]
- Deutsche Jose Carreras Leukamie Stiftung [R12/26, R13/33]
- Helmholtz-Gemeinschaft (Preclinical Comprehensive Cancer Center)
- Else Kroner-Fresenius Stiftung grant [EKFS-2014-A06]
- Deutsche Krebshilfe [111724, 111348]
- local Cologne Excellence Cluster on Cellular Stress Response in Aging Associated Diseases grant
- F. Hoffmann La Roche
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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.
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