title: NOTCH1 mutations identify a chronic lymphocytic leukemia patient subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment.
abstract: Induction therapy with fludarabine followed by rituximab and consolidation plus maintenance with rituximab improved response duration (RD) and overall survival (OS) in our patients with chronic lymphocytic leukemia (CLL). The aim of our study was to investigate the clinical impact of NOTCH1 mutations in this setting of patients. The study included 123 progressive CLL patients homogeneously assigned to first-line induction treatment with fludarabine followed by rituximab. Fifty-nine patients either in complete remission (CR) minimal residual disease positive (MRD+) after induction (n = 39) or in partial remission (PR, n = 20) underwent consolidation/maintenance therapy with rituximab. Sixteen patients in CR MRD + or PR underwent observation only. The presence of NOTCH1 mutations was investigated by amplification refractory mutation system (ARMS) PCR and by Sanger sequencing. NOTCH1 mutations occurred in 20 out of 123 (16.3 %) cases. Consolidated patients showed longer OS than unconsolidated patients (p = 0.030). Both NOTCH1 mutated and CR MRD+ or PR NOTCH1 mutated patients showed significantly shorter OS after treatment (p = 0.00014 and p = 0.0021, respectively). Moreover, NOTCH1 wild-type consolidated cases experienced significantly longer RD and OS than NOTCH1 mutated consolidated or not consolidated cases (p = 0.00001 and p = 0.018, respectively). Finally, the independent prognostic impact of NOTCH1 mutations for OS was confirmed in multivariate analysis (p < 0.001). The presence of NOTCH1 mutations identifies a CLL subset with worse prognosis in the setting of a rituximab-based induction and consolidation treatment.
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, PN, Italy.
authors.forename: Michele Dal
authors.initials: MD
authors.lastname: Bo
authors.forename: Maria Ilaria
authors.initials: MI
authors.lastname: Del Principe
authors.forename: Federico
authors.initials: F
authors.lastname: Pozzo
authors.forename: Dario
authors.initials: D
authors.lastname: Ragusa
authors.forename: Pietro
authors.initials: P
authors.lastname: Bulian
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capelli
authors.forename: Francesca Maria
authors.initials: FM
authors.lastname: Rossi
authors.forename: Pasquale
authors.initials: P
authors.lastname: Niscola
authors.forename: Francesco
authors.initials: F
authors.lastname: Buccisano
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bomben
authors.forename: Antonella
authors.initials: A
authors.lastname: Zucchetto
authors.forename: Luca
authors.initials: L
authors.lastname: Maurillo
authors.forename: Paolo
authors.initials: P
authors.lastname: de Fabritiis
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D060830:Consolidation Chemotherapy; D005260:Female; D005803:Genes, Immunoglobulin; D016158:Genes, p53; D006801:Humans; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D018365:Neoplasm, Residual; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D051881:Receptor, Notch1 / Q000235:genetics*; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D000069283:Rituximab; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D014740:Vidarabine; C024352:fludarabine