title: Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior.
abstract: Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.
authors: Ematologia e Trapianti, Università di Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy. forconif@unisi.it
authors: Francesco
authors: F
authors: Forconi
authors: Elisa
authors: E
authors: Sozzi
authors: Emanuele
authors: E
authors: Cencini
authors: Francesco
authors: F
authors: Zaja
authors: Tamara
authors: T
authors: Intermesoli
authors: Caterina
authors: C
authors: Stelitano
authors: Luigi
authors: L
authors: Rigacci
authors: Filippo
authors: F
authors: Gherlinzoni
authors: Renato
authors: R
authors: Cantaffa
authors: Anna
authors: A
authors: Baraldi
authors: Andrea
authors: A
authors: Gallamini
authors: Alfonso
authors: A
authors: Zaccaria
authors: Alessandro
authors: A
authors: Pulsoni
authors: Marco
authors: M
authors: Gobbi
authors: Maristella
authors: M
authors: Tassi
authors: Donatella
authors: D
authors: Raspadori
authors: Lorenzo
authors: L
authors: Leoncini
authors: Andrea
authors: A
authors: Rinaldi
authors: Elena
authors: E
authors: Sabattini
authors: Francesco
authors: F
authors: Bertoni
authors: Stefano A
authors: SA
authors: Pileri
authors: Francesco
authors: F
authors: Lauria
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017338:Cladribine / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region; D007943:Leukemia, Hairy Cell / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017338:Cladribine