Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior

Forconi, Francesco, Sozzi, Elisa, Cencini, Emanuele, Zaja, Francesco, Intermesoli, Tamara, Stelitano, Caterina, Rigacci, Luigi, Gherlinzoni, Filippo, Cantaffa, Renato, Baraldi, Anna, Gallamini, Andrea, Zaccaria, Alfonso, Pulsoni, Alessandro, Gobbi, Marco, Tassi, Maristella, Raspadori, Donatella, Leoncini, Lorenzo, Rinaldi, Andrea, Sabattini, Elena, Bertoni, Francesco, Pileri, Stefano A. and Lauria, Francesco (2009) Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior. Blood, 114 (21), 4696-4702. (doi:10.1182/blood-2009-03-212449). (PMID:19667403)

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.

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Contributors

Author: Francesco Forconi

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