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

Posted Oct 04 2009 11:12pm
Blood First Edition Paper, prepublished online August 10, 2009; DOI 10.1182/blood-2009-03-212449.

Hairy cell leukemia (HCL) is generally responsive to single-agent Cladribine and only a minority of patients are refractory and with poor prognosis. HCL generally express mutated (M) and, in a minority, unmutated (UM) immunoglobulin-heavy-chain-variable-region-genes (IGHV). In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival (EFS) after single-agent Cladribine. Of 58 HCL, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53/58 patients (91%), while treatment failures were observed in 5/58 (9%) patients. Failures associated significantly with UM-IGHV (5/5 failures vs 1/53 beneficial responses had UM-IGHV, p <.0001), leucocytosis (3/5 vs 3/53, p=.006), and bulky spleen (4/5 vs 4/53, p=.0008). The UM-HCL not benefiting from Cladribine characteristically had bulky spleen (4/5, 80%), leukocytosis (3/5, 60%) and TP53 defects (2/5, 40% vs 0/53 UM/M-HCL benefiting from Cladribine, p=.006), and progressed rapidly after first treatment (median EFS 7.5 months). Our data suggest that UM-HCL identify the minor subgroup failing Cladribine treatment and with more aggressive disease. High incidence of TP53 disfunction 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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