Hairy cell leukemias with unmutated IGHV genes define the minor subset refractory to single-agent cladribine and with more aggressive behavior
Open Access
- 19 November 2009
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 114 (21), 4696-4702
- https://doi.org/10.1182/blood-2009-03-212449
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.This publication has 44 references indexed in Scilit:
- Long‐term follow‐up of 233 patients with hairy cell leukaemia, treated initially with pentostatin or cladribine, at a median of 16 years from diagnosisBritish Journal of Haematology, 2009
- Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelinesBlood, 2008
- Selective influences in the expressed immunoglobulin heavy and light chain gene repertoire in hairy cell leukemiaHaematologica, 2008
- High density genome‐wide DNA profiling reveals a remarkably stable profile in hairy cell leukaemiaBritish Journal of Haematology, 2008
- The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemiaCancer, 2007
- Impact of mutant p53 functional properties onTP53mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 databaseHuman Mutation, 2007
- Complete molecular remission induced by concomitant Cladribine – Rituximab treatment in a case of multi-resistant Hairy Cell LeukemiaLeukemia & Lymphoma, 2007
- Eradication of minimal residual disease in hairy cell leukemiaBlood, 2006
- Hairy cell leukemia: at the crossroad of somatic mutation and isotype switchBlood, 2004