title: Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay.
abstract: The cytotoxic antimetabolite fludarabine is a widely used active agent in chronic lymphocytic leukaemia (CLL). However, cost and occasional adverse side-effects necessitate careful use. Identifying before treatment patients not likely to benefit from fludarabine could advance disease management both clinically and financially. We used the DiSC (differential staining cytotoxicity) assay, an ex vivo apoptotic drug response test, to identify the sensitivity or resistance to fludarabine of lymphocytes from B-cell CLL patients and compared the results with subsequent patient treatment, response and survival. Patients were grouped thus: those receiving fludarabine within 1 year of assay (+/- other cytotoxic drugs), and those receiving other chemotherapy (excluding fludarabine) within 1 year of assay. Fludarabine-test-resistance was found in 12/100 (12%) of untreated patients and 45/143 (31%) of previously treated patients (17/32 (53%) of patients previously treated with fludarabine). Treating fludarabine-test-resistant patients with fludarabine resulted in poor response compared with fludarabine-test-sensitive patients (7% v 69%) and short survival (median 7.9 v 41.7 months; relative risk (RR) = 14.8; P < 0.0001). 81% of fludarabine-test-resistant patients were test sensitive to other regimens. If treated with chemotherapy other than fludarabine, test-resistant patients responded better and survived substantially longer than those treated with fludarabine (RR = 2.9; P = 0.001). Not all CLL patients should receive fludarabine. Fludarabine-test-resistance by DiSC assay is a powerful independent prognostic factor. Pretreatment DiSC assay results could enable the toxic, clinical and financial costs of fludarabine treatment to be avoided in fludarabine-test-resistant patients. Disease management, response, survival and use of financial resources might be significantly improved if therapy choice in CLL patients was guided by DiSC assay.
authors.affiliation: Bath Cancer Research Unit, School of Postgraduate Medicine, University of Bath, Royal United Hospital, Bath. a.g.bosanquet@bath.ac.uk
authors.forename: A G
authors.initials: AG
authors.lastname: Bosanquet
authors.forename: S A
authors.initials: SA
authors.lastname: Johnson
authors.forename: S M
authors.initials: SM
authors.lastname: Richards
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002423:Cause of Death; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D015996:Survival Rate; D013812:Therapeutics; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014740:Vidarabine; C024352:fludarabine