Ex vivo assessment of drug response by differential staining cytotoxicity (DiSC) assay suggests a biological basis for equality of chemotherapy irrespective of age for patients with chronic lymphocytic leukaemia

Abstract

With a mean age at diagnosis for chronic lymphocytic leukaemia (CLL) of 65 years, development of optimal therapeutic regimens has been hampered by the advanced age of patients. In general, because of comorbidity older patients are not treated with the intent of achieving a complete response and so do not attain the quality of response of younger patients and do not survive as long. We have investigated whether or not ex vivo cellular sensitivity to cytotoxic drugs could be an underlying biological basis for this age differential in response and survival by comparing ex vivo drug response with age in untreated CLL patients. Cells from 365 untreated CLL patients aged 31.1-87.1 years (average 65.3 years) were tested for drug response by differential staining cytotoxicity (DiSC) assay with a panel of 10 drugs. An average of 280 results (range 196-361) obtained for each drug was compared with patient age. For chlorambucil, cyclophosphamide, prednisolone, vincristine, doxorubicin, epirubicin, fludarabine, cladribine and methylprednisolone, no relationship was found between ex vivo drug response and age (r Ͻ 0.12). For pentostatin, a possible but very weak relationship (r = 0.18; n = 210; P = 0.06) was found. We conclude that cellular sensitivity to cytotoxic drugs does not support the differential treatment of older and younger CLL patients. Leukemia (2000) 14, 712-715.

Mutation of p53 and consecutive selective drug resistance in B-CLL occurs as a consequence of prior DNA-damaging chemotherapy

“…All treatment methods induced apoptosis in a dose-dependent manner. As previously reported, individual patient drug sensitivity profiles showed a broad range of drug sensitivity patterns, 25 reflecting the patient heterogeneity seen in the clinic.…”

“…25 LC 90 doses, that is, the concentration of drug to produce a 90% reduction in cell survival compared with control cells, were determined by calculating the log dose at which the fitted survival probability was equal to 0. …”

Silencing of APAF‐1 in B‐CLL results in poor prognosis in the case of concomitant p53 mutation

“…For the in vitro chemosensitivity data, logistic curves were fitted to the cell survival data; the logit of survival probability was taken to be linear with respect to the logarithm of drug concentration. 27 LC 90 doses, i.e. the concentration of drug to produce a 90% reduction in cell survival compared with control cells, were determined by calculating the log-dose at which the fitted survival probability was equal to 0.1.…”

Bax expression correlates with cellular drug sensitivity to doxorubicin, cyclophosphamide and chlorambucil but not fludarabine, cladribine or corticosteroids in B cell chronic lymphocytic leukemia

“…22 LC 90 doses, ie the concentration of drug to produce a 90% reduction in cell survival compared with control cells, were determined by calculating the log dose at which the fitted survival probability was equal to 0.1. Drug sensitivity indices were calculated as a percent rank of the 39 specimens tested, the most resistant scoring 0% and the most sensitive 100%.…”