Fludarabine Treated CLL Patients Showed an Increased Chemoresistance Ex-Vivo.

Fludarabine is the most successful drug in patients with relapsed, progradient or refractory chronic lymphocytic leukemia (CLL). But also the use of fludarabine in primary therapy as an alternative to chlorambucil is in trial. Fludarabine induces higher response rates, but showed no improvement in overall survival. The reason for this clinical observation is unclear. In the present study we wanted to answer the question, if the induction of secondary resistance might be the cause for this contradiction.

METHODS. Peripheral blood samples from 42 patients with B-CLL were tested in the in-vitro chemosensitivity-test DiSC-assay with 11 drugs. 10 patients had received no therapy before the time of carrying out the In vitro test. 23 patients were pre-treated with prednisone, 8 patient with fludarabine and 5 patients with vincristine. Most of the patients received more then one drug before testing. The chemosensitivity were determined using the LC90.

RESULTS. The patients were divided into those who were pre-treated vs. not pre-treated with the fludarabine, prednisone or vincristine. The influences of pre-treatment to the sensitivity were analysed using the Mann-Whitney-U test for two independent groups. With fludarabine pre-treated patients had an significantly increased chemoresistance against fludarabine (2.4-fold; p=.004). The increase was also significant for bendamustin (4.4-fold), 2-CdA (3.4-fold), Gemcitabine (2.7-fold) and daunorubicin (1.5-fold). There was no significant influence observed onto the other drugs. Pre-treatment with vincristine or prednisone had no impact onto the chemosensitivity of any tested drug.

INTERPRETATION AND CONCLUSIONS. The results of this study demonstrate the capability of fludarabine to increase the chemoresistance against various drugs in CLL. The use of fludarabine in primary therapy should be discussable. The fact that fludarabine induces higher response rates, without an improvement in overall survival, might be understandable if the fludarabine treatment induces a negative long-term effect. The widely increase of the chemoresistance is such a negative long-term effect. Based on the presented data, we postulate that fludarabine induces a so called secondary resistance by selecting leukemic cells with a lower chemosensitivity under treatment.