Copyright, 1999, American Society of Hematology


P. Staib, T. Schinkothe, R. Henrichs, T. Siebert, S. Wiedenmann, C. Schoch, D. Voliotis, P.A. Horn, H. Tesch, B. Lathan, V. Diehl. Clinic I for Internal Medicine, University of Cologne, Germany; Clinic III for Internal Medicine Grosshadern, University of Munich, Germany.

In-vitro drug sensitivity tests like the differential staining cytotoxicity (DISC) assay were shown to correlate well with response rates and also survival in patients (pts) with various neoplastic diseases. We prospectively investigated the prognostic relevance of the DISC assay in adult pts with AML by using the chemosensitivity index Ci, a newer evaluation system we described before. Patients and Methods Pts with de-novo AML received TAD-HAM and pts. with relapsed or secondary AML Ida-FLAG for induction therapy. DISC assay was performed as described previously (Weisenthal 1983) using minor modifications. All drugs used for treatment were tested at 5 concentrations in primary cell cultures in duplicate or triplicate. The chemosensitivity index Ci was calculated according to dose-response curves for each clinically used drug and the area under the curve (AUC) as an exact measure for the in-vitro dose-response relation. The cut off point between resistance and sensitivity was adjusted at 0,5 for each drug by the AUC data of a subgroup of clinically resistant patients Ci 0,5 predicts resistance, C i >0,5 sensitivity to the particular drug. Results 122 pts were evaluable; 96 received TAD-HAM and 26 Ida-FLAG for induction therapy. 83 pts (68%) achieved CR and 23 (19%) reduction of BM blasts <10%, in both groups the maximum Ci (Ci-max) was >0,5 for at least one drug clinically used (TP=true positive correlation). 12 pts (10%) were nonresponders and identified with Ci-max 0,5 of all drugs given for therapy (TN=true negative). 3 pts (3%) with Ci-max >0,5 did not reach CR (FP=false positive) (c2 p<0,001). Overall predictive accuracy was 97%. Pts with C i-max >0,5 lived significantly longer with 26 months (median) than pts with Ci-max 0,5 who lived 2 months (logrank, p<0,0001). Karyotypes were available in 95 pts as follows 30 unfavourable, 49 normal, 3 intermediate and 13 favourable. In a cox regression multivariate analysis the chemosensitivity index Ci was identified as the strongest independent prognostic factor for overall survival (p<0,0001) compared to the karyotype and age />60 years (p<0,001 for both). Conclusions Our data suggest that the DISC assay evaluated by the chemosensitivity index Ci may provide a strong independent prognostic factor in AML. Cytogenetics, although one of the strongest prognostic parameter in AML, may still not precisely predict individual prognosis. Further studies are needed to proof the Ci as a possible independant prognostic factor in AML, which may serve for risk-adapted therapy strategies.

Poster Session Molecular Pharmacology of Drug Resistance I (945 AM-730 PM) Presentation Date Saturday, December 4, 1999, Time 945AM, Room Hall B, Poster Board Number 269