Bcr-Abl and Wilms Tumor Gene (WT1) Kinetics in Nilotinib (AMN107) Treated CML Patients.

Background: In normal hemopoesis WT1 expression is restricted to early progenitors and is rapidly down-regulated in maturing blood cells. WT1 transcript quantification therefore may be an adjunct diagnostic method in CML patients (pts) that remain Bcr-Abl positive under treatment. Especially, in advanced CML pts WT1 transcript kinetics may precede a change in Bcr-Abl kinetics and may therefore be helpful to indicate early response to treatment. Nilotinib is a potent, highly selective, second generation Bcr-Abl inhibitor which in vitro is 30-fold more potent than imatinib and is currently studied in imatinib resistant or intolerant pts.

Aim: The aim of this study was to compare kinetics of Bcr-Abl and WT1 transcripts in 33 CML pts with late chronic phase (CP) or advanced disease under treatment with nilotinib.

Methods: All pts were treated as part of an ongoing phaseI/II clinical trial with nilotinib at a standard dose of 400 mg BID. 20 pts were in chronic phase (CP), 4 in accelerated phase (AP) and 9 in blast crisis (BC). Among the CP pts 4/20 were enrolled because of toxicity to prior imatinib treatment. WT1 and Bcr-Abl kinetics were expressed in relation to Abl expression. Data points were taken at baseline and every 4 weeks thereafter. Quantitative PCR was carried out by Taqman-analysis.

Results: The median duration of nilotinib treatment was 8 months in CP pts, 4 in AP pts and 5.5 in BC pts. The follow up of all pts ranged between 3 and 13 months. All pts received imatinib prior to nilotinib and were Bcr-Abl positive at study entry. In CP samples WT1/Abl ratios (median:1.24x10⁻³) were 38 fold lower than Bcr-Abl/Abl (median:4.67x10⁻²) ratios at baseline (p≤0.014, t-test). However, in AP and BC pts no relevant difference of WT1/Abl and Bcr-Abl/Abl baseline levels were detectable. In BC patients a more rapid decline of WT1/Abl ratios compared to Bcr-Abl/Abl ratios was observed within the first four months of nilotinib therapy. In addition, in BC pts elevation of WT1 levels preceded hematologic relapses and was detectable earlier than elevation of Bcr-Abl/Abl ratios.

Conclusions:

1. In contrast to AP and BC pts in CP pts WT1/Abl ratios were significantly lower than Bcr-Abl/Abl ratios confirming the restriction of WT1 expression to early progenitors.

2. In BC pts under nilotinib therapy WT1/Abl ratios may be an early marker of response as compared to Bcr-Abl/Abl ratios.

3. A stable correlation of WT1/Abl and Bcr-Abl/Abl ratios was observed in AP pts under treatment.