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~ T H E EFFICACY AND TOLERABILITY OF ICL670, A ONCE-DAILY ORAL IRON CHELATOR, IN PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS) AND IRON OVERLOAD

N. Gattermann 1 *, M. Cazzola 2, R Greenberg 3, L Maertens 4, D. Soulieres 5, C. Rose 6, C. Ressayre-Djaffer 7, D. Albert], B. Rabault 7. 1Heinrich-Heine-University, Dusseldorf Germany; 2Universita Pavia Medical School & IRCCS Policlinico S. Matteo, Pavia, Italy; 3Stanford Hospital, Stanford, CA, USA; 4University Ho~Tital Gasthuisberg, Leuven, Belgium; 5Centre Ho~Titalier de l'Universitd de Montreal, Montreal, Canada; 6Centre Hospitalier Saint Vincent, Lille, France; 7Novartis Pharma AG, Basel, Switzerland *E-maih gattermann@med.uni- duesseldor f.de

Iron overload is a serious consequence of chronic blood transfusion therapy for anemia. ICL670 (deferasirox) is an investigational, once daily, oral iron chelator with high iron binding potency and selectivity. An open-label multicenter Phase II study has evaluated the efficacy and tolerability of ICL670 over 1 year in patients with transfusion-dependent anemia, including MDS.

Forty-seven patients (mean age 65.1 years; range 20.0 81.0) with MDS were treated with ICL670 5, 10, 20 or 30mg/kg depending on baseline liver iron content (LIC). ICL670 produced an overall dose-dependent reduction in LIC of 5 .7mgFe/gdw (SD ±6.3) and also had a dose- dependent effect on serum ferritin (overall reduction of 267.6±2053.1 gg/1). The median number of transfusions per patient was 14.0 (25 75% percentiles; 6 26). The median amount of blood given was 0.26mlRBC/kg/day (25 75% percentiles; 0.16 0.34). Four patients died due to disease-related causes; two patients discontinued for drug-related adverse events (AEs) (mild vomiting, mild increase in creatinine). AEs were reported by 45 patients and were generally mild or moderate. The most frequent treatment-related AEs were mild, transient gastrointestinal disturbances. There were no cases of drug- induced neutropenia or arthralgia. ICL670 appears to be a convenient, effective and well-tolerated oral chelator for the treatment of iron overload in MDS patients.

[ • EXISULIND SELECTIVELY INDUCES APOPTOSIS VIA c-jun KINASE ACTIVATION IN sAML/MDS

A. Czibere 1, W.C. Prall 1, L.E Zerbini 1, E Grall 1, E.C. Craigie ~, S.D. Ulrich ~, A.A.N. Giagounidis ~, R. Haas ~, T.A. Libermann 1, M. Aivado 1 *. 1Genomics Center of the Beth Israel Deaconess Medical Cente~ Harvard Medical School, Boston, MA, USA; 2Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Dusseldorf Germany *E-maih maivado@bidmc.harvard.edu

Treatment of patients suffering from myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia after MDS (sAML/MDS) is often unsuccessful. Pro- apoptosis with arsenic trioxide has recently been proposed as a novel therapeutic approach. Exisulind is a well tolerated, anti-inflammatory, oral drug with potentially pro- apoptotic effects. Therefore, we investigated its influence on proliferation, differentiation, cell cycle and apoptosis in two sAML/MDS cell lines, one de-novo AML cell line and healthy CD34+ bone marrow cells. Treatment of sAML/MDS cells with Exisulind clearly inhibited colony formation in the CFU-assays. Interestingly, Exisulind did not alter the percentages of sAML/MDS cells in G1-, G2-, M- or S-phase, but reduced proliferation and induced apoptosis in this cell type. Exisulind had no effect on de-novo AML or normal CD34+ cells. We detected increased c-jun NH2- terminal kinase (JNK) activity in sAML/MDS cells treated with Exisulind. Adding a JNK-inhibitor to Exisulind-treated sAML/MDS cells almost abrogated apoptosis, thus proving that Exisulind-mediated apoptosis in sAML/MDS cells is dependent on JNK activation.

We conclude that JNK is one mediator of apoptosis in sAML/MDS cells treated with Exisulind. Moreover, our data strongly suggests to explore the potential use of Exisulind as a novel, pro-apoptotic therapy for patients with MDS and sAML/MDS.