Imatinib in Combination With Cytarabine for the Treatment of Philadelphia-Positive Chronic Myelogenous Leukemia Chronic-Phase Patients: Rationale and Design of Phase I/II Trials Franc ¸ois Guilhot, Martine Gardembas, Philippe Rousselot, Michel Tulliez, Magda Vigier, Agne `s Buzyn, Franc ¸oise Rigal-Huguet, Laurence Legros, Mauricette Michallet, Christian Berthou, Albert Najman, Frederic Maloisel, Franc ¸ois-Xavier Mahon, Thierry Facon, Patrice Berthaud, and Joe ¨lle Guilhot, for the CML French Group Imatinib (Gleevec) (formerly STI571) has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic BCR-ABL fusion protein of chronic myelogenous leukemia (CML) cells. In recent phase I and II studies testing this new compound in patients who had failed to respond to interferon (IFN), hematological and cytogenetic responses were reported in most of those with chronic-phase CML. However, in some patients resistance has been associated with a single amino acid substitution in a threonine residue of the Abl kinase domain. In vitro studies examining the effects of imatinib plus cytarabine (Ara-C) using CML cell lines and colony-forming assays of CML patient samples have shown synergistic antiproliferative effects of this combination. Thus several groups decided to investigate this new combination with the hypothesis that cell resistance would be less frequent. The CML French Group performed a phase II trial to determine the safety and tolerability of a combination of imatinib and Ara-C for previously untreated patients with chronic-phase CML. Treatment was administered on 28-day cycles for 12 months. Patients were treated continuously with imatinib orally at a dose of 400 mg daily. Ara-C was given on days 14 to 28 of each cycle at an initial dose of 20 mg/m 2 /d via subcutaneous injection, hydroxyurea (HU) being stopped at least 7 days before imatinib. Recently, the Dutch group decided to explore a combination of high-dose Ara-C with imatinib in patients in chronic-phase CML. Preliminary results are encouraging. However, a long follow-up is required before concluding that these strategies will overcome cell resistance. Semin Hematol 40(suppl 2):92-97. © 2003 Elsevier Inc. All rights reserved. I N CHRONIC myelogenous leukemia (CML), the Philadelphia chromosome (Ph) is a fusion gene that encodes BCR-ABL, a chimeric protein with aber- rant tyrosine kinase activity. For many years, inter- feron (IFN)-based regimens and allogeneic stem cell transplantation were offered to patients in chronic phase, resulting in a substantial survival improve- ment. It became apparent that survival was improved in those patients who achieved durable cytogenetic responses. 1 However, such responses were achieved in a minority of IFN-treated patients and allogeneic bone marrow transplant was restricted to a small fraction of patients with a human leukocyte antigen (HLA)-matched donor. Imatinib (Gleevec or Glivec, Novartis, Switzer- land) (formerly STI571) has been shown to selec- tively inhibit the tyrosine kinase domain of the onco- genic BCR-ABL fusion protein. 6 The activity of this inhibitor has been demonstrated both in vitro and in vivo using BCR-ABL– expressing cells or animal models. Thus this selective competitive inhibitor of the BCR-ABL protein-tyrosine kinase has been used in a phase I dose-escalation study. 9 Substantial and durable hematological responses were reported in most of the patients with chronic-phase CML. A more recent phase II study has been conducted in a large cohort of patients in chronic phase who failed to respond to previous IFN therapy. 22 They received 400 mg of imatinib each day. Among the 454 patients in whom the chronic phase was confirmed, 60% achieved a major cytogenetic response (MCR) and 41% a complete cytogenetic response CCR. The com- From the Department of Oncology-Hematology and Cell Therapy, CHU la Mile ´trie, Poitiers, France; and the Divisions of Hematology, University Hospitals of Angers, St Louis, Paris, Cre ´teil, Nantes, Necker, Toulouse, Nice, Lyon, Brest, St Antoine, Strasbourg, Bor- deaux, and Lille, France; and Novartis Pharma France. Supported in part by grants from the Programme Hospitalier de Recherche Clinique and Novartis Pharma, Rueil-Malmaison, France. Address correspondence to Franc ¸ois Guilhot, MD, Department of Oncology-Hematology and Cell Therapy, CHU La Mile ´trie, Rue de la Mile `trie, 86021 Poitiers Cedex, France. © 2003 Elsevier Inc. All rights reserved. 0037-1963/03/4002-2016$30.00/0 doi:10.1053/shem.2003.50048 Seminars in Hematology, Vol 40, No 2, Suppl 2 (April), 2003: pp 92-97 92