Leukemia Research 35 (2011) 80–86 Contents lists available at ScienceDirect Leukemia Research journal homepage: www.elsevier.com/locate/leukres Pegylated IFN-2a combined to imatinib mesylate 600 mg daily can induce complete cytogenetic and molecular responses in a subset of chronic phase CML patients refractory to IFN alone or to imatinib 600 mg daily alone Franck E. Nicolini a,l,* , Sandrine Hayette b,l , Laurence Legros c,d,l , Philippe Rousselot e,l , Frédéric Maloisel f,l , Michel Tulliez g,l , Agnès Guerci h,l , Aude Charbonnier i,l , Thomas Prébet i , Franc ¸ oise Rigal-Huguet j , Kaddour Chabane b , Jean-Pierre Magaud b , Carole Paillet k , Christine Pivot k , Mauricette Michallet a,l a Département d’hématologie clinique, hôpital Edouard Herriot, Lyon, France b Hospices Civils de Lyon, centre hospitalier Lyon sud Laboratory for Molecular Biology, and UMR5239 CNRS, Pierre Bénite, France c Département d’hématologie clinique, hôpital de l’Archet, Nice, France d UMR6543, Université de Nice Sophia-Antipolis, Institute of Developmental Biology and Cancer Research, Nice, France e Département d’hématologie clinique, hôpital André Mignot, Le Chesnay, France f Département d’oncologie et d’hématologie, clinique Sainte Anne, Strasbourg, France g Laboratoire d’hématologie, hôpital Henri Mondor, Créteil, France h Département d’hématologie clinique, hôpital de Brabois, Vandoeuvre les Nancy, France i Département d’hématologie clinique, Institut Paoli Calmettes, Marseille, France j Pharmacie, hôpital Edouard Herriot, Lyon, France k Service d’Hématologie, Hôpital Purpan, Toulouse, France l French intergroup for CML (Fi-LMC group), Poitiers, France article info Article history: Received 7 February 2010 Received in revised form 8 April 2010 Accepted 13 April 2010 Available online 3 June 2010 Keywords: CML Imatinib resistance Peg-Interferon Philadelphia chromosome BCR-ABL BCR-ABL mutations abstract This phase I/II study was designed to demonstrate the tolerance and the efficacy of a combination of pegy- lated interferon- 2a to Imatinib mesylate (IM) 600 mg daily in cytogenetically IM-resistant but in CHR chronic phase CML patients. The combination was generally well tolerated in the 15 evaluable patients. A significant reduction of the Ph1 + BM metaphases was observed in these poor prognosis patients, with 2 long-term CCyR including 2 MMR. After a median follow-up of 43 months, 93% of patients are alive. The addition of PegIFN2a to IM600 is feasible, and able to overcome resistance within this context. © 2010 Elsevier Ltd. All rights reserved. 1. Introduction The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the introduction in the clinical arena in 1998 of therapies targeting the oncoprotein Bcr-Abl, which is sufficient to induce the disease by itself at initial stages. In early chronic phase, the vast majority of patients respond optimally [1,2] to imatinib mesylate (IM) 400 mg daily, however, in late chronic phase a sub- * Corresponding author at: Département d’hématologie, Pavillon E, hôpital Edouard Herriot, 5 place d’Arsonval, 69437 Lyon Cedex 03, France. Tel.: +33 4 72 11 73 15; fax: +33 4 72 11 74 04. E-mail address: franck-emmanuel.nicolini@chu-lyon.fr (F.E. Nicolini). stantial fraction (10–20%) of patients do not respond well and may represent a reservoir for overt resistance at molecular, cytogenetic or hematologic levels [3,4]. Despite the lack of specific knowledge on the mechanisms for IM-resistance, there is some evidence that escalating IM daily dose up to 800 mg may overcome hematolog- ical or cytogenetic resistance to conventional doses of IM [5] in chronic phase patients, but responses are not durable. Interferon is able to induce long-term disease control in chronic phase patients alone or in combination with cytarabine [6], particularly if a com- plete cytogenetic remission is obtained (10–20% of patients) [7,8]. Recently, the introduction of polyethylene glycol (pegylated) forms of interferon- (IFN-) in the treatment of CML, PegIFN2a [9] and PegIFN2b [10,11] have improved the tolerability of native IFN- while maintaining [10] or improving [9] its efficacy. The 0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2010.04.010