title: Nilotinib and peginterferon alfa-2a for newly diagnosed chronic-phase chronic myeloid leukaemia (NiloPeg): a multicentre, non-randomised, open-label phase 2 study.
abstract: BACKGROUND
  Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4·5 log (MR(4·5)), allowing the prospect of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR(4·5), avoid late side-effects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML).
  
  
  METHODS
  In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR(4·5) at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modified intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28.
  
  
  RESULTS
  Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR(4·5). Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the first 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints.
  
  
  CONCLUSIONS
  The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic effects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial.
  
  
  BACKGROUND
  Novartis Pharma.
authors.affiliation: Haematology Department, Centre Hospitalier Lyon Sud, Pierre Bénite, France; INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France. Electronic address: franck-emmanuel.nicolini@chu-lyon.fr.
authors.forename: Franck E
authors.initials: FE
authors.lastname: Nicolini
authors.affiliation: Haematology Department, Institut Bergonié, Bordeaux, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Etienne
authors.affiliation: Haematology Department, Hôtel Dieu, Nantes, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Viviane
authors.initials: V
authors.lastname: Dubruille
authors.affiliation: Haematology and Cellular Therapy Department, University Hospital of Poitiers, Poitiers, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Roy
authors.affiliation: Haematology Department, Institut Universitaire du Cancer Toulouse Oncopôle, Toulouse, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Haematology Department, Hôpital de l'Archet, Nice, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Legros
authors.affiliation: Laboratory for Haematology, Hôpital Henri Mondor, Créteil, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
authors.affiliation: Haematology Department, Hôpital Huriez, Lille, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Coiteux
authors.affiliation: Haematology Department, Hôpital de Brabois, Vandoeuvre-lès-Nancy, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Guerci-Bresler
authors.affiliation: Haematology Department, Centre Henri Becquerel, Rouen, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lenain
authors.affiliation: Haematology Department, Centre Hospitalier d'Annecy Genevois, Metz-Tessy, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Cony-Makhoul
authors.affiliation: Haematology Department, University Hospital of Angers, Angers, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Gardembas
authors.affiliation: Haematology Department, CHU d'Estaing, Clermont-Ferrand, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Hermet
authors.affiliation: Haematology and Oncology Department, Hôpital A Mignot, Le Chesnay, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.affiliation: Haematology Department, Hôpital Civil, Strasbourg, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Shanti
authors.initials: S
authors.lastname: Amé
authors.affiliation: Laboratory of Pharmacology, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gagnieu
authors.affiliation: Central Pharmacy, Hôpital Edouard Herriot, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Pivot
authors.affiliation: Laboratory of Molecular Biology, Centre Hospitalier Lyon Sud, Pierre Bénite, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hayette
authors.affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Maguer-Satta
authors.affiliation: Haematology Department, Centre Hospitalier Lyon Sud, Pierre Bénite, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Etienne
authors.affiliation: Laboratory of Haematology, Hôpital Haut Lévêque, avenue de Magellan, 33604 Pessac, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Dulucq
authors.affiliation: Adult Haematology Department, Hôpital Saint Louis, AP-HP, Paris, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
authors.affiliation: Laboratory of Haematology, Hôpital Haut Lévêque, avenue de Magellan, 33604 Pessac, France; French group of CML (Fi-LMC group), Laboratory of Haematology, Hôpital Haut Lévêque, Pessac, France.
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mahon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D011743:Pyrimidines; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib; C100416:peginterferon alfa-2a