title: Switching to nilotinib versus imatinib dose escalation in patients with chronic myeloid leukaemia in chronic phase with suboptimal response to imatinib (LASOR): a randomised, open-label trial.
abstract: BACKGROUND
  Optimal management of patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response remains undetermined. This study aimed to investigate the safety and efficacy of switching to nilotinib vs imatinib dose escalation for patients with suboptimal cytogenetic response on imatinib.
  
  
  METHODS
  We did a phase 3, open-label, randomised trial in patients with chronic myeloid leukaemia in chronic phase with suboptimal cytogenetic response to imatinib according to the 2009 European LeukemiaNet criteria, in Latin America, Europe, and Asia (59 hospitals and care centres in 12 countries). Eligible patients were aged 18 years or older with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase and Eastern Cooperative Oncology Group performance status of 0-2. Before enrolment, all patients had received 3-18 months of imatinib 400 mg once daily and had a suboptimal cytogenetic response according to 2009 ELN recommendations, established through bone marrow cytogenetics. By use of an interactive response technology using fixed blocks, we randomly assigned patients (1:1) to switch to nilotinib 400 mg twice per day or an escalation of imatinib dose to 600 mg once per day (block size of 4). Investigators and participants were not blinded to study treatment. Crossover was allowed for loss of response or intolerance at any time, or for patients with no complete cytogenetic response at 6 months. The primary endpoint was complete cytogenetic response at 6 months in the intention-to-treat population. Efficacy endpoints were based on the intention-to-treat population, with all patients assessed according to the treatment group to which they were randomised (regardless of crossover); the effect of crossover was assessed in post-hoc analyses, in which responses achieved after crossover were excluded. We present the final results at 24 months' follow-up. This study is registered with ClinicalTrials.gov (NCT00802841).
  
  
  RESULTS
  Between July 7, 2009, and Aug 29, 2012, we enrolled 191 patients. 96 patients were randomly assigned to nilotinib and 95 patients were randomly assigned to imatinib. Complete cytogenetic response at 6 months was achieved by 48 of 96 patients in the nilotinib group (50%, 95·18% CI 40-61) and 40 of 95 in the imatinib group (42%, 32-53%; difference 7·9% in favour of nilotinib; 95% CI -6·2 to 22·0, p=0·31). Excluding responses achieved after crossover, 48 (50%) of 96 patients in the nilotinib group and 34 (36%) of 95 patients in the imatinib group achieved complete cytogenic response at 6 months (nominal p=0·058). Grade 3-4 non-haematological adverse events occurring in more than one patient were headache (nilotinib group, n=2 [2%, including 1 after crossover to imatinib]; imatinib group, n=1 [1%]), blast cell crisis (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%]), and QT prolongation (nilotinib group, n=1 [1%]; imatinib group, n=1 [1%, after crossover to nilotinib]). Serious adverse events on assigned treatment were reported in 11 (11%) of 96 patients in the nilotinib group and nine (10%) of 93 patients in the imatinib group. Seven (7%) of 96 patients died in the nilotinib group and five (5%) of 93 patients died in the imatinib group; no deaths were treatment-related.
  
  
  CONCLUSIONS
  While longer-term analyses are needed to establish whether the clinical benefits observed with switching to nilotinib are associated with improved long-term survival outcomes, our results suggest that patients with suboptimal cytogenetic response are more likely to achieve improved cytogenetic and molecular responses with switching to nilotinib than with imatinib dose escalation, although the difference was not statistically significant when responses achieved after crossover were included.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jcortes@mdanderson.org.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: University of Campinas, Distrito de Barao Geraldo, Campinas, Brazil.
authors.forename: Carmino Antonio
authors.initials: CA
authors.lastname: De Souza
authors.affiliation: Hospital de Especialidades CMN La Raza, Instituto Mexicano del Seguro Social, Seris y Zaachila s/n, Colonia La Raza, Mexico, DF, Mexico.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ayala
authors.affiliation: Banco Municipal de Sangre, Dpt. Clinicas Hematologicas, Hemato-Oncologia, Esq Pirineos, Caracas, DC, Venezuela.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Lopez
authors.affiliation: Hospital Britanico, Buenos Aires, Argentina.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bullorsky
authors.affiliation: The Gujarat Cancer and Research Institute, Ahmedabad, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Shah
authors.affiliation: Peking University People's Hospital, Peking University Institute of Hematology, Beijing, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Kidwai Memorial Institute of Oncology, Bangalore, India; HCG Curie Centre of Oncology, Bangalore, India.
authors.forename: K Govind
authors.initials: KG
authors.lastname: Babu
authors.affiliation: Russian Research Institute of Hematology and Transfusiology, St Petersburg, Russia.
authors.forename: Kudrat
authors.initials: K
authors.lastname: Abdulkadyrov
authors.affiliation: Universidade Federal de São Paulo, Hospital Santa Marcelina, São Paulo, Brazil.
authors.forename: José Salvador Rodrigues
authors.initials: JSR
authors.lastname: de Oliveira
authors.affiliation: Shanghai Ruijin Hospital, Shanghai, China.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Shen
authors.affiliation: Department of Haematology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Sacha
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Israel
authors.initials: I
authors.lastname: Bendit
authors.affiliation: Guangzhou KingMed Center for Clinical Laboratory Co, Ltd, Guangzhou, Guangdong, China.
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Owugah
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Szczudlo
authors.affiliation: Novartis Healthcare Pvt Ltd, Raheja Mind Space, Hitech City Madhapur/Hyderabad, Rangareddy, India.
authors.forename: Sadhvi
authors.initials: S
authors.lastname: Khanna
authors.affiliation: Novartis Pharma SAS, Oncology Global Development & Global Medical Affairs, France.
authors.forename: Rafik
authors.initials: R
authors.lastname: Fellague-Chebra
authors.affiliation: Charité - University of Medicine Berlin, Campus Virchow-Klinikum, Medizinische Klinik mS, Hämatologie und Onkologie, Berlin, Germany.
authors.forename: Philipp D
authors.initials: PD
authors.lastname: le Coutre
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D024221:Antineoplastic Protocols / Q000592:standards; D001208:Asia; D054316:Biomarkers, Pharmacological / Q000737:chemistry; D001853:Bone Marrow / Q000737:chemistry; D057186:Comparative Effectiveness Research; D020732:Cytogenetic Analysis / Q000379:methods; D018450:Disease Progression; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology*; D005060:Europe; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D005500:Follow-Up Studies; D006261:Headache / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use*; D007843:Latin America; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008659:Metabolic Diseases / Q000139:chemically induced; D008875:Middle Aged; D010677:Philadelphia Chromosome / Q000187:drug effects*; D011743:Pyrimidines / Q000009:adverse effects* / Q000627:therapeutic use*; D011897:Random Allocation; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib