title: Sequential azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia: a single-arm, phase 1/2 study.
abstract: BACKGROUND
  The standard of care for myelodysplastic syndromes is hypomethylating agents such as azacitidine. However, responses to azacitidine are generally temporary, and outcomes after hypomethylating agent failure are dismal. Therefore, the development of more effective treatments is crucial to improve outcomes in patients with myelodysplastic syndromes. We aimed to assess azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia.
  
  
  METHODS
  We did this single-arm phase 1/2 study at the University of Texas MD Anderson Cancer Center, TX, USA. Patients of any age were eligible for phase 1 and 2a if they had relapsed or refractory acute myeloid leukaemia or myelodysplastic syndrome with bone marrow blasts more than 10%. For phase 2b, eligible participants were previously untreated with myelodysplastic syndrome with an International Prognostic Scoring System (IPSS) score of intermediate-1 or higher with up to 30% blasts. All participants received 75 mg/m(2) azacitidine once a day for days 1-5 for each 28 day cycle. We gave patients oral lenalidomide for 5 or 10 days starting on day 6. We assessed seven lenalidomide doses in a 3 + 3 phase 1 design (n=28). The primary endpoint in phase 1 was the maximum tolerated dose, and the primary endpoint in phase 2 was overall survival. Outcome analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01038635.
  
  
  RESULTS
  Between Dec 30, 2009, and June, 17, 2013, we enrolled 88 patients (28 in phase 1 and 60 in phase 2). One patient unexpectedly died in the phase 1 study at the highest dose level, six more patients were recruited with no further serious adverse events. We recorded no dose-limiting toxic effects, and the maximum tolerated dose of lenalidomide in combination with azacitidine in patients with acute myeloid leukaemia and myelodysplastic syndrome was initially established at 50 mg per day for 10 days. In the first 20 patients in phase 2, we noted a high rate of myelosuppression and myelosuppression-related toxic effects; therefore, we amended the lenalidomide dose to 25 mg per day for 5 days. We also adjusted the inclusion criteria to include patients with less than 30% blasts to focus mainly on patients with myelodysplastic syndromes. Median overall survival was 75 weeks (IQR 25-not reached) for the 40 patients in phase 2b. The most common grade 3-4 adverse events overall were neutropenic fever (n=27) and pneumonia (n=18).
  
  
  CONCLUSIONS
  We have identified a safe and active sequential treatment combination of azacitidine and lenalidomide for patient with myelodysplastic syndrome and have preliminary evidence that this dose is also safe for patients with acute myeloid leukaemia.
  
  
  BACKGROUND
  MD Anderson Cancer Center and Celgene.
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Courtney D
authors.initials: CD
authors.lastname: DiNardo
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Naval
authors.initials: N
authors.lastname: Daver
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Tapan
authors.initials: T
authors.lastname: Kadia
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Pemmaraju
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Pierce
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Leukaemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ggarciam@mdanderson.org.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D001374:Azacitidine / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D016019:Survival Analysis; D013792:Thalidomide / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D013792:Thalidomide; D001374:Azacitidine