title: Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia.
abstract: Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m(2) days 1-3, cytarabine 667 mg/m(2)/day continuous infusion days 6-8, and mitoxantrone (FLAM) 40 mg/m(2) day 9] yields complete remission rates of nearly 70% in newly diagnosed poor-risk acute myeloid leukemia. Between May 2011-July 2013, 165 newly diagnosed acute myeloid leukemia patients (age 18-70 years) with intermediate/adverse-risk cytogenetics were randomized 2:1 to receive FLAM or 7+3 (cytarabine 100 mg/m(2)/day continuous infusion days 1-7 and daunorubicin 90 mg/m(2) days 1-3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m(2)/day continuous infusion days 1-5 and daunorubicin 45 mg/m(2) days 1-2), whereas patients on FLAM were not re-treated based on day 14 bone marrow findings. The primary objective was to compare complete remission rates between one cycle of FLAM and one cycle of 7+3. Secondary end points included safety, overall survival and event-free survival. FLAM led to higher complete remission rates than 7+3 alone (70% vs. 46%; P=0.003) without an increase in toxicity, and this improvement persisted after 7+3+/-5+2 (70% vs. 57%; P=0.08). There were no significant differences in overall survival and event-free survival in both arms but post-induction strategies were not standardized. These results substantiate the efficacy of FLAM induction in newly diagnosed AML. A phase III study is currently in development. This study is registered with clinicaltrials.gov identifier: 01349972.
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA joshua_zeidner@med.unc.edu.
authors.forename: Joshua F
authors.initials: JF
authors.lastname: Zeidner
authors.affiliation: University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Foster
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Blackford
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.affiliation: The Blood and Marrow Transplant Program at Northside Hospital, Bone Marrow Transplant Group of Georgia, Atlanta, GA, USA.
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Morris
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Strickland
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.affiliation: Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, USA.
authors.forename: Prithviraj
authors.initials: P
authors.lastname: Bose
authors.affiliation: Texas Oncology, Baylor Charles A. Simmons Cancer Center, Dallas, TX, USA.
authors.forename: M Yair
authors.initials: MY
authors.lastname: Levy
authors.affiliation: Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Raoul
authors.initials: R
authors.lastname: Tibes
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA University of Maryland Medical Center, Stewart Greenebaum Cancer Center, Baltimore, MD, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Gocke
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
authors.affiliation: National Cancer Institute, Rockville, MD, USA.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Little
authors.affiliation: National Cancer Institute, Rockville, MD, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.affiliation: National Cancer Institute, Rockville, MD, USA.
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.affiliation: The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000401:mortality; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D015996:Survival Rate
chemical_list: D005419:Flavonoids; D010880:Piperidines; D003561:Cytarabine; C077990:alvocidib; D008942:Mitoxantrone; D003630:Daunorubicin