Randomized multicenter phase II study of flavopiridol (alvocidib), cytarabine, and mitoxantrone (FLAM) versus cytarabine/daunorubicin (7+3) in newly diagnosed acute myeloid leukemia
Joshua F. Zeidner,
Matthew C. Foster,
Amanda L. Blackford,
Mark R. Litzow,
Lawrence E. Morris,
Stephen A. Strickland,
Jeffrey E. Lancet,
Prithviraj Bose,
M. Yair Levy,
Raoul Tibes,
Ivana Gojo,
Christopher D. Gocke,
Gary L. Rosner,
Richard F. Little,
John J. Wright,
L. Austin Doyle,
B. Douglas Smith,
Judith E. Karp
Affiliations
Joshua F. Zeidner
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA;University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
Matthew C. Foster
University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA
Amanda L. Blackford
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Mark R. Litzow
Mayo Clinic, Rochester, MN, USA
Lawrence E. Morris
The Blood and Marrow Transplant Program at Northside Hospital, Bone Marrow Transplant Group of Georgia, Atlanta, GA, USA
Stephen A. Strickland
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
Jeffrey E. Lancet
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Prithviraj Bose
Virginia Commonwealth University, Massey Cancer Center, Richmond, VA, USA
M. Yair Levy
Texas Oncology, Baylor Charles A. Simmons Cancer Center, Dallas, TX, USA
Raoul Tibes
Mayo Clinic, Scottsdale, AZ, USA
Ivana Gojo
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA;University of Maryland Medical Center, Stewart Greenebaum Cancer Center, Baltimore, MD, USA
Christopher D. Gocke
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Gary L. Rosner
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Richard F. Little
National Cancer Institute, Rockville, MD, USA
John J. Wright
National Cancer Institute, Rockville, MD, USA
L. Austin Doyle
National Cancer Institute, Rockville, MD, USA
B. Douglas Smith
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Judith E. Karp
The Johns Hopkins Hospital, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
Serial studies have demonstrated that induction therapy with FLAM [flavopiridol (alvocidib) 50 mg/m2 days 1–3, cytarabine 667 mg/m2/day continuous infusion days 6–8, and mitoxantrone (FLAM) 40 mg/m2 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/m2/day continuous infusion days 1–7 and daunorubicin 90 mg/m2 days 1–3), across 10 institutions. Some patients on 7+3 with residual leukemia on day 14 received 5+2 (cytarabine 100 mg/m2/day continuous infusion days 1–5 and daunorubicin 45 mg/m2 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.
