Phase I clinical and pharmacokinetic study of a novel schedule of flavopiridol in relapsed or refractory acute leukemias.
BACKGROUND
A pharmacokinetically derived schedule of flavopiridol administered as a 30 min intravenous bolus followed by 4-hour continuous intravenous infusion (IVB/CIVI) is active in fludarabine-refractory chronic lymphocytic leukemia, but no studies examining the feasibility and maximum tolerated dose of this schedule have been reported in acute leukemia.


METHODS
We conducted a phase I dose escalation trial of single-agent flavopiridol in adults with relapsed/refractory acute leukemias, utilizing a modification of the intravenous bolus/continuous intravenous infusion approach, intensifying treatment for administration on days 1, 2, and 3 of 21-day cycles.


RESULTS
Twenty-four adults with relapsed/refractory acute myeloid leukemia (n=19) or acute lymphoblastic leukemia (n=5) were enrolled. The median age was 62 years (range, 23-78). The maximum tolerated dose of flavopiridol was 40 mg/m(2) intravenous bolus plus 60 mg/m(2) continuous intravenous infusion (40/60). The dose limiting toxicity was secretory diarrhea. Life-threatening hyperacute tumor lysis syndrome requiring hemodialysis on day 1 was observed in one patient. Pharmacokinetics were dose-dependent with increased clearance observed at the two highest dose levels. Diarrhea occurrence and severity significantly correlated with flavopiridol concentrations at the end of the 4-hour infusion, volume of distribution, and elimination half-life. Modest anti-leukemic activity was observed, with most patients experiencing dramatic but transient reduction/clearance of circulating blasts lasting for 10-14 days. One refractory acute myeloid leukemia patient had short-lived complete remission with incomplete count recovery.


CONCLUSIONS
Flavopiridol as a single agent given by intravenous bolus/continuous intravenous infusion causes marked, immediate cytoreduction in relapsed/refractory acute leukemias, but objective clinical responses were uncommon. With this schedule, the dose is limited by secretory diarrhea.
Blum
William
W
Division of Hematology and Oncology and the Comprehensive Cancer Center, Department of Medicine, The Ohio State University, B310 Starling-Loving Hall, 320 West 10 Avenue, Columbus, OH 43210, USA. william.blum@osumc.edu
Phelps
Mitch A
MA
Klisovic
Rebecca B
RB
Rozewski
Darlene M
DM
Ni
Wenjun
W
Albanese
Katie A
KA
Rovin
Brad
B
Kefauver
Cheryl
C
Devine
Steven M
SM
Lucas
David M
DM
Johnson
Amy
A
Schaaf
Larry J
LJ
Byrd
John C
JC
Marcucci
Guido
G
Grever
Michael R
MR
D000208:Acute Disease; D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010599:Pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D016879:Salvage Therapy / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
D005419:Flavonoids; D010880:Piperidines; C077990:alvocidib
Blood. 1998 Apr 1;91(7):2482-90
9516149
Ann Oncol. 2003 Aug;14(8):1270-3
12881391
J Clin Oncol. 2002 Oct 1;20(19):4074-82
12351605
Clin Cancer Res. 2005 Dec 1;11(23):8403-12
16322302
Clin Cancer Res. 2003 Feb;9(2):562-70
12576419
Clin Cancer Res. 2001 Jun;7(6):1590-9
11410495
Biochem Biophys Res Commun. 2002 Apr 26;293(1):566-71
12054639
Genome Biol. 2001;2(10):RESEARCH0041
11597333
Blood. 2007 Jan 15;109(2):399-404
17003373
Blood. 1989 Oct;74(5):1499-506
2676014
Blood. 2009 Mar 19;113(12):2637-45
18981292
Leuk Res. 2003 Apr;27(4):313-21
12531222
J Natl Cancer Inst. 1992 Nov 18;84(22):1736-40
1279187
J Clin Oncol. 1998 Sep;16(9):2986-99
9738567
Biochem Biophys Res Commun. 1994 Jun 15;201(2):589-95
8002990
Clin Cancer Res. 2000 Sep;6(9):3400-5
10999721
Clin Cancer Res. 2004 Aug 1;10(15):5038-47
15297405
J Clin Oncol. 2002 Apr 15;20(8):2157-70
11956278
Blood. 2008 Mar 15;111(6):3190-9
18192508
Clin Cancer Res. 2005 Jun 1;11(11):4176-81
15930354
Int J Clin Pharmacol Ther. 2003 Dec;41(12):610-1
14692715
Clin Cancer Res. 2002 Nov;8(11):3527-38
12429644
Life Sci. 1998;62(20):1861-73
9600328
J Biol Chem. 2001 Aug 24;276(34):31793-9
11431468
Clin Cancer Res. 2003 Jan;9(1):307-15
12538483
Cancer Chemother Pharmacol. 2002 Dec;50(6):465-72
12451473
Invest New Drugs. 2004 Aug;22(3):315-22
15122079
Blood. 2000 Jul 15;96(2):393-7
10887097
Anticancer Drugs. 2003 Feb;14(2):125-35
12569299
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jun 1;868(1-2):110-5
18490204
Leuk Res. 2005 Nov;29(11):1253-7
15916806
J Clin Oncol. 2003 Dec 15;21(24):4642-9
14673054
Blood. 2002 Dec 15;100(13):4325-36
12393746
Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4467-73
17671131
Blood. 1999 Jun 1;93(11):3983-93
10339508
J Biol Chem. 2000 Sep 15;275(37):28345-8
10906320
J Clin Oncol. 2003 May 1;21(9):1740-5
12735303
J Clin Oncol. 2001 Apr 1;19(7):1985-92
11283131
Cancer Res. 2003 Jan 1;63(1):93-9
12517783
Pharm Res. 2002 May;19(5):588-94
12069159
Cancer Res. 1996 Jul 1;56(13):2973-8
8674031
Life Sci. 2003 Oct 17;73(22):2841-54
14511769
Ann Pharmacother. 2003 Oct;37(10):1369-74
14519054
J Clin Oncol. 2000 Jan;18(2):371-5
10637252