Randomized phase II study of two schedules of flavopiridol given as timed sequential therapy with cytosine arabinoside and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia.
BACKGROUND
Flavopiridol is a protein-bound, cytotoxic, cyclin dependent kinase inhibitor. A phase II trial of flavopiridol followed by ara-C and mitoxantrone with flavopiridol given by 1-h bolus for adults with newly-diagnosed, poor-risk acute myelogenous leukemia yielded 67% complete remission with median disease-free survival of 13.6 months.


METHODS
We compared bolus flavopiridol (50 mg/m(2)/day, Arm A) versus 'hybrid' flavopiridol (30 mg/m(2) over 30 min followed by 40 mg/m(2) over 4 h, Arm B) followed by ara-C and mitoxantrone in 78 patients (39 per arm) with newly diagnosed, poor-risk acute myelogenous leukemia. To mitigate imbalance, patients were stratified by presence or absence of secondary leukemia and therapy for antecedent disorder.


RESULTS
Death at or before Day 60 occurred in 8% of patients per arm. Complete remission plus complete remission with incomplete recovery was 68% (Arm A, 62%; Arm B, 74%) overall, and 65% or over in both arms for patients with secondary leukemia and leukemia with adverse genetics. In Arm A 91% and in Arm B 86% of patients received chemotherapy and/or allogeneic transplantation in complete remission. Median overall survival for all remission patients has not been reached for either arm, with median disease free survival of 13.6 months for Arm A and of 12.0 months for Arm B.


CONCLUSIONS
Both flavopiridol schedules produce comparably encouraging results in adults with poor-risk acute myelogenous leukemia. Given the greater ease of bolus administration, we are conducting a randomized phase II study of bolus flavopiridol followed by ara-c and mitoxantrone versus conventional induction therapy for patients aged 70 years and under with intermediate or poor-risk acute myelogenous leukemia. This study is registered at www.clinicaltrials.gov as #NCT 00407966.
Division of Hematologic Malignancies, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231-1000, USA. jkarp2@jhmi.edu
Judith E
JE
Karp
Elizabeth
E
Garrett-Mayer
Elihu H
EH
Estey
Michelle A
MA
Rudek
B Douglas
BD
Smith
Jacqueline M
JM
Greer
D Michelle
DM
Drye
Karen
K
Mackey
Kathleen Shannon
KS
Dorcy
Steven D
SD
Gore
Mark J
MJ
Levis
Michael A
MA
McDevitt
Hetty E
HE
Carraway
Keith W
KW
Pratz
Douglas E
DE
Gladstone
Margaret M
MM
Showel
Megan
M
Othus
L Austin
LA
Doyle
John J
JJ
Wright
John M
JM
Pagel
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005419:Flavonoids / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / 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
D005419:Flavonoids; D010880:Piperidines; D003561:Cytarabine; C077990:alvocidib; D008942:Mitoxantrone