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.

Abstract

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.

DESIGN AND 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.

• Authors: Judith E Karp, Elizabeth Garrett-Mayer, Elihu H Estey, Michelle A Rudek, B Douglas Smith, Jacqueline M Greer, D Michelle Drye, Karen Mackey, Kathleen Shannon Dorcy, Steven D Gore, Mark J Levis, Michael A McDevitt, Hetty E Carraway, Keith W Pratz, Douglas E Gladstone, Margaret M Showel, Megan Othus, L Austin Doyle, John J Wright, John M Pagel
• Journal: Haematologica (Haematologica) Vol. 97 Issue 11 Pg. 1736-42 (Nov 2012) ISSN: 1592-8721 [Electronic] Italy
• PMID: 22733022 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Flavonoids
• Piperidines
• Cytarabine
• alvocidib
• Mitoxantrone

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Cytarabine (administration & dosage, adverse effects)
• Disease-Free Survival
• Female
• Flavonoids (administration & dosage, adverse effects)
• Humans
• Leukemia, Myeloid, Acute (drug therapy, mortality)
• Male
• Middle Aged
• Mitoxantrone (administration & dosage, adverse effects)
• Piperidines (administration & dosage, adverse effects)
• Survival Rate