Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and -intolerant chronic-phase chronic myeloid leukemia.
OBJECTIVE
Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported.


METHODS
In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.


RESULTS
With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%).


CONCLUSIONS
Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.
Division of Hematology/Oncology, University of California, San Francisco School of Medicine, Box 1270, 505 Parnassus Ave, San Francisco, CA 94143, USA. nshah@medicine.ucsf.edu
Neil P
NP
Shah
Hagop M
HM
Kantarjian
Dong-Wook
DW
Kim
Delphine
D
Réa
Pedro E
PE
Dorlhiac-Llacer
Jorge H
JH
Milone
Jorge
J
Vela-Ojeda
Richard T
RT
Silver
H Jean
HJ
Khoury
Aude
A
Charbonnier
Nina
N
Khoroshko
Ronald L
RL
Paquette
Michael
M
Deininger
Robert H
RH
Collins
Irma
I
Otero
Timothy
T
Hughes
Eric
E
Bleickardt
Lewis
L
Strauss
Stephen
S
Francis
Andreas
A
Hochhaus
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D000069439:Dasatinib; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D015996:Survival Rate; D013844:Thiazoles / Q000008:administration & dosage*; D016896:Treatment Outcome
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000069439:Dasatinib