Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.
The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.
Cortes
Jorge
J
M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. jcortes@mdanderson.org
Rousselot
Philippe
P
Kim
Dong-Wook
DW
Ritchie
Ellen
E
Hamerschlak
Nelson
N
Coutre
Steven
S
Hochhaus
Andreas
A
Guilhot
Francois
F
Saglio
Giuseppe
G
Apperley
Jane
J
Ottmann
Oliver
O
Shah
Neil
N
Erben
Philipp
P
Branford
Susan
S
Agarwal
Prasheen
P
Gollerkeri
Ashwin
A
Baccarani
Michele
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D020127:Recovery of Function / Q000187:drug effects*; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases; D000069439:Dasatinib