An imatinib-only window followed by imatinib and chemotherapy for Philadelphia chromosome-positive acute leukemia: long-term results of the CMLALL1 trial.
We report long-term results in 40 patients with Philadlephia chromosome-positive (Ph+) acute leukemia who received an imatinib monotherapy window to evaluate in vivo effects on BCR-ABL signaling prior to induction chemotherapy. The first 25 patients (cohort 1) received the LALA-94 protocol without further imatinib (newly diagnosed Ph+ acute lymphoblastic leukemia [ALL]) or induction chemotherapy followed by single-agent imatinib. Subsequent patients (cohort 2) continued imatinib concurrently with either LALA-94 (newly diagnosed Ph + ALL) or other intensive chemotherapy regimens. Cohort 2 had a complete response (CR) rate of 93% and 5-year survival of 69%. For newly diagnosed Ph+ ALL, survival was superior in cohort 2 compared with cohort 1. Toxicity was similar to that expected for chemotherapy alone. Among 10 evaluable patients, rapid loss of phospho-CRKL occurred during the imatinib window in seven patients (all achieved CR) and incomplete inhibition in three patients (none with CR). In summary, a pharmacodynamic window design permitted biomarker assessment of BCR-ABL targeting without compromising clinical outcomes.
Cancer Therapeutics Unit, Nucleus Network , Melbourne, Victoria , Australia.
Jason D
JD
Lickliter
Kerry
K
Taylor
Jeff
J
Szer
Andrew
A
Grigg
Christopher
C
Arthur
Timothy P
TP
Hughes
Simon
S
Durrant
Robin
R
Filshie
Ian
I
Irving
Michael
M
Seldon
Jennifer
J
Ellacott
Andrew W
AW
Boyd
James
J
D'Rozario
Kim
K
Rooney
Kevin
K
Lynch
Ken
K
Bradstock
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D003520:Cyclophosphamide / Q000627:therapeutic use; D003907:Dexamethasone / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D010677:Philadelphia Chromosome / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014700:Verapamil / Q000627:therapeutic use; D014750:Vincristine / Q000627:therapeutic use; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C082869:CRKL protein; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; D014700:Verapamil; D016044:Fusion Proteins, bcr-abl
Chemotherapeutic approaches; lymphoid leukemia; pharmacotherapeutics; signaling therapies