A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias.
The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl) tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 (38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid. Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib.
Medizinische Klinik III/Abteilung Haematologie, Johann Wolfgang Goethe Universität, 60590 Frankfurt, Germany. ottmann@em.uni-frankfurt.de
Oliver G
OG
Ottmann
Brian J
BJ
Druker
Charles L
CL
Sawyers
John M
JM
Goldman
Jose
J
Reiffers
Richard T
RT
Silver
Sante
S
Tura
Thomas
T
Fischer
Michael W
MW
Deininger
Charles A
CA
Schiffer
Michele
M
Baccarani
Alois
A
Gratwohl
Andreas
A
Hochhaus
Dieter
D
Hoelzer
Sofia
S
Fernandes-Reese
Insa
I
Gathmann
Renaud
R
Capdeville
Stephen G
SG
O'Brien
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000592:standards / Q000633:toxicity; D001549:Benzamides; D001752:Blast Crisis / Q000150:complications / Q000188:drug therapy / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000592:standards / Q000633:toxicity; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011743:Pyrimidines / Q000008:administration & dosage* / Q000592:standards / Q000633:toxicity; D012074:Remission Induction / Q000379:methods; D016879:Salvage Therapy; D016019:Survival Analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate