PHILADELPHIAImatinib mesylate (Gleevec) is significantly more effective
than interferon/cytarabine at reducing BCR-ABL protein blood levels in patients
with chronic myeloid leukemia (CML); levels of BCR-ABL continue to drop with
increasing duration of therapy; and patients in complete cytogenetic response (CCR)
who have a 3-log or greater reduction in BCR-ABL rarely develop progressive
disease, according to Timothy Hughes, MD.
Dr. Hughes, of the Institute of Medical and Veterinary Science, Adelaide,
South Australia, reported these observations at the 44th Annual Meeting of the
American Society of Hematology (abstract 345), based on interim analysis of
molecular responses of patients in the IRIS (International Randomized
Interferon vs STI571) trial.
In the IRIS study (reported in the New England Journal of Medicine
348:994-1004, 2003), imatinib 400 mg/d was compared with interferon-alfa plus
intermittent low-dose cytarabine (interferon/Ara-C) as first-line therapy for
CML in chronic phase. Complete cytogenetic remission was defined as 0%
Ph-positive cells in the marrow. Patients were allowed to cross over to the
alternative arm for toxicity or lack or response.
The goal of the molecular analysis was to correlate CCR with molecular re-sponses
(BCR-ABL transcript levels) assessed by quantitative polymerase chain reaction
At median follow-up of 18 months, there were CCRs (best observed response
rates) in 74% of patients randomized to imatinib and 8% of those randomized to
Patients in CCR had BCR-ABL levels measured by Q-PCR, performed at one of
three central laboratories at the time of CCR and every 3 months in follow-up.
The BCR-ABL value was normalized to the BCR transcript level to compensate for
variations in the quality of the RNA.
"The imatinib group had BCR-ABL transcripts 2.5 logs below baseline at the
time of CCR. By 15 months, those levels had decreased to 3.7 logs below
baseline, Dr. Hughes said. The patients on interferon/Ara-C had no difference
in BCR-ABL transcript levels at the time of CCR, compared with baseline, and no
significant fall afterward, "but the numbers in that group are too small for
final conclusions," he said.