Imatinib Reduces Leukemia Load, Prolongs CML Remissions

PHILADELPHIA—Imatinib 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 (Q-PCR).

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 interferon/Ara-C.

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.

Although the median values were similar, 32% of imatinib patients had a greater than 3 log reduction at the time of CCR vs 0% of interferon/Ara-C patients.

Extrapolating using the overall CCR rates, the researchers estimated that a greater than 3 log reduction in BCR/ABL levels was achieved in 39% of all imatinib patients but in only 2% of all interferon/Ara-C patients, and that 13% of imatinib patients achieved a greater than 4 log reduction by 12 months on trial.

The reduction in BCR-ABL transcript levels correlated dramatically with freedom from progression. "None of the imatinib patients in CCR who had a greater than 3-log reduction at 12 months had progression after 12 months," Dr. Hughes said.