Imatinib Affects Key Molecular Abnormality in Chronic Myeloid Leukemia

Laurie Barclay, MD

October 08, 2003

Oct. 8, 2003 -- The molecular response in chronic myeloid leukemia (CML) as measured by reduction in BCR-ABL transcripts is greater with imatinib than with the combination of interferon-alfa and cytarabine in patients with complete cytogenetic responses, according to the results of a randomized trial published in the Oct. 9 issue of the New England Journal of Medicine. The editorialist suggests that molecular remission will be the standard for future studies.

"The level of BCR-ABL transcripts can predict the duration of remission in patients who have a complete cytogenetic remission during therapy with interferon alfa," write Tim P. Hughes, MD, from the Institute of Medical and Veterinary Science in Adelaide, Australia, and colleagues from the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. "Imatinib mesylate (Gleevec, Novartis) is a tyrosine kinase inhibitor that blocks the kinase activity of BCR-ABL, thus inhibiting the proliferation of Ph-positive progenitors. Imatinib has shown activity against all phases of CML, though responses are most substantial and durable in patients who are in the chronic phase."

In this study, 1,106 patients with chronic CML were randomized to initial treatment with imatinib or interferon-alfa. At 12 months, 68% of the imatinib group and 7% of the interferon-alfa plus cytarabine group had a complete cytogenetic remission. In these patients, levels of BCR-ABL transcripts had fallen by at least 3 log in 57% of those in the imatinib group and in 24% of the interferon-alfa plus cytarabine group ( P = .003).

An estimated 39% of all patients treated with imatinib but only 2% of all those treated with interferon-alfa plus cytarabine had a reduction in BCR-ABL transcript levels of at least 3 log ( P < .001) at 12 months. For these patients, the probability of remaining progression-free at 24 months was 100% compared with 95% probability for patients with a reduction of less than 3 log and 85% probability for patients who were not in complete cytogenetic remission at 12 months ( P < .001).

"Patients in the imatinib group who had a reduction in the level of BCR-ABL transcripts of at least 3 log had a negligible risk of disease progression over the subsequent 12 months," the authors write. "We propose that a reduction in BCR-ABL transcript levels of at least 3 log be used to define a major molecular response.... The frequency of major molecular responses achieved in this study should serve as a benchmark against which future studies aiming to optimize therapy for CML can be measured."

Novartis funded, designed, and interpreted data from this study and supported all its investigators.

In an accompanying editorial, Bob Löwenberg, MD, PhD, from Erasmus University Medical Center in Rotterdam, the Netherlands, suggests that definitions of incomplete and major cytogenetic responses "may soon become anachronisms. The focus of drug therapy in CML will shift toward achieving complete molecular remissions.... Insight into the full therapeutic potential of imatinib as a single agent (with respect to dose, schedule, and follow-up) will need to be acquired through studies with longer follow-up. Moreover, the efficacy of combinations of imatinib with other active agents must be explored."

N Engl J Med. 2003;349:1399-1401, 1423-1432

Reviewed by Gary D. Vogin, MD

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