Second-Line Imatinib Produces CCRs in CML Patients

SAN DIEGO—In the IRIS study, newly diagnosed chronic myelogenous leukemia (CML) patients who crossed over from interferon (IFN)-alfa plus cytarabine (ara-C) to imatinib mesylate (Gleevec) and achieved a complete cytogenetic response (CCR = elimination of Ph+ cells), had reductions in bcr-abl similar to those on first-line imatinib, according to a presentation at the 45th Annual Meeting of the American Society of Hematology (ASH abstract 635). Their probability of achieving a CCR, is somewhat diminished, however, compared with those treated with first-line imatinib, said Jerald P. Radich, MD, Fred Hutchinson Cancer Research Center, Seattle.

In IRIS (International Randomized Trial of Interferon/ara-C vs STI571), 1,106 CML patients had received imatinib 400 mg or IFN/ara-C. About 62% of IFN patients, for various reasons (eg, loss or failure of response, increasing WBC, intolerance), crossed over to imatinib (compared with 2% of imatinib patients crossing over to IFN).

For the IRIS Q-PCR (quantitative polymerase chain reaction) study, pre-study samples and samples collected every 3 months after CCRs were achieved were analyzed to determine a bcr-abl log reduction for 370 first-line imatinib patients (1,156 samples) and 112 second-line cross-over patients (199 samples).

First-Line Patients

In previously published results (N Engl J Med 349:1421-1430, 2003), an estimated 39% of imatinib and 2% of IFN patients achieved a major molecular response (3 log or more bcr-abl reduction) after 12 months of treatment. Among those patients with 3 log or more reductions, progression-free survival (PFS) was 100% at 24 months. For those with CCRs but less than 3 log reductions, PFS was 95%. In patients without CCR, PFS was 85%.

Dr. Radich stated that further follow-up has shown that bcr-abl log reductions have been at least maintained, and may be improved in first-line imatinib patients, with about 3.5 bcr-abl log reductions out to about 24 months. While at 3 months, about 75% had not achieved CCR, at 24 months only 24% had not achieved CCR; 68% achieved CCR at 12 months (see Table).

Progression-free survival was 100% at both 3 and 12 months in those with 3 log or more bcr-abl reductions; 98% and 95%, respectively, at those times with less than 3 log reductions; and 86% and 85% in patients without CCR. For these same groups, estimated PFS at 30 months was 100%, 93%, and 81%, respectively. Looking at CCR status at 3 months, Dr. Radich said that estimated 30-month PFS for these groups was 100%, 96%, and 85%, respectively. "You can start teasing apart what’s going to happen in the next 2 years based on CCRs," he added.

Cross-over Patients

Turning to cross-over patients, Dr. Radich observed the same trend as found in first-line patients, starting with about 2.8 log reductions in bcr-abl and plateauing at around 3.5 log reductions at around 15 months, but noted that fewer achieved CCR in second-line treatment. At 3 months, 83% had not achieved CCR, and at 12 months 49% had not (43% at 18 months) (see Table).

"With second-line imatinib therapy, fewer people achieve complete cytogenetic responses, but if they do have a molecular response, it is just as good as with front-line therapy," Dr. Radich said.

Dr. Radich concluded, "After 24 months, an estimated 55% of imatinib patients achieve 3 log or more reductions, which predict progression-free survival. Cross-over patients to imatinib who achieve CCR have bcr-abl reductions similar to first-line imatinib patients."

Dr. Radich had pointed out at the outset of his presentation, "the theme here is the power of monitoring in setting a course of how you can best treat patients via imatinib or alternatives. We want to emphasize the need to monitor cytogenetic data. . . . From there, you can start tailoring therapy based on response."