Imatinib Produces Excellent Clinical Responses in Newly Diagnosed CML

ORLANDO—Imatinib mesylate (STI-571, Gleevec) is showing excellent results in newly diagnosed patients with chronic myelogenous leukemia (CML) in the early chronic phase, scientists reported at the 43rd Annual Meeting of the American Society of Hematology (abstract 577). The response rates reported are significantly higher than those seen in previous trials of interferon regimens.

Protocol Change for
 IRIS Study

EAST HANOVER, New Jersey—In an interim analysis of the ongoing phase III International Randomized Study of Interferon vs STI-571 (IRIS) for initial treatment in newly diagnosed chronic myelogenous leukemia (CML) patients, substantially higher response rates were found in the imatinib mesylate (Gleevec, STI-571) arm.

Based on this finding, the Independent Data Monitoring Board has recommended a change in the protocol to enable the patients on standard therapy (interferon-alfa and cytarabine) who have not achieved a major cytogenetic response after 1 year of treatment to switch to imatinib.

"Imatinib should now be considered as frontline therapy for all newly diagnosed patients with Ph [Philadelphia chromosome]-positive chronic myelogenous leukemia. It may have the potential to eliminate the disease for long periods, and perhaps permanently," said lead investigator Hagop Kantarjian, MD, professor of medicine and chairman of the leukemia service, M.D. Anderson Cancer Center.

Dr. Kantarjian reviewed the interim results of an ongoing phase II trial in which patients with early Ph+ CML were treated with imatinib at 400 mg daily as initial therapy. Interferon-alfa and cytarabine (ara-C) will be added after 12 months if cytogenetic responses are unsatisfactory.

50 Patients Enrolled

The trial enrolled 50 newly diagnosed patients, with 47 patients currently evaluable after 3 months of treatment and 44 evaluable for efficacy with 6-month follow-up.

After 3 months of treatment, 77% (36 patients) had achieved a complete or major cytogenetic response (Ph less than 35%); after 6 months of treatment, 86% (38 patients) had achieved a complete or major cytogenetic response. The hematologic response rate (normalization of blood counts lasting for at least 4 weeks) was 98% (46 patients) at 4-month follow-up.

Cytogenetic Response Rates

The complete and partial cytogenetic response rates at 6 months of 56% and 30%, respectively, are "remarkable," Dr. Kantarjian said. In comparison, in previously reported studies of interferon-alfa regimens, 3% to 12% of patients achieved a major cytogenetic response after 6 months of therapy.

Complete and major cytogenetic responses may serve as surrogate endpoints for survival. "With interferon, if patients get a complete cytogenetic response, their 10-year survival is estimated to be 70% to 80%. Since many patients achieved a complete response with imatinib, I’m hoping that the overall survival will be much longer," he said.

Side Effects ‘Insignificant’

Dr. Kantarjian said that the side effects seen with imanitib were "insignificant." He noted that less than 5% of patients experienced severe to life-threatening drug-related toxicity. The most common nonhematologic grade 3-4 adverse events were liver toxicity (6%), skin rashes (6%), and muscle cramps (2%).

Neutropenia and thrombocytopenia were seen in 22% of patients (granulocyte counts less than 1 million ×10³/L in 16%; platelet counts less than 50 million × 10³/L in 6%).

In an interview, Dr. Kantarjian discussed the impact of schedule and dosing on treatment outcomes.

"We are going to continue treating patients until their quantitative PCR for the Philadelphia chromosome is under 0.05% for about a year and then we will stop and see if they do not relapse," he said.

Effect Is Dose Sensitive

He noted that the effect of imatinib is very dose sensitive and that a dose below 300 mg is not effective. The study data indicate that 400 mg daily is an acceptable dosage, but that a higher dose (800 mg) may be more effective.

This research demonstrates that imatinib has significant activity in newly diagnosed CML, Dr. Kantarjian said, and "the first time that we have gotten such high complete and major response rates with any therapy. We hope that imatinib will be two or three times better than past therapies."