At the recent annual meeting of the American Society of Hematology held in San Diego, researchers reported improved results with certain types of leukemia. These outcomes were achieved by using higher drug dosages to treat early chronic myelogenous leukemia (CML), and equivalent results occurred with a more convenient subcutaneous, rather than intravenous, route for delivering a biologic for chronic lymphocytic leukemia (CLL).

Leukemia response criteria

In hematologic cancers, response is defined by quality of remission assessed according to the degree to which bone marrow is cleared of tumor cells. Research suggests a strong correlation between the strongest remission, a complete molecular response (CMR), and a patient's ability to sustain a complete cytogenetic remission (CCR)(see table).

For the standard dose (400 mg) of imatinib mesylate (Gleevec, Novartis) in CML patients in whom interferon (INF) therapy has failed, CCRs have been in the 40%-60% range. For previously untreated patients, noted Jorge Cortes, M.D., department of leukemia, M. D. Anderson Cancer Center, Houston, CCRs are in the 70%-80% range. CMR rate with 400 mg has been in the 4%-10% range.

Early data on chronic-phase CML have shown that some patients with cytogenetic resistance or relapse with 400 mg imatinib respond to higher imatinib doses (800 mg). Higher imatinib doses (600 mg versus 400 mg) have also improved responses in accelerated-phase patients and in those failing IFN therapy. Cortes looked at frontline imatinib in CML, comparing a study of standard dose (400 mg, n=50) and two studies of high doses (800 mg daily, n=114 and n=61).

After three months of treatment, CCRs were reported in 36% of patients receiving 400 mg and in 55% of those receiving 800 mg. After median follow-up of 42 months in the 400-mg study and 21 months in the 800-mg studies, the CCR rates were 78% and 89%, respectively—a strong trend for the higher dose (p=0.057). CMRs were significantly more common in the higher dose studies (25% versus 8% at 18 months; 40% versus 22% at 24 months). Survival rates, however, were similar between groups. Hematologic toxicities were increased at the higher dose but were generally transient, with 16%-17% unable to tolerate them. "These are very good, very early data," Cortes stated.

A further study in 103 patients with de novo chronic phase CML presented by associate professor of hematology Timothy Hughes, M.D., Institute of Medical and Veterinary Science, Adelaide, Australia, evaluated 600 mg/day with selective intensification to 800 mg/day based on quality of response. For that study (the TIDEL trial), imatinib doses were raised from 600 mg to 800 mg in patients who did not achieve a major cytogenetic response (0%-35% Philadelphia chromosome positive cells) by six months, or who did not achieve polymerase chain reaction (PCR)-negativity by 12 months.

Compared with a historical control CCR rate, the IRIS (Insulin resistance intervention after stroke) trial, 400 mg, the rate at a year for the 600-mg dose for TIDEL patients was 89% versus 69% (p<0.0001). While at 18 months the rate for major molecular reduction (> 3 log reduction in BCR-ABL) was similar (40% IRIS, 47% TIDEL) between the IRIS group and the 600- to 800-mg TIDEL groups, the percentage of patients with a > 4 log reduction was ~58% for the TIDEL strategy versus ~3% for IRIS.

"This shows that the moderate increase in dose with selective dose intensification is giving dramatically superior results," Hughes said. He pointed out also that responses for patients able to tolerate only doses of 500 mg and lower were substantially lower. "Dose intensity may be critically important to maximize molecular response," he said, adding that clinicians had worked hard to maximize doses, giving GCSF (granulocyte colony-stimulating factor) to minimize neutropenia. As a result, 77% of patients were able to tolerate at least 600 mg daily.