ORLANDO-Low-dose cytarabine can be safely administered in combination with imatinib mesylate (Gleevec, also known as STI-571) to chronic myelogenous leukemia (CML) patients in blast crisis, but is unlikely to provide substantial benefit or salvage relapses.
ORLANDOLow-dose cytarabine can be safely administered in combination with imatinib mesylate (Gleevec, also known as STI-571) to chronic myelogenous leukemia (CML) patients in blast crisis, but is unlikely to provide substantial benefit or salvage relapses.
For patients in the chronic phase, the drug combination produces results similar to those observed in phase I trials with imatinib alone. These findings were presented by Brian Druker, MD, of Oregon Health & Science University, Portland, at the 43rd Annual Meeting of the American Society of Hematology (ASH abstract 3511).
The phase I trial followed in vitro studies showing synergistic antiproliferative effects when cytarabine was used with imatinib in CML cell lines and colony-forming assays of CML patient samples. As part of the phase I study, 62 CML patients were treated with a combination of imatinib plus low-dose cytarabine.
Patients in myeloid or lymphoid blast crisis (n = 28), plus four patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), were treated with escalating doses of 400, 600, or 1,000 mg of imatinib daily, with cytarabine at a fixed dose of 20 mg/m² on days 15 through 28 of each cycle. Response rates, durability of response, and toxicities were similar to those reported in phase I studies of imatinib alone.
A total of 11 patients (34%) went on to receive stem cell transplants, Dr. Druker reported. "So it is our conclusion that you can certainly use imatinib plus cytarabine in a preparative regimen for patients prior to transplant, but other combinations need to be considered for patients not eligible for transplant."
Another cohort of eight patients in myeloid blast crisis who relapsed while on imatinib continued on treatment with imatinib daily, and cytarabine was added at 20 mg/m² on days 1 to 14. All of these patients later discontinued treatment due to disease progression.
"In terms of salvage, we did not see much of a response," Dr. Druker said. "There was one patient on the salvage therapy who had a decrease in peripheral blood blasts that did not translate into a marrow response."
The combination of imatinib and cytarabine was also tested among CML patients in the chronic phase either resistant or intolerant to interferon. In 18 patients, imatinib was administered at a dose of 400 mg/d for 28 days, with cytarabine given at escalating doses of 5, 10, or 20 mg/m² on days 15 through 28 of each cycle. An additional cohort of four patients received imatinib at a dose of 600 mg/d for 28 days and cytarabine at 20 mg/m² on days 15 to 28 of each cycle.
Of the 22 patients treated in this study, 19 (86%) achieved a complete hematologic response. Major cytogenetic responses were seen in 32%, including 23% with a complete response and 9% with a partial response. These response rates are similar to those seen in phase I trials with imatinib alone.
Grade 3 and 4 hematologic toxicities occurred in 68% of patients. Nonhematologic toxicities were more frequent than with imatinib alone. For example, nausea occurred in 77% of patients receiving imatinib plus cytarabine vs 55% on imatinib alone, Dr. Druker reported. Edema occurred in 73% of patients receiving the combination therapy vs 52% receiving only imatinib.
Although there were no clear differences in grade 3 or 4 toxicities between those receiving 400- or 600-mg doses of imatinib, no patients receiving the 600-mg dose of imatinib plus 20 mg/m² of cytarabine were able to maintain the original dose, suggesting dose-limiting toxicity.
For patients in the chronic phase, 400 mg/d of imatinib with 20 mg/m² of cytarabine on days 15 to 28 was determined to be the maximum tolerated dose, Dr. Druker concluded.
Different schedules, doses, and drug combinations should continue to be tried, he advised. "Phase II studies in newly diagnosed patients are ongoing to determine the response rate to this combination in a larger patient population," Dr. Druker said.