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Dasatinib Overcomes Imatinib Resistance for Chronic Myeloid Leukemia
Dec. 12, 2005 (Atlanta) ~ Dasatinib, an investigational oral drug, produces positive results in patients with chronic myeloid leukemia (CML) who become resistant or intolerant to imatinib, the mainstay treatment for CML, researchers reported here at the 47th annual meeting of the American Society of Hematology.
"The efficacy is very good," Andreas Hochhaus, MD, a professor of internal medicine at Heidelberg University in Mannheim, Germany, said during a press conference. "[Dasatinib] was effective and well tolerated in patients in all phases of CML."
In a phase 2 study of dasatinib (BMS-354825) in 186 patients who were resistant or intolerant to imatinib (START-C), 90% of patients experienced a complete hematologic response and 45% achieved a major cytogenetic response after 6 months of treatment.
The study, conducted by 75 investigators in 20 countries, included 394 chronic CML patients with imatinib resistance or intolerance. The 186 patients available for analysis either failed to respond to imatinib at the maximum tolerated doses or showed evidence of BCR-ABL mutations associated with imatinib insensitivity.
Dasatinib was administered to patients at 70 mg twice daily, based on phase 1 data and optimal inhibition of BCR-ABL activity from biomarker analysis. Patients who did not respond initially received escalating doses up to 90 mg twice daily; dose reductions to 50 or 40 mg twice daily were allowed in patients experiencing adverse effects. Complete blood counts were assessed weekly for 12 weeks; bone marrow was collected every three months. Median time from CML diagnosis to treatment was about 70 months.
All of the patients initially had been treated with imatinib, with slightly more than half of patients treated for 5 years. About 70% also had been receiving interferon alpha therapy since diagnosis. A total of 127 patients were resistant to imatinib; 59 were classified as intolerant to imatinib.
The researchers reported that within the first 6 months of treatment, 90% of patients experienced a complete hematologic response, with 87% of resistant patients and 97% of intolerant patients responding. Forty-five percent of patients achieved a major cytogenetic response that was considered complete in 33% of patients.
"There was efficacy in a number of patients harboring a variety of BCR-ABL mutations," Dr. Hochhaus said during his presentation. "The responses were durable."
Using molecular analysis and more sensitive assays, the researchers found that patients had reductions in the BCR-ABL transcriptions. "Patients with all types of mutations responded," Dr. Hochhaus said. "Dasatinib appeared to work in all but 1 mutation, the T1351." As expected, 3 patients with the T1351 mutation did not respond to treatment with dasatinib.
"Dasatinib was well tolerated," Dr. Hochhaus reported. "The toxicity was mild to moderate."
Adverse effects included reversible myelosuppression, diarrhea in 27% of patients, rash in 15%, fluid retention in 22%, pleural effusion in 11%, and increased activity of liver enzymes in 51%, he reported.
The researchers also presented interim results on 167 patients with advanced disease who were either in myeloid blast crisis or in the accelerated phase.
Thirty-one percent of the 68 patients in myeloid blast crisis who were resistant to imatinib had major hematologic responses and 29% achieved major cytogenetic responses. Of the 99 patients in the accelerated phase who were treated with dasatinib, 59% achieved major hematologic response and 31% achieved major cytogenetic response.
John Goldman, MD, a professor of hematology at Imperial College in London, England, and a Fogarty scholar at the Hematology Branch of the National Heart, Lung, and Blood Institute in Bethesda, Maryland, said a small percentage of CML patients are relapsing after 4 or 5 years of imatinib therapy. "We definitely need new and better treatments for these patients," he told Medscape in an interview seeking outside comment. "This is very good news for patients with imatinib intolerance."
"Dasatinib is 300 times more potent in inhibiting kinase cells and the most common mutations," Dr. Goldman explained. "There are remarkable results in most patients with imatinib resistance, with patients achieving normal blood counts and a significant number achieving cytogenetic responses with good tolerance and durability."
It is likely that initiating dasatinib treatment earlier in patients with CML will protect a larger number of patients from relapsing, Dr. Goldman said. "A drug like dasatinib, with improved potency, may provide better results in the future than seen with imatinib. That ultimately could be the best news for patients."
The study was funded by Bristol-Myers Squibb (BMS), the maker of dasatinib. Dr. Hochhaus has received research support from BMS and is a member of the BMS advisory board. Three coauthors are employees of BMS. Other authors reported various financial relationships with Novartis Oncology, Johnson & Johnson, and Pharmion.
ASH 47th Annual Meeting: Abstract 41. Presented Dec. 11, 2005.
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