Combination of Drugs Up Front in CML May Prolong Remission
Zosia Chustecka
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August 23, 2007 — At present, patients with chronic myeloid leukemia (CML) are treated with imatinib (Gleevec, Novartis) and then, when resistance develops, with dasatinib (Sprycel, Bristol-Myers Squibb), but a better option may be to use both drugs in combination from the beginning. This would prevent the development of compound mutations that confer resistance against these drugs and may prolong the duration of remission, says Charles Sawyers, MD, from the Memorial Sloan-Kettering Cancer Center, in New York.
Dr. Sawyers and colleagues report on the potential hazards of sequential therapy and suggest a role for combination therapy in a paper published online August 16 in the Journal of Clinical Investigation and scheduled for the September issue.
The rationale for using these drugs sequentially is partly historical and partly based on a molecular understanding of resistance mechanisms, the researchers explain. Imatinib was the first to be approved, on the basis of a very high single unit response rate, and it is indicated for first-line use, whereas dasatinib is approved as a second-line agent after failure of therapy with imatinib, as it was initially evaluated in imatinib-resistant or imatinib-intolerant patients.
Both drugs act as kinase inhibitors and target the fusion oncogene BCR-ABL. Patients taking imatinib sometimes become resistant to the drug because they develop BCR-ABL point mutations, of which more than 50 distinct examples have been reported clinically, the researchers explain. Dasatinib is effective against nearly all the imatinib-resistant mutations, with the exception of the T3151 "gatekeeper" mutation, which confers resistance to imatinib, dasatinib, and also to nilotinib (Novartis), the follow-on compound to imatinib that is still under clinical development. At present, the only drug to overcome that T3151 mutation is the experimental compound VX-608 (Vertex, Novartis).
"However, as clinical experience with dasatinib grows, it is becoming clear that patients can also relapse on treatment after an initial response, particularly in the setting of advanced-phase CML," the team writes. They analyzed BCR-ACL genotypes in CML patients who had taken both imatinib and then dasatinib and relapsed on both drugs, and they found "evolving resistant BCR-ABL kinase domain mutations in all cases."
"This is an important point," Dr. Sawyers told Medscape in an interview, "as it shows that the drug target continues to mutate and that BCR-ABL is the escape mechanism." Hence, further drug development should continue to focus on BCR-ABL and not on any of the other mechanisms that are thought to also be involved, he commented.
Another important point is that the some of the mutations that arise after imatinib relapse are unique, Dr. Sawyers said, adding: "They would have never arisen if both drugs had been used together in the first place." In their series of 17 patients, the team found 5 patients who had developed compound mutations. They had gone through 2 or 3 tumor cell–acquired mutations and were no longer responsive to imatinib or dasatinib, so "the horse is out of the barn," he said. Using both drugs together in the first place may avoid this situation, Dr. Sawyers asserts. "We have shown that these compound mutations do not occur in the laboratory and predict that they would not occur in the clinic," he said. However, the T3151 mutation may still occur, and so there is an argument for also including a drug such as VX-608 up front in the combination used for initial therapy, he added.
The suggestion to use combination drug therapy up front instead of using these drugs sequentially would represent a major change in clinical practice, and before it could be recommended, the suggestion would need to be tested in clinical trials, Dr. Sawyers said. A clinical trial would need to test the combination of imatinib and dasatinib vs the sequential use of these agents, to see whether the combination is safe and whether it does indeed prolong the duration of the remission.
Dr. Sawyers said that his team had tried to initiate a feasibility study along these lines but could not recruit sufficient numbers of patients and were met with a lack of enthusiasm among clinical colleagues. "The problem is one of perception," Dr. Sawyers commented. Relapse on imatinib is only 4% per year, he noted, and so the drug is regarded as very effective. "It has produced extraordinary results compared with what we were seeing before it was available, but we should be able to do even better."
The authors declare no conflicts of interest.
J Clin Invest. Published online August 16, 2007. Abstract
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Zosia Chustecka is news editor for Medscape Hematology-Oncology and prior news editor of jointandbone.org, a website acquired by WebMD. A veteran medical journalist based in London, UK, she has won a prize from the British Medical Journalists Association and is a pharmacology graduate. She has written for a wide variety of publications aimed at the medical and related health professions. She can be contacted at ZChustecka@webmd.net.
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