The development of the targeted agent imatinib (Gleevec) has been a landmark event in the treatment of patients with chronic myeloid leukemia (CML). However, over time, the cancer can become resistant to this treatment, usually because of mutations in the protein that imatinib targets. Two studies presented at the 48th Annual Meeting of the American Society of Hematology (ASH), held last month in Orlando, highlight new compounds in development that can effectively treat CML when imatinib is no longer effective.
"This is important progress for patients who relapse on imatinib therapy," said Charles A. Linker, MD, University of California, San Francisco. "Not only does this research show the efficacy of new treatments for imatinib-resistant disease, it also demonstrates the value of looking at each patient's mutation pattern to determine an individual course of therapy."
Nilotinib After Imatinib Failure
Treatment with imatinib has allowed patients with chronic myelogenous leukemia (CML) to experience a nearly 90% 5-year survival rate, as the drug blocks the tyrosine kinase BCR-ABL, an abnormal protein driving the overproduction of abnormal white blood cells characteristic of leukemia. However, many patients have eventually developed resistance to this treatment because their cancer cells are able to mutate and adapt, causing their disease to relapse.
Researchers studied nilotinib (Tasigna), a novel treatment that blocks the BCR-ABL protein, to determine its effectiveness among patients for whom imatinib has stopped working. In vitro work showed effectiveness even in patients developing BCR-ABL mutations associated with resistance to imatinib. Investigators looked at blood samples from 101 CML patients, 64 of whom were in the early or chronic phase, 22 in the later or accelerated phase, and 15 in the final or blast crisis phase of the disease, and screened for the BCR-ABL gene mutation that signals CML.
Prior to treatment with nilotinib, researchers found 28 different BCR-ABL mutations in 61 patients. Of this group, nine showed two mutations, three showed three mutations, and one patient showed four mutations. When treated with nilotinib twice a day (400 mg), 70% of patients with mutations experienced a hematologic response, with the highest rate of response seen in patients in the chronic phase (78%), followed by accelerated phase (75%) and blast crisis (25%). Patients without mutations responded even better to the therapy, as 88% experienced a hematologic response rate.
Chronic-phase patients whose genetic mutations had shown sensitivity to nilotinib in the lab achieved a complete cytogenetic response within 3 to 6 months. Two patients with the BCR-ABL mutation T315Ia mutation highly resistant to both imatinib and nilotinib in the labshowed no signs of relapse of disease after 1 month and 11 months of treatment with nilotinib, respectively.
"This preliminary data suggests that nilotinib may help patients for whom imatinib has stopped working by overcoming the gene mutations that cause imatinib resistance," said Andreas Hochhaus, MD, of the Medical Faculty Mannheim of the University of Heidelberg, Germany. "It also shows the importance of determining each patient's specific gene mutation, to apply individualized dosage of nilotinib according to the mutation pattern."
Dasatinib After Imatinib Failure