New Options to Treat Chronic Myeloid Leukemia, Overcome Imatinib Resistance

January 1, 2007

The development of the targeted agent imatinib (Gleevec) has been a landmark event in the treatment of patients with chronic myeloid leukemia (CML).

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 T315I—a mutation highly resistant to both imatinib and nilotinib in the lab—showed 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

Dasatinib (Sprycel) blocks the production of BCR-ABL and it has been shown to treat CML and acute lymphoblastic leukemia (ALL) that have become resistant to the standard therapy of imatinib. Another study presented at ASH looked at the type of gene mutations that are more responsive to treatment with dasatinib to confirm the best targets for future therapy. Blood samples from 394 patients being treated with dasatinib (198 chronic phase, 78 accelerated phase, 53 myeloid blast crisis, and 65 lymphoid blast crisis/ALL) were monitored in 3-month intervals to determine how the preexisting genetic mutations responded to the therapy and if new mutations emerged. Prior to treatment, 46 different BCR-ABL mutations were detected in 202 patients—162 patients showed one, 33 patients showed two, 6 patients showed three, and 1 patient showed four mutations.

Patients with mutations responded well to therapy, as complete hematologic response was achieved in 91% of chronic phase patients, 62% of accelerated phase patients, 41% of myeloid blast crisis patients, and 34% of lymphoid blast crisis/ALL patients. Complete cytogenetic responses were similar and occurred in 37% of chronic phase patients, 27% of accelerated phase patients, 28% of myeloid blast crisis patients, and 51% of lymphoid blast crisis patients.

Researchers observed two response patterns in studying treatment with dasatinib: Some patients experienced a decrease in the BCR-ABL expression and the proportion of the mutated clone simultaneously, while others experienced a decrease in BCR-ABL followed by a decrease of the mutated clone after a delay of 4 to 6 months. Five patients developed new mutations associated with resistance to dasatinib, including T315I. The T315I mutation is highly resistant to both imatinib and dasatinib.

"Dasatinib is an excellent treatment option for patients who have become resistant to imatinib," said lead researcher, Martin C. Müller, MD, Medical Faculty Mannheim of the University of Heidelberg, Germany. "However, we noted that response depended heavily on the type of genetic mutation, which may signal a method for individualizing each patient's dose."