Treatment with Nilotinib for Patients with Chronic Myeloid Leukemia (CML) Who Failed Prior Therapy with Imatinib and Dasatinib.

Nilotinib (AMN107) is a selective Bcr-Abl kinase inhibitor which is aproximately 30-fold more potent than imatinib. Phase I and II studies confirmed the efficacy of nilotinib in imatinib-resistant CML. Dasatinib (BMS-354825) is a dual Src-Abl kinase inhibitor recently approved for the treatment of CML in all stages of the disease after imatinib failure. With the availability of more new tyrosine kinase inhibitors, one important question is the existence of cross-resistance between these new agents. To help answer this question, we analyzed the outcome of patients with CML who receive therapy with nilotinib after having failed therapy with dasatinib. Seven patients were treated: 6 had previously shown hematologic resistance to imatinib and one had intolerance to imatinib. Dasatinib failure was due to hematologic resistance in all 7 patients after a median of 16 weeks (range 4 to 32) on therapy. Median age was 50 years (range, 15 to 78 years); median follow-up on nilotinib was 5 months (range, 1 to 14 months). At the start of therapy with nilotinib, 1 patient was in chronic (CP), 1 in accelerated (AP), and 5 in blastic phase (BP). Mutations were found in 2 of 4 patients assessed before nilotinib therapy (F317L and E355G, respectively). All patients received nilotinib 400 mg BID (n=5) or 800 mg single daily dose (n=2). Of the 7 evaluable patients, one patient (in AP) responded (complete hematologic response). This patient had no mutations identified at baseline. At the last follow-up, 5 patients are alive: 3 with active disease, one in CHR, and one in complete molecular remission post allogeneic stem cell transplantation. We conclude that nilotinib has modest activity in patients with CML resistant to both imatinib and dasatinib.