Talpaz M et al. (2006) Dasatinib in imatinib-resistant Philadelphia chromosome–positive leukemias. N Engl J Med 354: 2531–2541

Kantarjian H et al. (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome–positive ALL. N Engl J Med 354: 2542–2551

Chronic myeloid leukemia (CML) is caused by upregulated activity of the ABL tyrosine kinase, which is encoded by the BCR–ABL fusion gene created by formation of the Philadelphia chromosome. Imatinib, an ABL tyrosine kinase inhibitor, is the first-line treatment for newly diagnosed CML, but mutations in the BCR–ABL gene can impair the ability of this drug to bind, causing drug resistance. Results from two phase I dose-escalation studies have been published that describe the efficacy of two BCR–ABL tyrosine kinase inhibitors, dasatinib and nilotinib, in imatinib-resistant patients with CML or Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph-ALL).

Talpaz et al. studied the effects of 15–240 mg/day dasatinib in 84 patients with CML or Ph-ALL who were resistant to or intolerant of imatinib. The drug led to complete hematologic responses in 37/40 patients with chronic-phase CML, and major hematologic responses in 31/44 patients with CML with blast crisis, accelerated-phase CML, or Ph-ALL. Dasatinib produced responses in all BCR–ABL genotypes apart from the T315I mutation, which had already been shown to be resistant to imatinib in vitro. Myelosuppression was common but not dose-limiting, and resolved in most patients who experienced cytogenetic remission; the authors nonetheless recommend further investigation of this phenomenon. Dasatinib did not lead to a recurrence of nonhematologic toxic effects in those patients who could not tolerate imatinib. Many patients with blast-crisis CML and Ph-ALL developed resistance to dasatinib, however, and the authors acknowledge that this might be the eventual outcome in many patients, although responses were maintained in 95% of the patients with chronic-phase disease, and 82% of those with accelerated-phase disease over median follow-up of 12 months and 5 months, respectively. These preliminary results nevertheless support the use of dasatinib as a single-agent therapy for imatinib-resistant CML and Ph-ALL. The drug recently received approval by the FDA for use in these conditions.

Kantarjian et al. treated 119 patients with imatinib-resistant CML or Ph-ALL with 50–1,200 mg/day nilotinib. The drug produced hematologic response rates of 74% and 39%, and cytogenetic response rates of 55% and 27%, in patients with the accelerated and blastic phases of the disease, respectively. Of the 12 patients with chronic-phase disease, 11 (92%) had a complete hematologic response. Nilotinib was not as effective, however, in patients with Ph-ALL. Like dasatinib, this drug was effective in cases with BCR–ABL mutations, but not in those with a T315I mutation. The toxic effects commonly seen with imatinib were not evident; however, some other adverse effects were seen, including myelosuppression, which was dose-related and dose-limiting. The authors conclude that nilotinib is active in CML and has a reasonably favorable safety profile, especially at an optimum dose of 400 mg twice daily. Nilotinib is still under review by the FDA.

The possibility that some BCR–ABL mutations may be targeted by imatinib but resistant to other kinase inhibitors suggests that combination therapy might be the best option for initial treatment of CML; successful long-term treatment might require a combination of several different kinase inhibitors. Phase II studies of several BCR–ABL inhibitors are ongoing.