It is estimated that the incidence rate of chronic myeloid leukemia (CML), a type of blood and bone marrow malignancy in which too many white blood cells are produced, varies from 0.6 to 2 cases per 100,000 persons each year.2 More than 95 percent of people with CML are affected with the Philadelphia chromosome (Ph+), a unique chromosomal abnormality that harbors a leukemic gene called BCR-ABL. This gene promotes the disease and allows the disease to progress to terminal acute leukemia – defined as “accelerated” and “blast” phase – if the disease is not properly treated. The current standard first-line treatment for Ph+ CML is the targeted BCR-ABL inhibitor, imatinib.

Nilotinib, a second-generation BCR-ABL inhibitor, recently received FDA approval (June 2010) as a first-line therapy for this patient population based on the results from an 18-month study that found that nilotinib demonstrated superior efficacy as compared with standard therapy imatinib, with higher and faster molecular responses. This study also showed that rates of progression to accelerated or blast phase were also significantly lower for nilotinib than for imatinib.

In order to confirm that the efficacy of nilotinib is durable over a three-year time frame, the period of time when most of the failures to imatinib are described, researchers from the Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA) Chronic Myeloid Leukemia (CML) Working Party (WP) in Italy enrolled 73 patients with newly diagnosed Ph+ CML into a phase II clinical trial in which patients received nilotinib 400 mg twice daily. Currently, the median follow-up is longer than three years. The primary endpoint of the study was the complete cytogenetic response (CCgR) rate at 12 months – meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow. Other outcomes evaluated in the study included overall survival, progression-free survival, failure-free survival, and event-free survival.

At different key milestones throughout the study, the CCgR rate was high (78 percent at three months, 96 percent at six, 12, and 18 months). Within 12 months, the cumulative CCgR rate for study participants was 100 percent, which means that all patients achieved CCgR at least once. Additionally, after a median follow-up of 36 months, overall survival, progression-free survival, and failure-free survival reached 99 percent for each, and event-free survival was 92 percent. The cumulative major molecular response (MMR) rate, a more sensitive measurement of response, was 96 percent at 12 months. The MMR rate was 52 percent at three months, 66 percent at six months, 85 percent at one year, 81 percent at 18 months, and 82 percent at two years. In patients who achieved an MMR, none progressed to accelerated or blast phase CML. Furthermore, only one patient in the entire study progressed to accelerated or blast phase due to the development of another BCR-ABL mutation called a T315I mutation.

“While it is important to rapidly induce responses in these patients, it is also important that these responses last as long as possible,” said lead study author Gianantonio Rosti, MD, Scientific Secretary of the GIMEMA CML WP, Department of Hematology and Oncology, University of Bologna, Bologna, Italy. “Results from this study not only show that nilotinib quickly induces high rates of response, but responses also are durable and stable beyond three years, translating into optimal outcomes for newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia.”


Source: ASH