Earlier today dasatinib (Sprycel?, Bristol-Myers Squibb) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myelogenous Leukaemia in Chronic Phase (CML-CP).
CML is a slow-growing type of leukemia in which the body produces an uncontrolled number of abnormal white blood cells. CML is most commonly diagnosed in those aged 60-65 and the incidence is estimated at 1-2 cases per 100,000. CML occurs when pieces of two different chromosomes break off and attach to each other. The new chromosome is called the Philadelphia-positive chromosome, which contains an abnormal gene called BCR-ABL that signals cells to make too many white blood cells. There is no known cause for the genetic change that causes CML.
Dasatinib is an oral BCR-ABL inhibitor, currently approved by the European Commission for the treatment of adults for all phases of CML (chronic, accelerated, or myeloid or lymphoid blast phase) with resistance or intolerance to prior therapy including imatinib. Dasatinib is also approved for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to prior therapy.
At nanomolar concentrations, dasatinib reduces the activity of one or more proteins responsible for the uncontrolled growth of the leukemia cells of patients with CML or Ph+ ALL.
The decision by the European Medicines Agency (EMA) follows the presentation of results from the pivotal DASISION study in which dasatinib 100 mg once daily demonstrated a superior rate of confirmed complete cytogenetic response (CCyR)[*] compared to imatinib by 12 months in chronic phase CML patients. The data was presented as a late-breaking abstract at the 46th Annual Meeting of the American Society of Clinical Oncology, during the Best Abstracts section of the Presidential Symposium at the 15th Congress of the EHA and published in New England Journal of Medicine in June 2010.
The ongoing DASISION (Dasatinib versus Imatinib Study in Treatment-Na?ve CP-CML Patients) study, results of which were published in the NEJM in June 2010, 77% of patients in the dasatinib arm vs. 66% of patients in the imatinib arm achieved confirmed CCyR (two consecutive assessments of CCyR) within 12 months (p=0.007). Additionally, 83% of dasatinib patients vs. 72% of imatinib patients achieved CCyR by one year (p=0.001). The time to CCyR was shorter for dasatinib patients than imatinib patients (hazard ratio = 1.5, p<0.0001), with more than half of dasatinib patients (54%) achieving CCyR within three months. Dasatinib patients were also twice as likely as imatinib patients to achieve a major molecular response[**] (MMR), a more sensitive method of assessment of treatment response,[3,4] during the course of the study (hazard ratio = 2.0, p<0.0001).
Commonly reported adverse events (of all grades) with dasatinib and imatinib respectively included superficial oedema (9% and 36%), pleural effusions (10% and 0%), nausea (8% and 20%), rash (11% and 17%) and muscle inflammation (4% and 17%).
The European Medicines Agency’s CHMP adopted the positive opinion based on the 12 month results from the DASISION trial. The European Commission generally grants the Marketing Authorization within three months of a positive CHMP opinion.
Commenting on the developments, a spokesperson of Bristol-Myers Squibb, Renzo Canetta, Vice-President, Oncology Global Clinical Research, said: ” We are committed to working together with regulatory authorities in different countries around the world to help ensure that CML patients and their physicians are provided with treatment options that can achieve optimal outcomes for their patients whether they are newly diagnosed or resistant or intolerant to previous treatment.”
– 1. Baccarani, M. and Dreyling, M. Annals of Oncology. 2010;21:165-167
– 2 Kantarjian H, et al. N Engl J Med. 2010 Jun 17;362(24):2260-70.
– 3 Branford S. Hematology. 2007:376-83.
– 4 Hughes T, et al. Blood. 2006;108:28-37
[*] Complete cytogenetic response (CCyR) is defined as the absence of Philadelphia chromosome-positive metaphases on cytogenetic assessment of bone marrow cells.
[**] Major molecular response (MMR) is defined as a BCR-ABL transcript level of [less than or equal to]0.1% (3 log reduction) as measured by real-time quantitative polymerase chain reaction (RQ-PCR) of peripheral blood.