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The US Food and Drug Administration (FDA) today approved bosutinib (Bosulif, Pfizer) as a new treatment option for adult patients with previously treated Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).

Despite the availability of other therapies, there continues to be a need for additional options for CML patients, given the observed challenges with treatment-related toxicities and drug resistance, according to the manufacturer. Currently, there are no approved therapies available for CML patients who have failed treatment with imatinib (Gleevec, Novartis) and the second-generation products nilotinib (Tasigna, Novartis Oncology) and dasatinib (Sprycel, Bristol-Myers Squibb).

Bosutinib is an oral, once-daily, second-generation inhibitor of Abl and Src family kinases. It is a potent ATP-competitive inhibitor of the BCR-ABL oncogene, and unlike competitors, it has minimal inhibitory activity against c-KIT and PDGFR.

The Philadelphia chromosome is a hallmark of CML, and it initiates a series of events leading to the development of Bcr-Abl, a tyrosine kinase that causes CML cells to reproduce rapidly. Therapeutic agents such as imatinib, dasatinib, and nilotinib target the inhibition of the Abl tyrosine kinase. In addition, the Src family of nonreceptor tyrosine kinases have also been identified as potential mediators of Bcr-Abl-induced leukemogenesis.

Study 200

The approval was based on the efficacy and safety data from Study 200, a single-arm study of bosutinib that enrolled 571 patients with previously treated Ph+ CML, including those resistant or intolerant to imatinib as well as patients who were previously treated with dasatinib or nilotinib.

The study was composed of 2 parts. In part 1, chronic phase CML patients resistant to imatinib received bosutinib daily in order to determine the maximum tolerated dose. In the second part, the study was expanded to determine the efficacy and safety of bosutinib in patients in other phases of Ph+ CML, including those resistant or intolerant to imatinib therapy alone, or resistant or intolerant to imatinib and second-generation tyrosine kinase inhibitors.

The initial results from a cohort of Study 200 that included 118 patients with chronic phase Ph+ CML waspreviously presented at the American Society of Hematology 2010 annual meeting and at the 2011 annual meeting of the American Society of Clinical Oncology.

The cohort consisted of patients with Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL) who were primarily refractory to full-dose imatinib (600 mg), experienced disease progression/relapse while on full-dose imatinib, or were intolerant of any dose of imatinib. Participants were all at least 3 months post stem cell transplantation.

At 24 weeks, 33.8% of patients in chronic-phase CML, who had received previous treatment with imatinib, had a major cytogenetic response (MCyR). At a minimum follow-up of 23 months, 53.4% of patients achieved an MCyR, and of this cohort, approximately half (52.8%) had an MCyR that was sustained for at least 18 months. The median duration of MCyR has not reached for this group.

Among patients with chronic-phase CML who had been treated with imatinib and at least 1 other tyrosine kinase inhibitor (n=108), the MCyR by 24 weeks was 26.9%. With a minimum follow-up of 13 months, 32.4% achieved an MCyR, and of this group, 51.4% had an MCyR that lasted for at least 9 months. The median duration has also not been reached for this cohort.

Only 4% (n=16) of patients transformed from chronic phase to the advanced or blast phase during treatment with bosutinib.

Adverse events were similar to what has previously been reported for this agent, with the most common being diarrhea, nausea, vomiting, rash, headache, and fatigue. Grade 3/4 hematologic effects included thrombocytopenia, neutropenia, and anemia, but all were usually transient.

In August 2011, the European Medicines Agency (EMA) accepted bosutinib for review as a treatment for adult patients with newly diagnosed Ph+ CML in the chronic phase. Pfizer is now currently in discussions with the EMA to revise the indication for bosutinib in its marketing authorization application. The new plan is to seek regulatory approval that will focus on previously treated adult patients with chronic-, accelerated-, and blast-phase Ph+ CML.