Treatment with the investigational drug bosutinib produced promising rates of response among patients with chronic-phase chronic myeloid leukemia (CML) that had previously been treated with Gleevec® (imatinib). The results of this Phase I/II trial were published in Blood.
Each year in the United States, approximately 5,000 people are diagnosed with CML. Most cases of CML are characterized by a chromosomal abnormality—the Philadelphia chromosome—in which genetic material is exchanged between chromosome 9 and chromosome 22. This exchange brings together two genes: BCR and ABL. The combination of these two genes into the single BCR-ABL gene results in the production of a protein that contributes to uncontrolled cell growth.
Recognition of the pivotal role of the BCR-ABL protein in CML led to the development of Gleevec, which blocks the activity of this protein. Gleevec produced high rates of remission among patients with chronic-phase CML and dramatically changed the treatment of this disease. Newer drugs that target the BCR-ABL protein include Tasigna® (nilotinib) and Sprycel® (dasatinib). Both Tasigna and Sprycel appear to be superior to Gleevec for the initial treatment of patients with CML and are approved by the FDA for this purpose.
Bosutinib is a third-generation tyrosine kinase inhibitor that targets both Abl and Src kinases. Targeting of Src by bosutinib is thought to be important as over-expression of Src kinases has been associated with resistance to Gleevec.
To evaluate bosutinib among CML patients who were resistant to Gleevec or who could not tolerate Gleevec, researchers conducted a Phase I/II clinical trial among 288 patients. All had CML in chronic phase and all had previously been treated with Gleevec.
- At six months, 31% of patients had a major cytogenetic response.
- After two years, 86% of patients had a complete hematologic remission, 53% had a major cytogenetic response, and 64% of those with a complete cytogenetic response had a major molecular response.
- Two-year overall survival was 92% and two-year survival without cancer progression was 79%.
- The most common side effect of treatment was mild or moderate diarrhea.
These results suggest that bosutinib may be effective and generally well tolerated for the treatment of chronic-phase CML that has previously been treated with Gleevec.
Reference: Cortes JE, Kantarjian HM, Brummendorf TH et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive CML patients with resistance or intolerance to imatinib. Blood. Early online publication August 24, 2011.