Ponatinib Combination with Hyper-CVAD in Ph-Positive ALL
Leukemia Insights - Spring 2012
Hyper-CVAD has good activity in Philadelphia-positive B-ALL, with CR rates of 90 percent. Despite improvement in CR rates and median CR durations compared with earlier published ALL regimens, three-year survival and disease-free survival are less than 10 percent. Thomas et. al. have reported CR rates of 94 percent using hyper-CVAD and imatinib. Long-term follow-up of patients who received the hyper-CVAD and imatinib regimen continue to demonstrate favorable disease- free survival rates compared with hyper-CVAD alone.
Dasatinib is 325-fold more potent than imatinib in cells transduced with wild-type BCR-ABL, and has demonstrated preclinical activity against 18 of 19 imatinib-resistant BCR-ABL mutants. We are currently conducting a Phase II study to evaluate the clinical efficacy of an intensive short-term chemotherapy regimen (Hyper-CVAD program) given in combination with the tyrosine kinase inhibitor dasatinib for Philadelphia-positive acute lymphoblastic leukemia. Interim results from this study have been encouraging, with a CR rate of 94 percent, median disease-free survival and median overall survival have not been reached, and an estimated 2-year survival of 64%10.
In several front-line studies of Ph-positive ALL, relapses were noted with a high incidence of T315I mutation. This mutation is sensitive to ponatinib, a third- generation pan-BCR-ABL inhibitor. Therefore, combining ponatinib and chemotherapy in Ph-positive ALL might enhance overall activity, reduce resistance resulting from T315I clones and improve cures. We have designed a study combining hyper-CVAD and ponatinib 45 mg orally daily. This study is open for newly diagnosed Ph-positive ALL, including patients who have received one cycle of chemotherapy.