Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial

Abstract

Therapeutic options for chronic myelogenous leukemia (CML) resistant to 400 to 600 mg imatinib are limited. Escalating imatinib doses may overcome resistance. Dasatinib, a significantly more potent inhibitor of BCR-ABL, is safe and effective in this population. Patients with imatinibresistant chronic-phase (CP) CML were randomized 2:1 to 140 mg dasatinib (n ‫؍‬ 101) or 800 mg imatinib (n ‫؍‬ 49). With a median follow up of 15 months, complete hematologic responses were observed in 93% and 82% of patients receiving dasatinib and high-dose imatinib (P ‫؍‬ .034), respectively. Dasatinib resulted in higher major cytogenetic response rates (52%) than high-dose imatinib (33%) (P ‫؍‬ .023); this included complete cytogenetic response in 40% and 16% (P ‫؍‬ .004). Major molecular responses were also more frequent with dasatinib (16% versus 4%; P ‫؍‬ 0.038). Treatment failure (hazard ratio [HR], 0.16; P < .001) and progression-free survival (HR, 0.14; P < .001) both favored dasatinib. Superficial edema (42% versus 15%) and fluid retention (45% versus 30%) were more prevalent with imatinib; pleural effusion was more common with dasatinib (17% versus 0%). Grade 3 to 4 nonhematologic toxicity was minimal. Cytopenias were more frequent and severe with dasatinib. Dasatinib represents a safe and effective therapy for CP-CML resistant to conventional imatinib doses with improved cytogenetic and molecular response rates and progression-free survival relative to high-dose imatinib. (Blood. 2007;109:5143-5150)

A bioinformatical and functional approach to identify novel strategies for chemoprevention of colorectal cancer

“…Src activation is blocked by the tyrosine kinase inhibitor dasatinib, which dually inhibits Src family kinases and Bcr-Abl, with the latter not being present in adenoma cells. Dasatinib is well tolerated and the drug has entered the clinic for patients with leukemia (Kantarjian et al, 2007). Dasatinib has shown activity against colon cancer cells in preclinical models (Serrels et al, 2006;Kopetz et al, 2009).…”

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

“…69 Results from phase 2 trials led to the approval of dasatinib in the United States, the European Union, and other regions for use in imatinib-resistant CML. [70][71][72][73] In SRC/ABL Tyrosine Kinase Inhibition Activity Research Trial C (or the START-C trial), dasatinib was administered at 70 mg twice daily to 387 patients who had CML-CP and resistance (n ¼ 288) or intolerance (n ¼ 99) to imatinib. 70 After a median follow-up of 15.2 months, 91% of patients achieved a CHR, 59% achieved an MCyR, and 49% achieved a CCyR.…”

Combined effects of novel heat shock protein 90 inhibitor NVP-AUY922 and nilotinib in a random mutagenesis screen

“…Second-generation TKIs have demonstrated increased inhibitory potency against BCR-ABL tyrosine kinase and have shown efficacy in treating patients with number of the BCR-ABL kinase domain mutations that develop on imatinib (Kantarjian et al, 2006(Kantarjian et al, , 2007Ottmann et al, 2007). Despite the significant clinical activity demonstrated in clinical trials, a number of patients do not show durable response (Garg et al, 2009).…”