Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: Efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily

摘要: Patients with chronic myeloid leukemia (CML) who progress from the phase (CML-CP) to blast (CML-BP) have a poor prognosis.1 In these patients, conventional chemotherapy regimens are of limited value, and 2-year survival rates after allogeneic stem cell transplantation (SCT) do not exceed 20%.1 CML is characterized by presence Philadelphia chromosome (Ph), which encodes oncogenic breakpoint cluster region-Abelson murine viral fusion protein (BCR-ABL) tyrosine kinase.2 Although BCR-ABL gene expression sufficient for initiation sustenance CML-CP, crisis often additional molecular cytogenetic defects. It believed that defects orchestrated through both BCR-ABL-dependent BCR-ABL-independent mechanisms.2 Imatinib (Glivec/Gleevec; Novartis, Basel, Switzerland) kinase inhibitor (TKI) used in treatment CML.3,4 Whereas this drug has dramatically improved prognosis patients hematologic remission imatinib CML-BP low (remission rate, 7.9%–26%) short duration (median, 6–10 months).4–6 The development primary acquired resistance involves multiple mechanisms, including mutations activation SRC family kinases (SFK).7,8 Dasatinib (Sprycel; Bristol-Myers Squibb, New York, NY), multikinase an vitro potency against unmutated 325 times greater than imatinib, inhibits most known mutants.9,10 also other kinases, SFK.9 Orally administered dasatinib produced consistent clinical benefit accelerated (CML-AP), CML-BP, Ph-positive acute lymphoblastic (ALL) resistant or intolerant approved use at dosing regimen 70 mg twice daily.11–15 A 3 dose-optimization study imatinib-resistant CML-CP demonstrated 100 once daily had similar efficacy tolerability relative daily16; consequently, currently recommended initial dose daily. Because once-daily been evaluated advanced-phase CML, trial was designed assess 140 versus CML-AP, ALL intolerance imatinib. Data follow-up available now, results subset reported here.