Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily: two-year follow-up of a randomized phase 2 study (START-R).
ABSTRACT In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg.
A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49).
At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012).
After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.
Full-textDOI: · Available from: Nelson Hamerschlak, Jun 27, 2015
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ABSTRACT: Tyrosine kinase inhibitors (TKIs) have dramatically improved the results of therapy of chronic myeloid leukemia. However the management with more potent second generation TKIs (2GTKIs) is required for imatinib-intolerant and imatinib-resistant patients. The frontline use of 2GTKIs results in higher rates of deeper and faster responses than with imatinib, it can enable many patients to qualify for participation in studies of treatment-free remission. The BCR/ABL transcript level at 3 months of TKI treatment has become a new prognostic factor. In this paper the recent clinical results of chronic myeloid leukemia therapy with imatinib in first line and with 2GTKIs in first and second line settings are reviewed, and updated PALG recommendations regarding the diagnosis, standard monitoring procedures, definitions of responses and treatment are presented.Acta haematologica Polonica 10/2013; DOI:10.1016/j.achaem.2013.07.008
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ABSTRACT: Dasatinib is a dual Abl/Src tyrosine kinase inhibitor (TKI) designed as a prototypic short-acting BCR-ABL-targeted TKI that inhibits BCR-ABL with greater potency compared with imatinib, nilotinib, bosutinib, and ponatinib and has been shown to have potential immunomodulatory effects. Dasatinib is approved for the treatment of all phases of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to prior imatinib treatment and first-line treatment for CML in chronic phase. In this article, the development of dasatinib as a treatment for patients with CML is reviewed. This is a review of the relevant literature regarding dasatinib development in CML (2003-2013). Dasatinib demonstrates efficacy against most BCR-ABL mutations arising during imatinib therapy and is effective in treating patients with imatinib resistance due to other mechanisms. Randomized trial data show that first-line dasatinib provides superior responses compared with imatinib and enables patients to achieve early, deep responses correlated with improved longer-term outcomes. Dasatinib has a generally acceptable safety profile, with most adverse events (AEs) proving manageable and reversible. Cytopenias are commonly observed with dasatinib, and some nonhematologic AEs including pleural effusion have been consistently reported. Dasatinib is an effective treatment option for patients with CML.Journal of Cancer Research and Clinical Oncology 08/2013; 139(12). DOI:10.1007/s00432-013-1488-z · 3.01 Impact Factor
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ABSTRACT: Since its approval in 2001 for frontline management of chronic myelogenous leukemia (CML), imatinib has proven to be very effective in achieving high remission rates and improving prognosis. However, up to 33% of patients will not achieve optimal response. This has led researchers to develop new second- and third-generation tyrosine kinase inhibitors. In this article, we review the mechanisms of resistance, recommendations for monitoring, assessment of milestones, and management options for patients with CML who are resistant to imatinib therapy. We further explain the potential pitfalls that can lead to unnecessary discontinuation, the prognosis of patients whose condition fails to respond to treatment, and the upcoming therapies.04/2013; 4(2):103-17. DOI:10.1177/2040620712468289