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- Baccarani, Michele, et al.
(författare)
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Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia : a European LeukemiaNet Study
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 113:19, s. 4497-4504
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Tidskriftsartikel (refereegranskat)abstract
- Imatinib mesylate (IM), 400 mg daily, is the standard treatment of Philadelphia-positive (Ph(+)) chronic myeloid leukemia (CML). Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. To investigate whether the systematic use of a higher dose of IM could lead to better results, 216 patients with Ph(+) CML at high risk (HR) according to the Sokal index were randomly assigned to receive IM 800 mg or 400 mg daily, as front-line therapy, for at least 1 year. The CCgR rate at 1 year was 64% and 58% for the high-dose arm and for the standard-dose arm, respectively (P = .435). No differences were detectable in the CgR at 3 and 6 months, in the molecular response rate at any time, as well as in the rate of other events. Twenty-four (94%) of 25 patients who could tolerate the full 800-mg dose achieved a CCgR, and only 4 (23%) of 17 patients who could tolerate less than 350 mg achieved a CCgR. This study does not support the extensive use of high-dose IM (800 mg daily) front-line in all CML HR patients. This trial was registered at www.clinicaltrials.gov as #NCT00514488.
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| 5. |
- Porkka, Kimmo, et al.
(författare)
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Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:4, s. 1005-12
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Tidskriftsartikel (refereegranskat)abstract
- Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
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| 6. |
- Porkka, Kimmo, et al.
(författare)
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Suboptimal responses in chronic myeloid leukemia : milestones and mechanisms
- 2009
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Ingår i: Expert Review of Hematology. - : Informa UK Limited. - 1747-4086 .- 1747-4094. ; 2:1, s. 81-91
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Tidskriftsartikel (refereegranskat)abstract
- Patients with chronic myeloid leukemia who fail to achieve timely treatment responses have a worse prognosis. Although many patients respond well to first-line treatment with imatinib, a significant proportion relapse or experience an inadequate response. Since effective alternative Bcr-Abl inhibitors are available (i.e., dasatinib or nilotinib), several regional groups have proposed milestones for imatinib failure or suboptimal response based on the achievement of specified levels of response within a defined treatment duration. A suboptimal response indicates that, although patients may continue to receive a benefit from continuing imatinib treatment at the assigned dose, long-term outcome may be better with an alternative strategy. The underlying mechanisms behind suboptimal responses are multifactorial and may differ from those causing relapse.
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