7
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Imatinib mesylate (IM), an original Abl tyrosine kinase inhibitor, entered the clinics in 1998 for the treatment of patients with chronic myeloid leukemia (CML). The drug is universally considered the treatment of choice for most, if not all, patients with CML. Importantly, lessons learned from patients with CML have been applied successfully for the treatment of patients with other disorders where IM has since been found to be active by virtue of its ability to target other kinases, such as c-kit in patients with gastrointestinal stromal tumors. IM is associated with mild to moderate toxicity, mostly reversible by dose reduction or discontinuation of the drug. Most adverse effects occur within the first 2 years of starting therapy; however, late effects, many being unique, are now being recognized. In this report, we assess the toxicity associated with IM, with an emphasis on the long-term adverse effects.

          Related collections

          Most cited references 60

          • Record: found
          • Abstract: found
          • Article: not found

          Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

          The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.

            Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.

              Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.
                Bookmark

                Author and article information

                Journal
                Biologics
                Biologics: Targets & Therapy
                Biologics : Targets & Therapy
                Dove Medical Press
                1177-5475
                1177-5491
                2010
                2010
                02 December 2010
                : 4
                : 315-323
                Affiliations
                [1 ]University of Tennessee Medical College, Memphis, Tennessee, USA;
                [2 ]Guy’s and St Thomas’ NHS Hospital, Great Maze Pond, London, UK
                Author notes
                Correspondence: Tariq I Mughal, Guy’s and St Thomas’s NHS Hospital, Great Maze Pond, London SE19RT, UK, Email tmughal911@ 123456hotmail.com
                Article
                btt-4-315
                10.2147/BTT.S5775
                3010822
                21209726
                © 2010 Mughal and Schrieber, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Review

                Molecular medicine

                chronic myeloid leukemia, chronic phase, imatinib mesylate

                Comments

                Comment on this article