Gleevec scientific update |
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Haematologica. 2008 Aug 25.
Kancha RK, von Bubnoff N, Miething C, Peschel C, Götze KS, Duyster J.
Klinikum rechts der Isar, Technical University of Munich, Germany.
Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation.
Treatment with imatinib is very effective in Bcr-Abl positive leukemia. However, development of resistance to this drug is a common phenomenon in late stage disease. The Bcr-Abl protein localizes to the cytoplasm in transformed cells but can enter the nucleus upon treatment with imatinib. Using leptomycin B (LMB), a nuclear export blocker, it has been shown that reactivated nuclear Bcr-Abl kinase activity can induce cell death, thus presenting an interesting potential treatment option for imatinib resistant disease. Here we show that the combination of imatinib and LMB effectively induces cell death in imatinib-resistant Ba/F3 cells which display Bcr-Abl amplification or signs of clonal evolution. However, no such synergism is observed in imatinib-resistant Ba/F3 cells carrying the T315I mutation of Bcr-Abl or those which have lost Bcr-Abl expression. Thus, a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.
Ther Clin Risk Manag. 2008 Feb;4(1):149-62.
Din OS, Woll PJ.
Academic Department of Clinical Oncology, University of Sheffield Weston Park Hospital, Sheffield, UK.
Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate.
Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.
Anticancer Res. 2008 Jul-Aug;28(4C):2317-20.
Pectasides D, Nikolaou M, Pectasides E, Koumarianou A, Valavanis C, Economopoulos T.
Second Department of Internal Medicine, Propaedeutic, Oncology Section, General Hospital Attikon, University of Athens, Haidari, Athens, Greece.
Complete response after imatinib mesylate administration in a patient with chemoresistant stage IV seminoma.
The case of a young man with stage IV chemoresistant pure seminoma overexpressing KIT, who achieved complete remission (CR) after the administration of imatinib mesylate (400 mg once daily), along with a third-line chemotherapy regimen, consisting of paclitaxel (150 mg/m2), oxaliplatin (100 mg/m2) and gemcitabine (800 mg/m2) every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support is reported. The patient had received first- and second-line regimens consisting of ifosfamide, bleomycin, etoposide cisplatin (5 cycles, every 3 weeks) and methotrexate, vinblastine, actinomycin D, cyclophosphamide, cisplatin (3 cycles, every 3 weeks) respectively, without having normalized beta-human chorionic gonadotrophin (beta-HCG) levels. Following treatment with imatinib plus third-line chemotherapy (paclitaxel, oxaliplatin, gemcitabine), the levels of beta-HCG were reduced to within the normal limits during the first month of treatment. Therefore, the patient underwent surgical resection of the residual disease from the retroperitoneum and liver, which proved to be only necrotic tissue. The patient is under close follow-up, with no evidence of disease, 36 months after the completion of chemotherapy and 32 months post surgery.
Leukemia. 2008 Aug 28.
Cortes J, Kim DW, Raffoux E, Martinelli G, Ritchie E, Roy L, Coutre S, Corm S, Hamerschlak N, Tang JL, Hochhaus A, Khoury HJ, Brümmendorf TH, Michallet M, Rege-Cambrin G, Gambacorti-Passerini C, Radich JP, Ernst T, Zhu C, Van Tornout JM, Talpaz
Department of Leukemia; MD Anderson Cancer Center, Houston, TX, USA.
Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase.
Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in
Bone Marrow Transplant. 2008 Sep 1.
Magro L, Catteau B, Coiteux V, Bruno B, Jouet JP, Yakoub-Agha I.
Service des Maladies du Sang, Lille, France.
Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD.
Treatment of sclerodermatous chronic GVHD (cGVHD) remains disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFbeta) and PDGF pathways. Recently, the drug's effects on fibroblasts have been reported in both in vitro and in vivo studies. The inhibition of fibroblast growth and decreased collagen production in dermal fibroblasts is thus a logical therapeutic approach. Two patients who developed refractory sclerodermatous cGVHD following allo-SCT received imatinib mesylate at the dose of 400 mg/day. In both patients, the scleroderma symptoms disappeared within 3 months of initiation of the treatment. At the time of this report, the two patients were both alive and had a very good skin response. This report shows that imatinib is effective in patients with refractory sclerodermatous cGVHD. Considering its well-documented clinical profile in other diseases, imatinib is a promising candidate for the treatment of sclerodermatous cGVHD.
Scott Med J. 2008 Aug;53(3):8-12.
Shepherd P, Dhanapala C, Maguire C, White J, Drummond M, Holyoake T, Johnson PR.
Department of Haematology, Western General Hospital, Edinburgh.
Successful use of National Cancer Registry data to monitor the effective use of imatinib for treating chronic myeloid leukaemia.
Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources. METHODS: All imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML. RESULTS: One hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases. CONCLUSIONS: We believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases.
Curr Clin Pharmacol. 2008 Sep;3(3):198-203.
Pursche S, Schleyer E, von Bonin M, Ehninger G, Said SM, Prondzinsky R, Illmer T, Wang Y, Hosius C, Nikolova Z, Bornhäuser M, Dresemann G.
Carl-von-Basedow Klinikum Merseburg, Abteilung Innere Medizin II, Weibetae Mauer 52, 06217 Merseburg, Germany.
Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients.
Background: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine - as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine - are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). Methods: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). Results: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). Conclusion: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008 Jun;152(1):121-3.
Skoumalova I, Vondrakova J, Rohon P, Rozmanova S, Jarosova M, Indrak K, Prochazka M, Santava A, Faber E.
Department of Hemato-Oncology, Teaching Hospital Olomouc, Czech Republic.
Successful childbirth in a patient with chronic myelogenous leukemia treated with imatinib mesylate during early pregnancy.
Aims: To report a case of successful pregnancy in a patient with chronic myelogenous leukemia treated with imatinib mesylate for the first 4 months of pregnancy. Results: Imatinib mesylate is potentially teratogenic and its use during pregnancy in humans can lead to abortion or development of fetal abnormalities in nearly 40% of fully reported cases. We report a case of a 28-year-old woman who delivered a healthy child of normal weight after having been treated with imatinib for Ph1-positive CML during the first four months of her pregnancy. She refused advocated interruption and for the rest of the pregnancy was treated with interferon. The treatment was associated with a rapid 2-log increase in the leukemia clone measured by the real-time polymerase chain reaction. Reintroduction of imatinib after delivery resulted in achievement of the complete cytogenetic response again. Conclusions: We discuss possible strategies for successful management of pregnancy in CML patients treated with imatinib.
Cancer Lett. 2008 Sep 20
Weigel MT, Meinhold-Heerlein I, Bauerschlag DO, Schem C, Bauer M, Jonat W, Maass N, Mundhenke C.
Department of Obstetrics and Gynecology, Breast Center, University Hospital Schleswig-Holstein, Campus Kiel, Michaelisstrasse 16, 24105 Kiel, Germany.
Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling.
INTRODUCTION: Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR alpha and beta, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival. METHODS: Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10muM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay. RESULTS: Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR beta and Akt was detected. CONCLUSIONS: The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients.
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Drug category:Anti-cancer drugs
 Gleevec scientific update
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