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In vitro activity of imatinib in cells from patients with adult acute lymphoblastic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2005 (English)In: Anti-Cancer Drugs, ISSN 0959-4973, E-ISSN 1473-5741, Vol. 16, no 6, 631-634 p.Article in journal (Refereed) Published
Abstract [en]

We evaluated the in vitro activity of imatinib on BCR-ABL-positive and -negative tumor cells from patients with adult acute lymphoblastic leukemia (ALL), and investigated in vitro interactions between imatinib and conventional agents. A non-clonogenic cytotoxicity assay was used to analyze p190 BCR-ABL-positive (n = 4), p210 BCR-ABL-positive (n = 2) and BCR-ABL-negative (n = 9) tumor cells from adult ALL patients. The in vitro cytotoxic effect of imatinib was studied alone, and in combination with the cytotoxic agents cytarabine, prednisolone, vincristine, daunorubicin, asparaginase and mercaptopurine. The BCR-ABL-positive samples were significantly (p < 0.05) more sensitive to imatinib than the BCR-ABL-negative at the concentrations 0.1, 1 and 10 muM. Interestingly, the two p210 samples were somewhat less sensitive to imatinib than the p190 samples. Daunorubicin, prednisolone and cytarabine showed the largest benefit from combination with imatinib compared to the most active single agent. The study confirms that drug sensitivity to imatinib is specific for BCR-ABL-positive samples. The results also suggest that combinations between imatinib and daunorubicin, predisolone or cytarabine may be advantageous for the treatment of Philadelphia-positive ALL.

Place, publisher, year, edition, pages
2005. Vol. 16, no 6, 631-634 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-92962PubMedID: 15930891OAI: oai:DiVA.org:uu-92962DiVA: diva2:166295
Available from: 2005-04-27 Created: 2005-04-27 Last updated: 2013-07-04Bibliographically approved
In thesis
1. Acute Lymphoblastic Leukaemia in Adult Patients: Studies of Prognostic Factors, Treatment Results and in vitro Cellular Drug Resistance
Open this publication in new window or tab >>Acute Lymphoblastic Leukaemia in Adult Patients: Studies of Prognostic Factors, Treatment Results and in vitro Cellular Drug Resistance
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Treatment results and clinical characteristics in adult acute lymphoblastic leukaemia (ALL) were evaluated regarding three issues: a new treatment with cytarabine up-front, stem cell transplantation and a comparison between adult and paediatric treatment protocols. All studies were conducted on a national basis. Furthermore, activity of imatinib was investigated by in vitro cytotoxicity assay.

The national protocol was evaluated in 153 adult ALL patients. A high complete remission rate, 86%, was achieved with 29% overall survival at 3-years. Favourable outcome was identified in patients < 40 years with precursor B phenotype and continuous complete remission was higher for precursor B compared to T-ALL.

Stem cell transplantation was evaluated in 187 patients. No differences in outcome between allogeneic and autologous transplantation were found, with the exception of Philadelphia-positive ALL, in which allogeneic transplantation was preferable. Limited chronic graft-versus-host disease (compared to none) resulted in superior disease free survival.

The paediatric NOPHO-92 and the Adult protocols were evaluated for 243 ALL-patients. Superior remission rate and survival were achieved for 10-18 year-olds treated according to the Paediatric protocol compared to both 15-25 and 25-40 year-olds treated according to the Adult protocol. Treatment protocol was a significant prognostic factor for patients aged 15-20 years.

Fluorometric Microculture Cytotoxicity Assey was used to analyze 15 tumour cell samples from ALL patients. High concordance was determined between in vitro sensitivity to imatinib and presence of BCR-ABL. Daunorubicin, prednisolone and cytarabine had the greatest benefit from a combination with imatinib.

The national adult treatment protocol’s results were consistent with international trials regarding precursor B ALL but may be under performing for T-ALL. Adolescents may benefit from treatment according to the Paediatric protocol. No difference in outcome between allogeneic and autologous stem cell transplantation was determined except for Philadelphia-positive patients, despite the indication of a graft-versus-leukaemia effect.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 54 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 30
Keyword
Medicine, acute lymphoblastic leukaemia, adult, adolescent, chemotherapy, stem cell transplantation, in vitro assay, imatinib, Medicin
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-5768 (URN)91-554-6229-4 (ISBN)
Public defence
2005-05-19, Enghoffsalen, Akademiska sjukhuset, Ingång 50, Uppsala, 09:15
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Supervisors
Available from: 2005-04-27 Created: 2005-04-27 Last updated: 2011-06-10Bibliographically approved

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Hallböök, HeleneÅleskog, AnnaLarsson, RolfSundström, ChristerLindhagen, Elin

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