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Evaluation of antileukaemic effects of rapamycin in patients with imatinib‐resistant chronic myeloid leukaemia
Author(s) -
Sillaber C.,
Mayerhofer M.,
Böhm A.,
Vales A.,
Gruze A.,
Aichberger K. J.,
Esterbauer H.,
Pfeilstöcker M.,
Sperr W. R.,
Pickl W. F.,
Haas O. A.,
Valent P.
Publication year - 2008
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.2007.01892.x
Subject(s) - imatinib , sirolimus , medicine , myeloid , pharmacology , pi3k/akt/mtor pathway , myeloid leukemia , cancer research , in vivo , immunology , biology , apoptosis , microbiology and biotechnology , biochemistry
ABSTRACT Background Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML). Patients and methods We treated six patients with imatinib‐resistant CML in haematological relapse (leukocytes > 20 000 µL −1 ) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose‐adjustment allowed to reach a target rapamycin serum concentration of 10–20 pg mL −1 . Results A major leukocyte response with decrease to less than 10 000 µL −1 was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by 3 H‐thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib‐resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors. Conclusions Rapamycin shows antileukaemic effects in imatinib‐resistant CML in vitro and in vivo . Larger trials with rapamycin or rapamycin‐derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.