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Blood, 15 November 2005, Vol. 106, No. 10, pp. 3532-3537.
Prepublished online as a Blood First Edition Paper on July 28, 2005; DOI 10.1182/blood-2005-04-1640.
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Submitted April 22, 2005
Accepted July 5, 2005
In vitro profiling of the sensitivity of pediatric leukemia cells to Tipifarnib (ZarnestraTM): Identification of T-cell ALL and FAB M5 AML as the most sensitive subsets
Bianca F Goemans*, Christian M Zwaan, Amy Harlow, Anne H Loonen, Brenda E Gibson, Karel Hahlen, Dirk Reinhardt, Ursula Creutzig, Michael C Heinrich, and GertJan J Kaspers
Dept. of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands
Dept. of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands; Dept. of Pediatric Hematology/Oncology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health Sciences University Cancer Institute and Portland VA Medical Center, Portland, Oregon, USA
MRC Childhood Leukaemia Working Party, Glasgow, United Kingdom
Dept. of Pediatric Hematology/Oncology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands; Dutch Childhood Oncology Group, The Hague, The Netherlands
AML-BFM Study Group, Munster, Germany
* Corresponding author; email: bf.goemans{at}vumc.nl.
Although the prognosis of pediatric leukemias has improved considerably, many patients still relapse. Tipifarnib (ZarnestraTM), a farnesyl transferase inhibitor (FTI), was developed to target malignancies with activated RAS, including leukemia. We tested 52 pediatric acute myeloid leukemia (AML) and 36 pediatric acute lymphoblastic leukemia (ALL) samples for in vitro sensitivity to Tipifarnib using a total cell-kill assay and compared these results to those obtained with normal bone marrow (N BM) samples (n=25). AML samples were more sensitive to Tipifarnib compared to B-cell precursor ALL (BCP ALL) or N BM samples. Within AML, FAB M5 samples were most sensitive to Tipifarnib. T-ALL samples were significantly more sensitive than BCP ALL and N BM samples. In AML there was a marked correlation between Tipifarnib resistance and daunorubicin or etoposide resistance, but not to cytarabine or 6-thioguanine. RAS mutations were present in 32% of AML and 18% of ALL samples, but there was no correlation between RAS mutational status and sensitivity to Tipifarnib. Future studies are needed to identify biomarkers predictive of Tipifarnib sensitivity. In addition, clinical studies, especially in T-cell ALL, seem warranted.
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