In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia
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Sara Strese1, Saadia Bashir Hassan1, Ebba Velander2, Caroline Haglund1, Martin Höglund3, Rolf Larsson1, Joachim Gullbo1,2
1Department of Medical Sciences, Division of Cancer Pharmacology and Computational Medicine, Uppsala University, Uppsala, Sweden
2Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
3Department of Medical Sciences, Division of Hematology, Uppsala University, Uppsala, Sweden.
Joachim Gullbo, email: Joachim.Gullbo@medsci.uu.se
Keywords: melflufen, drug development, alkylator, pre-clinical, acute myeloid leukemia
Received: May 20, 2016 Accepted: November 06, 2016 Published: December 10, 2016
The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34+ progenitor cells and a more differentiated CD34+ derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.
Saadia Bashir Hassan
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