A Phase II Trial of Autologous Bone Marrow Transplantation (ABMT) in Acute Leukemia with Edelfosine Purged Bone Marrow
Alkyl-lysophospholipids are analogs of naturally occurring lyso-phospholipids initially synthesized as immunologic modifiers to render macrophages more cytocidal to tumor cells1. However, early experiments indicated that these compounds had direct anti-tumor activity 2. In addition, it was found that these compounds were selectively toxic to tumor cells and had less effect on normal cells3–5. The most active of these compounds was 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, formerly termed ET-18OCH3 and more recently named edelfosine. If indeed the compounds were selectively toxic to leukemic cells and spared normal cells, particularly normal bone marrow progenitor cells, they might prove effective in purging leukemic cells from remission marrows in patients with acute leukemia who were candidates for ABMT. Incubation of human leukemic cell lines and freshly obtained leukemic cells from patients demonstrated that the compounds were active whether measured by viability, tritiated thymidine incorporation or clonogenic assays 6–8. When a sensitive cell line (HL60) was mixed with normal marrow cells and incubated with varying doses of edelfosine for 1 to 4 hours it was found that a 4 hour incubation with 50 μg/ml eliminated clonogenic leukemic cells with no effect on normal marrow progenitor cells 9. In a murine leukemic model in which a remission marrow was simulated by mixing WEHI 3/b leukemic cells with normal murine marrow cells and exposing the mixture in vitro to edelfosine prior to injection intravenously into lethally irradiated littermates resulted in a dose responsive prolongation of survival with apparent cures 10. Similar results were obtained after freezing and thawing the mixture prior to injection11. Following these results a phase I clinical trial was initiated and the results have been published 12. It was found that a 4 hour incubation at a dose of 75 µ/ml was the optimal dose for purging. Based on these results a phase II trial was designed with participation by multiple institutions.
KeywordsComplete Remission Leukemic Cell Acute Leukemia Peripheral Blood Stem Cell Autologous Bone Marrow Transplantation
Unable to display preview. Download preview PDF.
- 1.Munder PG, Weltzien HU, Modolell M: Lysolecithin analogs: a new class of immunopotentiators. Immunodeficiency and immunostimulation, in Miescher PA (ed): Seventh international symposium on immunopathology, Basel/Stuttgard, Schwabe & Co, 1976, p 411Google Scholar
- 2.Munder PG, Modolell M, Bausert W, Oettgen HF, Westphal O: alkyllysophospholipids in cancer therapy, in Hersh EM (ed): Augmenting agents in cancer therapy, New York, Raven Press, 1981, p 441Google Scholar
- 4.Modelell M, Andreesen R, Pahlke W, Brugger U, Munder PG: Disturbance of phospholipid metabolism by the selective destruction of tumor cells by alkyl-lysophospholipids. Cancer Res 39: 4681, 1979Google Scholar
- 13.Gorin NC, Aegerter P, Auvert B, Meloni B, Goldstone AH, Burnett A, Carella A, Korbling M, Herve P, Maraninchi D, Lowenberg R, Verdonck LF, de Planque M, Hermans J, Helbig W, Porcellini A, Rizzoli V, Alesandrino EP, Franklin IM, Reiffers J, Colleselli P, Goldman JM: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75: 1606, 1990PubMedGoogle Scholar
- 14.Laporte JP, Douay L, Lopez M, Labopin M, Jouet JP, Lesage S, Stachowiak L, Fouillard L, Isnard F, Noel-Walter MP, Pene F, Deloux J, Van Dan Akker J, Bauters F, Najman A, Gorin NC: One hundred twenty-five adult patients with primary acute leukemia autografted with marrow purged by mafosfamide: a 10-year single institution experience. Blood 84: 3810, 1994PubMedGoogle Scholar