BCR-ABL ANTISENSE OLIGODEOXYNUCLEOTIDE IN-VITRO PURGING AND AUTOLOGOUS BONE-MARROW TRANSPLANTATION FOR PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA IN ADVANCED PHASE

BCR-ABL antisense oligodeoxynucleotides (ODN) have provided evidence o f antileukemia effect when tested in vitro against Philadelphia-positi ve (Ph-pos) cells and in vivo when injected into leukemic mice. On the basis of the results obtained in vitro at diagnosis, eight patients w ith chronic myelogenous leukemia (CML) were selected and submitted to autologous bone marrow transplantation (ABMT) with bone marrow (BM) ce lls purged in vitro with junction-specific (J-sp) BCR-ABL antisense OD N at the time of transformation in accelerated phase or during second chronic phase. Mononuclear BM cells were treated in vitro for 24 or 72 hours with 150 mu g/mL of antisense ODN yielding a median recovery of 47.6% mononuclear cells, 48.8% CD34(+) cells, and 20.3% clonogenic ce lls, After a conditioning regimen including busulphan and etoposide, t he reinfused treated cells allowed engraftment and hematologic reconst itution in all patients, Evaluation of the antileukemic effect by stan dard cytogenetic analysis and fluorescence in situ hybridization showe d a complete karyotypic response in two cases and a minimal or no resp onse in the other six, The patient autografted in second chronic phase died in blast crisis 7 months after ABMT; of the seven patients autog rafted in transformation, three developed blast crisis 21 to 39 months after reinfusion, one died from unrelated BMT complications 30 months after ABMT, and three are in persistent second chronic phase 14 to 26 months after autograft, The low toxicity of the protocol and the hemo poietic reconstitution observed in all patients make this approach fea sible; the marked karyotypic response observed in some patients and th e duration of the second chronic phase show that ODN-mediated BM purgi ng and autograft is a promising treatment for this high-risk group of CML. (C) 1998 by The American Society of Hematology.