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BCR-ABL Antisense Oligodeoxynucleotide In Vitro Purging and
Autologous Bone Marrow Transplantation for Patients With Chronic
Myelogenous Leukemia in Advanced Phase
Paolo de Fabritiis,
Maria Concetta Petti,
Enrico Montefusco,
Maria
Stefania De Propris,
Roberta Sala,
Roberto Bellucci,
Marco Mancini,
Alessandro Lisci,
Francesco Bonetto,
Tim Geiser,
Bruno Calabretta, and
Franco Mandelli
From the Dipartimento di Biotecnologie Cellulari ed Ematologia,
Università "La Sapienza," Rome; Centro Ricerca
Sperimentale, Istituto Regina Elena, Rome, Italy; Lynx Therapeutics
Inc, Hayward, CA; and Kimmel Cancer Center, Thomas Jefferson
University, Philadelphia, PA.
BCR-ABL antisense oligodeoxynucleotides (ODN) have provided evidence
of antileukemia effect when tested in vitro against
Philadelphia-positive (Ph-pos) cells and in vivo when injected into
leukemic mice. On the basis of the results obtained in vitro at
diagnosis, eight patients with chronic myelogenous leukemia (CML) were
selected and submitted to autologous bone marrow transplantation (ABMT) with bone marrow (BM) cells purged in vitro with junction-specific (J-sp) BCR-ABL antisense ODN 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 µg/mL of antisense
ODN yielding a median recovery of 47.6% mononuclear cells, 48.8%
CD34+ cells, and 20.3% clonogenic cells. After a
conditioning regimen including busulphan and etoposide, the reinfused
treated cells allowed engraftment and hematologic reconstitution in all
patients. Evaluation of the antileukemic effect by standard cytogenetic analysis and fluorescence in situ hybridization showed a complete karyotypic response in two cases and a minimal or no response in the
other six. The patient autografted in second chronic phase died in
blast crisis 7 months after ABMT; of the seven patients autografted 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 hemopoietic
reconstitution observed in all patients make this approach feasible;
the marked karyotypic response observed in some patients and the
duration of the second chronic phase show that ODN-mediated BM purging
and autograft is a promising treatment for this high-risk group of CML.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3156-3162
© 1998 by The American Society of Hematology.
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