few months of remission. It is unclear if survival among treated patients would exceed that expected by the natural history of this chronic disease.

Autografts for CML have been one of the first places that gene-directed therapy with antisense oligodeoxynu-cleotides (AS-ODN) have been employed. Two pilot studies deserve note. Not surprisingly, AS-ODN directed against BCR-ABL were the first target to be tested in CML. Eight patients in transformation to advanced disease were subjected to autologous transplantation using marrow that had had antisense against BCR-ABL incubating for 24-72 hours prior to cyropreservation. Two patients had a complete cytogenetic response by FISH. The remainder had minimal or no response. Toxicity was negligible. Another oligodeoxynucleotide target protein has been the c-myb proto-oncogene,55 which is felt to play an essential role in both hematopoiesis and leukemogenesis. Because leukemia cells show enhanced reliance upon myb's ability to transactivate a number of important growth regulatory genes important in CML, myb inhibition is an attractive therapeutic target in this disease. Twenty-four patients underwent bone marrow harvest with incubation of their marrow for either 24 or 72 hours in AS-ODN targeted against c-myb. After conditioning with busulfan with or without cytoxan, the purged marrow cells were reinfused. Myb and RNA transcript numbers decreased appreciably in approximately half of patients. Two patients achieved a complete cytogenetic response and three more had major cytogenetic responses. However, unlike the AS-ODN targeted against BCR-ABL, significant delayed engraftment was seen among all those treated with 72-hour incubation, requiring back up marrow infusion in a number of patients.

Imatinib has been utilized both prior to harvesting and following autologous transplantation.5657 Given its impressive success in upfront CML therapy, the number of autologous stem cell transplants that have been performed for this disease has plummeted.

However, imatinib has only transient activity in advanced phase disease.58 A role for imatinib in combination with autografting may ultimately be established among patients initially presenting with advanced phase disease who are either poor candidates for allogeneic transplant or lack suitable donors. Several groups have shown that Ph~ stem cell collection is feasible among patients treated with complete cytogenetic responses to imatinib who are mobilized with GCSF.59

Because approximately one quarter of patients treated with imatinib will achieve more than 3 log reduction or even molecular clearance of BCR-ABL, these patients could be considered ideal candidates for harvesting of stem cells, either for immediate use or during disease progression period on imatinib. At present, one remaining question is: for whom would this approach be warranted? Patients with negative quantitative PCR studies for BCR-ABL would initially seem to be attractive candidates, since these patients are most likely to be able to mobilize BCR-ABL negative harvests as measured by PCR. Yet disease progression models consider such patients to be at the lowest risk of progression, with current estimates ranging as low as less than 1% risk of progression/year.60 Those for whom disease control is suboptimal and progression is probable are unlikely to produce uncontaminated grafts even with imatinib.

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