title: Philadelphia chromosome-negative engraftment after autologous transplantation with granulocyte-macrophage colony-stimulating factor for chronic myeloid leukemia.
abstract: Autologous bone marrow transplantation (BMT) has not been curative in chronic myeloid leukemia (CML), because of the inability to purge CML from the autograft and the absence of the allogeneic T cell-mediated antileukemic activity. However, recent advances demonstrate that normal progenitors can be selected from CML marrows by a variety of techniques, including isolation by their small size. Furthermore, we found that myeloid growth factors have a potent antileukemic effect against CML progenitors in vitro by inducing their terminal differentiation. Based on these data, we initiated a trial of autologous BMT in patients with high-risk CML. Autografts were processed in an attempt to enrich for normal progenitors, first by isolating small cells by counterflow centrifugal elutriation and then incubating them in granulocyte-macrophage colony-stimulating factor (GM-CSF) for 72 hours. After a conditioning regimen of busulfan and cyclophosphamide, all patients received GM-CSF daily for 2 months. The median age of the 13 patients in the trial was 45 years (range 17-56 years). The median duration of disease before BMT was 24 months (range 13-72 months). Eight patients were in chronic phase (CP), and five were in accelerated phase (AP). All patients failed to achieve a cytogenetic response to interferon-alpha and were 100% Philadelphia chromosome (Ph)+ before BMT. There were three transplant-related deaths, all AP patients. All of the remaining 10 patients engrafted with some degree of Ph- hematopoiesis; despite high-risk features, nine patients engrafted 100% Ph-. All patients relapsed cytogenetically at a median of 6 months (range 4-22 months). These results demonstrate that autologous BMT can consistently induce complete Ph- engraftment in CP patients. GM-CSF appears to produce a clinical antileukemic effect against CML after autologous BMT.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, Maryland 21287-8967, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Gladstone
authors.forename: A
authors.initials: A
authors.lastname: Bedi
authors.forename: C B
authors.initials: CB
authors.lastname: Miller
authors.forename: S J
authors.initials: SJ
authors.lastname: Noga
authors.forename: C A
authors.initials: CA
authors.lastname: Griffin
authors.forename: S
authors.initials: S
authors.lastname: Piantadosi
authors.forename: P J
authors.initials: PJ
authors.lastname: Cagnoni
authors.forename: R A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: B D
authors.initials: BD
authors.lastname: Smith
authors.forename: T T
authors.initials: TT
authors.lastname: Douglas
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D016026:Bone Marrow Transplantation / Q000379:methods* / Q000401:mortality; D002469:Cell Separation / Q000379:methods; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006133:Growth Substances / Q000627:therapeutic use; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000401:mortality / Q000628:therapy*; D015465:Leukemia, Myeloid, Accelerated Phase / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D012008:Recurrence; D015996:Survival Rate; D014182:Transplantation, Autologous
chemical_list: D006133:Growth Substances; D016178:Granulocyte-Macrophage Colony-Stimulating Factor