title: Distinct patterns of minimal residual disease associated with graft-versus-host disease after allogeneic bone marrow transplantation for chronic myelogenous leukemia.
abstract: OBJECTIVE
  Allogeneic bone marrow transplantation (BMT) has been shown to provide effective therapy for chronic myelogenous leukemia (CML), but previous reports have also demonstrated the persistence of bcr-abl-positive cells for months to years after BMT in the majority of patients. To evaluate the biologic significance of persistent bcr-abl-positive cells, we examined the relationship between clinical parameters known to affect the risk of relapse and the ability to detect bcr-abl-positive cells post-BMT.
  
  
  METHODS
  We analyzed 480 samples from 92 patients at two transplant centers for the presence of bcr-abl-positive cells by polymerase chain reaction (PCR). Two different BMT preparative regimens and protocols for prevention of graft-versus-host disease (GVHD) were used. One center used cyclophosphamide plus total-body irradiation (CY/TBI) and T-cell-depleted marrow; the second center used busulfan plus cyclophosphamide (Bu/CY) and untreated marrow with cyclosporine and methotrexate (Csp/MTX) as GVHD prophylaxis.
  
  
  RESULTS
  We first determined the percent of patients at each center with > or = one PCR-positive (PCR+) result at defined intervals post-BMT. Between 0 and 6 months post-BMT, the majority of patients (80% to 83%) in both populations had PCR-detectable bcr-abl-positive cells. Between 6 and 24 months post-BMT, 80% to 88% of patients who received T-cell-depleted marrow remained PCR+, as compared with 26% to 30% of patients who received unmodified marrow. After 24 months post-BMT, the percentage of PCR+ patients was not significantly different in the two populations. This pattern of detection of bcr-abl-positive cells post-BMT followed the development of chronic GVHD in patients who received unmodified marrow. All patients were also divided into three groups based on post-BMT PCR results as follows: (1) persistent PCR+ (n = 29), (2) intermittent PCR-negative ([PCR-] n = 40), and (3) persistent PCR- (n = 23). These three groups were found to have a low, intermediate, and high probability of maintaining remission and disease-free survival, respectively (P = .0001). Intermittent or persistent PCR- results, which reflect levels of minimal residual disease < or = the limit of detection by PCR, were clearly associated with both acute (P = .004) and chronic (P = .000005) GVHD. Nevertheless, 44% of patients without GVHD also had intermittent or persistent PCR- assays.
  
  
  CONCLUSIONS
  The persistence of PCR-detectable bcr-abl-positive cells early post-BMT in more than 80% of patients suggests that neither BMT preparative regimen effectively eradicates CML cells in most patients. Subsequently, acute and/or chronic GVHD are associated with a decreased ability to detect residual bcr-abl-positive cells, which suggests that immunologic mechanisms mediated by donor cells are important for inducing long-term remissions after BMT. The demonstration that 44% of patients without GVHD had either low or undetectable levels of residual leukemia suggests the presence of mechanisms capable of suppression or eradication of CML independent of GVHD.
authors.affiliation: Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA 02115, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pichert
authors.forename: D C
authors.initials: DC
authors.lastname: Roy
authors.forename: R
authors.initials: R
authors.lastname: Gonin
authors.forename: E P
authors.initials: EP
authors.lastname: Alyea
authors.forename: R
authors.initials: R
authors.lastname: Bélanger
authors.forename: M
authors.initials: M
authors.lastname: Gyger
authors.forename: C
authors.initials: C
authors.lastname: Perreault
authors.forename: Y
authors.initials: Y
authors.lastname: Bonny
authors.forename: I
authors.initials: I
authors.lastname: Lerra
authors.forename: C
authors.initials: C
authors.lastname: Murray
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001853:Bone Marrow / Q000737:chemistry*; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000032:analysis*; D006086:Graft vs Host Disease / Q000453:epidemiology* / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D016133:Polymerase Chain Reaction; D014184:Transplantation, Homologous; D016896:Treatment Outcome
chemical_list: D016044:Fusion Proteins, bcr-abl