title: Quantitation of mafosfamide-resistant pre-colony-forming units in allogeneic bone marrow transplantation: relationship with rate of engraftment and evidence for long-lasting reduction in stem cell numbers.
abstract: Current assays of human committed-stem cells are of limited value in predicting the rate of engraftment or in assessing the integrity of the stem cell pool after allogeneic bone marrow (BM) transplantation (BMT). We have used a limiting dilution assay of mafosfamide-resistant progenitors (pre-colony-forming units [CFU]), which are ancestral to committed progenitors such as CFU-granulocyte-macrophage (GM) to analyze the kinetics of myeloid engraftment after BMT and to assess the size of the stem cell pool at intervals up to 66 months thereafter. In 24 patients transplanted for chronic myeloid leukemia in chronic phase (eight with matched unrelated donors and 16 with sibling donors), the rate of neutrophil engraftment correlated strongly with the number of pre-CFU transfused per kilogram recipient body weight (r = .7, P < .005) but not with CFU-GM per kilogram or nucleated cells per kilogram. In 25 patients studied 6 to 66 months after allogeneic BMT, the mean number of pre-CFU in the marrow was 3.1/10(5) mononuclear cells (MNC) (median, 3.47; range, 0.4 to 23.3), compared with 24.7/10(5) MNC (median, 27.3; range, 4.2 to 180) in 25 normal subjects. CFU-GM were also reduced in these patients, but with considerable overlap into the normal range (mean +/- SD: 54 +/- 45.6 per 10(5) MNC; normal, 129 +/- 61.6). Low pre-CFU but not low CFU-GM levels were associated with reduced peripheral blood white blood cell counts in post-BMT patients. Pre-CFU and CFU-GM levels were not related to the interval posttransplant and remained low for up to 66 months. We conclude that the pre-CFU assay measures a population of stem/progenitor cells that are important in the kinetics of engraftment after allogeneic BMT. Our data suggest that pre-CFU levels may remain low for some years after BMT in humans.
authors.affiliation: Leukaemia Research Fund (LRF) Centre for Adult Leukaemia, Royal Postgraduate Medical School, London, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Kirkland
authors.forename: A
authors.initials: A
authors.lastname: Spencer
authors.forename: R J
authors.initials: RJ
authors.lastname: Davidson
authors.forename: C
authors.initials: C
authors.lastname: McDonald
authors.forename: J M
authors.initials: JM
authors.lastname: Goldman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D002452:Cell Count; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D006084:Graft Rejection / Q000473:pathology*; D006085:Graft Survival; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D011237:Predictive Value of Tests; D014184:Transplantation, Homologous
chemical_list: D000970:Antineoplastic Agents; C048341:mafosfamide; D003520:Cyclophosphamide