title: Loss of marrow reserve from dose-intensified chemotherapy results in impaired hematopoietic reconstitution after autologous transplantation: CD34(+), CD34(+)38(-), and week-6 CAFC assays predict poor engraftment.
abstract: Autologous hematopoietic stem cell transplantation (HSCT) is an increasingly successful modality for treating a variety of malignant disorders in the clinic. Experimental and clinical data suggest that prior exposure to cytotoxic agents that damage primitive stem cells results in impaired hematopoiesis after autologous HSCT. To further investigate the ability to predict for impaired hematopoiesis, we measured different stem/progenitor cell populations transplanted and time to engraftment. Patients with previously untreated, advanced-stage follicular lymphoma were treated in sequential prospective protocols with 6-8 cycles of standard-dose (SD) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or four cycles of a higher-dose (HD) CHOP and granulocyte colony-stimulating factor, to induce remission prior to high-dose cyclophosphamide, total body irradiation, and autologous bone marrow transplantation (ABMT). Cryopreserved marrow samples obtained prior to ABMT were assayed for CD34(+), CD34(+)38(-), and cobblestone area-forming cell (CAFC) frequencies. Despite receiving similar numbers of nucleated cells at ABMT, HD-CHOP patients took significantly longer to attain platelet engraftment than the SD-CHOP patients. Marrow from the HD-CHOP patients contained significantly lower CD34(+), CD34(+)38(-), and week 6-8 CAFC frequencies than marrow from SD-CHOP-treated patients. Time to platelet engraftment was plotted against progenitor/stem cell numbers transplanted for each patient and threshold values were developed for all three stem/progenitor cell populations. These values were 0.5 x 10(6) CD34(+) cells/kg, 0.14 x 10(6) CD34(+)38(-) cells/kg, and 9500 week-6 CAFC/kg transplanted. Approximately 50% of patients received marrow progenitor/stem cell numbers above the threshold values and all engrafted without delay. However, transplantation of stem/progenitor cell numbers below threshold values did not uniformly predict for delayed platelet engraftment. These data provide further evidence for the association of low marrow reserve at ABMT, low numbers of stem/progenitor cells transplanted, and delayed hematopoietic recovery. However, there remains a group of patients who have rapid platelet engraftment after ABMT despite low numbers of progenitor/stem cells transplanted. These data suggest the presence of a crucial stem cell population not represented by the stem/progenitor cell populations studied in these experiments.
authors.affiliation: Joint Center for Radiation Therapy, Department of Radiation Oncology, Harvard Medical School, Boston, MA, USA.
authors.forename: S N
authors.initials: SN
authors.lastname: Robinson
authors.forename: A S
authors.initials: AS
authors.lastname: Freedman
authors.forename: D S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: L M
authors.initials: LM
authors.lastname: Nadler
authors.forename: P M
authors.initials: PM
authors.lastname: Mauch
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology*; D002452:Cell Count; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006085:Graft Survival; D006410:Hematopoiesis / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009244:NAD+ Nucleosidase / Q000032:analysis; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D014182:Transplantation, Autologous; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D011241:Prednisone