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

Objective. Autologous hematopoietic stem cell transplantation (HSCT) is an increasingly successful modality for treating a variety of malignant disord ers in the clinic. Experimental and clinical data suggest that prior exposu re 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 stent/progenitor cell populations transplanted and time to engraftment. Methods. Patients with previously untreated, advanced-stage follicular lymp homa were treated in sequential prospective protocols with 6-8 cycles of st andard-dose (SD) cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or four cycles of a higher-dose (HD) CHOP and granulocyte colony-s timulating 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. Results. Despite receiving similar numbers of nucleated cells at ABMT, HD-C HOP patients took significantly longer to attain platelet engraftment than the SD-CHOP patients. Marrow from the HD-CHOP patients contained significan tly lower CD34(+), CD34(+)38(-), and week 6-8 CAFC frequencies than marrow from SD-CHOP-treated patients. Time to platelet engraftment was plotted aga inst progenitor/stem cell numbers transplanted for each patient and thresho ld values were developed for all three stem/progenitor cell populations. Th ese values were 0.5 X 10(6) CD34(+) cells/kg, 0.14 x 10(6) CD34(+)38(-) cel ls/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 c ell numbers below threshold values did not uniformly predict for delayed pl atelet engraftment. Conclusions. 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 pati ents who have rapid platelet engraftment after ABMT despite low numbers of progenitor/stem cells transplanted. These data suggest the presence of a cr ucial stem cell population not represented by the stem/progenitor cell popu lations studied in these experiments. (C) 2000 International Society for Ex perimental Hematology. Published by Elsevier Science Inc.