EFFECT OF CHEMOTHERAPY FOR ACUTE MYELOGENOUS LEUKEMIA ON HEMATOPOIETIC AND FIBROBLAST MARROW PROGENITORS

Since reduced marrow cellularity and prolonged pancytopenia following autologous bone marrow transplantation (ABMT) have been frequently obs erved in patients with acute myelogenous leukemia (AML) included in th e AML10 GIMEMA/EORTC trial, the question was raised to what extent hem atopoietic and microenvironmental progenitor cells were involved in th ese patients, Marrow hematopoietic progenitors were investigated by a short-term methylcellulose assay quantitating multipotent CFU-Mix, ery throid BFU-E and granulocyte-macrophage CFU-GM, as well as a long-term assay quantitating long-term culture-initiating cells (LTC-IC), The m arrow microenvironment was studied by evaluating the incidence of fibr o-blastoid progenitors (CFU-F) and the capacity of stromal layers to s upport allogeneic hematopoietic progenitors, As compared to normal con trols (n = 57), AML patients (n = 26) showed a statistically significa nt reduction of the mean (+/- s.e.m.) number of CFU-Mix (5.3 +/- 0.6 v s 0.8 +/- 0.2, P less than or equal to 0.0001), BFU-E (68 +/- 5 vs 20 +/- 4, P less than or equal to 0.0001), CFU-GM (198 +/- 11 vs 144 +/- 15, P less than or equal to 0.008), and LTC-IC (302 +/- 46 vs 50 +/- 8 , P less than or equal to 0.001), The mean (+/- s.e.m.) incidence of m arrow CFU-F was not significantly reduced as compared to normal contro l (48 +/- 6 vs 52 +/- 7, P less than or equal to 0.73). Seventeen AML stromal layers were tested for their capacity to support the growth of allogeneic hematopoietic progenitors, Seven samples failed to support any progenitor cell growth, seven had a significantly lower supportiv e activity as compared to normal stromal layers (13 +/- 5 vs 249 +/- 5 6, P less than or equal to 0.002), whereas three cultures could not be analyzed due to contamination, In conclusion, induction and consolida tion regimens used in AML patients of the AML10 protocol induce a mark edly defective in vitro growth of primitive hematopoietic progenitors and a severe functional defect of marrow stroma, The association of he matopoietic with microenvironmental damage might play a key role in th e delayed hematopoietic regeneration observed following ABMT in patien ts of the AML10 trial.