Characterization of late and early hematopoietic progenitor/stem cell sensitivity to mafosfamide

The preservation of the hematopoietic value of the graft is essential in the context of bone marrow purging for autologous transplantation. In the present study we have investigated mafosfamide toxicity to transplantable hematopoietic stem cells using combinations of recombinant growth factors (GF) in semi-solid assays and by measurement of Long-Term Culture Initiating Cells (LTC-IC). Our data show that various subtypes of progenitor/stem cells were inhibited in a dose-dependent manner by mafosfamide. A hierarchy appeared clearly regarding sensitivity to the drug in the following order of increasing resistance: PCM CFU-GM (grown in presence of placenta-conditioned medium), 4R CFU-GM (grown in presence of GM-CSF + IL-3 + G-CSF + EPO), 5R CFU-GM (grown in presence GM-CSF + IL-3 + G-CSF + EPO + SCF) and LTC-IC with respective lethal dose 95 (LD95) levels of 40 micrograms, 55 micrograms, 90 micrograms and 140 micrograms/10(7) MNC (P = 0.05 to P = 0.018). Even the primitive stem cells treated with very high doses of mafosfamide (2 to 4 times the usually recommended dose) responded to a combination of SCF + GM-CSF + G-CSF + IL-3 in liquid marrow culture, suggesting that they were functionally spared by the treatment. We also observed a higher sensitivity of 5R CFU-GM and LTC-IC from patients with hematological malignancies, compared with normal donors, when marrow was treated with the dose chosen for clinical purging.(ABSTRACT TRUNCATED AT 250 WORDS)