Efficacious but insidious: a retrospective analysis of fludarabine-induced myelotoxicity using long-term culture-initiating cells in 100 follicular lymphoma patients.

OBJECTIVE: Fludarabine has been recognized as effective treatment in patients with follicular lymphoma (FL), but can induce myelotoxicity of unknown mechanism.

MATERIALS AND METHODS: Myelotoxicity was assessed by cultivation of two types of hematopoietic progenitor cells: colony-forming units granulocyte-macrophage (CFU-GM) and long-term culture-initiating cells (LTC-IC). Pretreatment amounts of CFU-GM and LTC-IC were correlated to age, gender, stage of disease, bone marrow involvement, and previous therapy. Posttreatment comparison of CFU-GM and LTC-IC was performed after different regimens of chemotherapy: fludarabine-based (FND +/- R), procarbazine-based (COPP +/- R), and CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) +/- R(Rituximab).

RESULTS: One-hundred patients (median age 55 years; 21 patients relapsed) treated for FL were analyzed. The total number of progenitor hematopoietic cells in both types of cultures varied in wide ranges; for LTC-IC between 0 and 874 cells/mL with a median of 77.71 cells/mL and for CFU-GM between 0 and 531 x 10(2) cells/mL with a median of 30.58 x 10(2) cells/mL. Bone marrow involvement, gender, stage of disease, or previous therapy had no influence on LTC-IC and CFU-GM counts. We identified an increase in LTC-IC, but not CFU-GM, associated with age (p = 0.01). Median figures for CFU-GM and LTC-IC were found to be significantly lower after FND +/- R and COPP +/- R than after CHOP +/- R therapy, compared to baseline values (p < 0.01).

CONCLUSIONS: Fludarabine and procarbazine have a dramatic influence, especially on the most immature hematopoietic cells, mirrored in reduced numbers of LTC-IC. This finding is consistent with clinical observations (poor mobilization after fludarabine) and offers an insight into the mechanism of fludarabine-induced myelotoxicity.