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.


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.
Janikova
Andrea
A
Department of Internal Medicine, Haematooncology, University Hospital and Faculty of Medicine of Masaryk University Brno, Czech Republic. ajanikova@fnbrno.cz
Koristek
Zdenek
Z
Vinklarkova
Jaroslava
J
Pavlik
Tomas
T
Sticha
Michal
M
Navratil
Milan
M
Kral
Zdenek
Z
Vasova
Ingrid
I
Mayer
Jiri
J
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D001855:Bone Marrow Diseases / Q000139:chemically induced* / Q000473:pathology; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D036102:Peripheral Blood Stem Cell Transplantation; D011241:Prednisone / Q000008:administration & dosage; D011344:Procarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000633:toxicity; D012189:Retrospective Studies; D000069283:Rituximab; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000633:toxicity; D014750:Vincristine / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000964:Antimetabolites, Antineoplastic; D016898:Interferon-alpha; D011344:Procarbazine; D000069283:Rituximab; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008942:Mitoxantrone; D014740:Vidarabine; C024352:fludarabine; D011241:Prednisone