In vitro marrow purging in chronic myelogenous leukemia: effect of mafosfamide and recombinant granulocyte--macrophage colony-stimulating factor.
Clinical and experimental evidence revealing Ph1-negative hematopoietic stem cells in the majority of chronic myelogenous leukemia (CML) patients, suggests that autologous bone marrow transplantation (ABMT) may represent a therapeutic approach for these patients. It was the aim of the present study to evaluate the efficacy of the cyclophosphamide derivative mafosfamide as a marrow purging agent in a group (n = 15) of CML patients. Chemical purging was followed by a short-term liquid culture phase supplemented with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF). Mafosfamide (100 micrograms/ml) incubation induced a marked inhibition of progenitor cell growth, the percentages of surviving CFU-GEMM, BFU-E, and CFU-GM being 3.4, 5.4, and 4.9, respectively. At the cytogenetic level, the purging procedure failed to show any modulating effect on Ph1-negative clones in 9/15 cases. In contrast, 6/15 cases showed a significant increase in the mean (+/- SD) percentage of Ph1-negative metaphases in response to rGM-CSF (46 +/- 26, p less than or equal to 0.05), mafosfamide incubation (53 +/- 12, p less than or equal to 0.01), and the combination of mafosfamide incubation plus rGM-CSF (63 +/- 29, p less than or equal to 0.025). Immunological analysis revealed that mafosfamide incubation induced a significant enrichment of MY10 (28 +/- 9, 0.05) B73.1-positve cells (25 +/- 9, p less than or equal to 0.05). Four mafosfamide-responsive patients with CML in second chronic phase have been autografted with mafosfamide purged marrow. In all patients a Ph1-negative phase lasting 5-14 months was observed. In conclusion, it appears that (a) in a subgroup of CML patients mafosfamide purging is effective in reducing the size of the malignant clone and might induce through its cytotoxic and immune actions a modification of the balance between leukemic and normal clones, and (b) this experimental approach may be used as a screening test to select patients to undergo marrow harvest and ABMT with mafosfamide purged marrow.
Carlo-Stella
C
C
Department of Hematology, University of Parma, Italy.
Mangoni
L
L
Piovani
G
G
Almici
C
C
Garau
D
D
Caramatti
C
C
Rizzoli
V
V
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation / Q000473:pathology; D003114:Colony-Forming Units Assay; D003520:Cyclophosphamide / Q000031:analogs & derivatives*; D005069:Evaluation Studies as Topic; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006801:Humans; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative / Q000145:classification / Q000473:pathology / Q000601:surgery; D015466:Leukemia, Myeloid, Chronic-Phase / Q000145:classification / Q000473:pathology / Q000601:surgery*; D008297:Male; D008875:Middle Aged
D000970:Antineoplastic Agents; C048341:mafosfamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide