Effects of in vivo treatment with PIXY321 (GM-CSF/IL-3 fusion protein] on proliferation kinetics of bone marrow and blood myeloid progenitor cells in patients with sarcoma

H. E. Broxmeyer, L. Benninger, S. Cooper, N. Hague, R. S. Benjamin, S. Vadhan-Raj

Research output: Contribution to journalArticle

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Abstract

PIXY321, a stimulator of multipotent colony-forming units (CFU-GEMM), burst-forming unit-erythroid (BFU-E), and colony-forming units granulocyte/macrophage (CFU-GM) progenitor cell proliferation in vitro, is currently being assessed in phase-I/-II clinical trials. We evaluated kinetics of CFU-GEMM, BFU-E, and CFU-GM proliferation in bone marrow (BM), blood, and granulocyte (CFU-G) and macrophage (CFU-M) progenitors in BM of chemotherapy-naive patients with sarcoma-administered PIXY321 (25 to 1000 μg/m2/day subcutaneously for 14 days). BM and/or blood cells from three to four patients at each dosage were assessed before, during, 1 to 2 days, and 7 days following treatment with PIXY321. Cells were pulse-treated in vitro with or without high-specific activity tritiated thymidine (3H-dThr) (to assess the percentage of progenitors in S-phase of cell cycle) and cultured for immature and more mature subsets of CFU-GEMM, BFU-E, CFU-GM, and for CFU-G and CFU-M. Despite heterogeneity in baseline cycling status of progenitors in BM, administration of 125 to 500 μg PIXY321 to patients at least doubled (p < 0.001) cycling rates of all BM progenitors. The cycling rates of blood progenitors increased from a slow or non-cycling state to > 38% cells in cycle. Within 1 to 2 days after cessation of PIXY321 infusion, all progenitors were in a slow or noncycling phase below that of many of the pre-BM samples (immature and mature CFU-GM and mature BFU-E) or were back to background levels (CFU-G, CFU-M, CFU-GEMM, and immature BFU-E). These cycling effects were similar to those previously noted for BM CFU-GM and BFU-E in patients on clinical trial with GM-CSF. In contrast, higher dosages of PIXY321, especially 1000 μg, increased cycling of BM and blood progenitor cells early during treatment, but cycling rates decreased while patients were still being administered PIXY321; decreased cycling was maintained after cessation of PIXY321. PIXY321 is thus highly active in vivo as a stimulator of multipotential and more lineage-restricted progenitors. The kinetics of progenitor cell proliferation noted in this study highlight differences seen with GM-CSF and G-CSF. The effects described here could be of relevance in design of future clinical trials using PIXY321 as an adjunct treatment in patients undergoing cytoreductive therapy.

Original languageEnglish (US)
Pages (from-to)335-340
Number of pages6
JournalExperimental Hematology
Volume23
Issue number4
StatePublished - Jan 1 1995

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Keywords

  • Clinical trial
  • PIXY321
  • Progenitor kinetics

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

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