RESUMO
Sixteen patients with acute myeloid leukemia (AML) were treated with a continuous i.v. infusion of mAb PM-81, an IgM mAb directed against the cellular differentiation antigen CD15, which is expressed on leukemia cells of >95% of patients with AML. MAb PM-81, also referred to as MDX-11, is capable of activating human and rabbit complement and lysing CD15-positive AML cells. In this Phase I study, patients were treated with 0.5, 1.0, or 1.5 mg/kg MDX-11 delivered over a 24-h period followed by conventional chemotherapy. Transient decreases in circulating blast cells postinfusion (prior to chemotherapy) were observed at all doses. We were able to show MDX-11 binding to bone marrow blasts in those patients who achieved stable serum levels of MDX-11. Serum MDX-11 was detectable at the 1. 0- and 1.5-mg/kg doses. Doses of 0.5 and 1.0 mg/kg were generally well tolerated, with no toxicities greater than grade II (Eastern Cooperative Oncology Group) reported. However, two of five patients receiving the 1.5-mg/kg dose experienced grade IV toxicities that resolved with treatment (one of these patients completed the infusion). Common toxicities reported included fever, chills, and hypotension. Only one patient developed human antimouse antibodies at 4 weeks posttreatment. This study determined that 1.0 mg/kg is a biologically effective dose that can be administered safely with little toxicity. Based on these results, we are pursuing a Phase I/II study of MDX-11 infusion following chemotherapy for patients with relapsed AML.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoglobulina M/imunologia , Leucemia Mieloide/terapia , Antígenos CD15/imunologia , Doença Aguda , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Estudos de Viabilidade , Feminino , Células HL-60 , Humanos , Leucemia Mieloide/imunologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-IdadeRESUMO
Bone marrow and peripheral blood from 28 adult patients with acute myeloid leukemia (AML) were analyzed for the surface expression of the Thy-1 antigen by dual-colour flow cytometry. The Thy-1 antigen was expressed on greater than 5% of cells from seven patients with the proportions of Thy-1 positive cells ranging from 8.1% to 85.0%. The CD34+ Thy-1+ phenotype was present in all seven cases. The expression of Thy-1 on leukemia cells from patients with AML may need to be considered in the development of methods of normal stem cell isolation from these patients.
Assuntos
Crise Blástica , Leucemia Mieloide/imunologia , Leucemia Mieloide/patologia , Antígenos Thy-1/análise , Doença Aguda , Adulto , Idoso , Antígenos CD/análise , Antígenos CD34/análise , Medula Óssea/imunologia , Medula Óssea/patologia , Aberrações Cromossômicas , Feminino , Humanos , Imunofenotipagem , Cariotipagem , Leucemia Mieloide/sangue , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Antígenos Thy-1/sangueRESUMO
Human umbilical cord blood (CB) is a rich source of hematopoietic stem cells for both research and stem cell transplantation. In clinical studies, it appears that recovery from myeloablative therapy using CB requires significantly fewer cells than a typical allogeneic marrow transplant. This suggests that CB may be enriched for early hematopoietic progenitors. The present studies were undertaken to determine the presence of CD34+ cells in CB with the phenotypic characteristics of multipotential stem cells. In 22 CB harvests, the average percentage of CD34+ cells was 1.33 +/- 0.21% (SE), a value similar to that in adult normal bone marrows (BM). However, the distribution of CD34+ cells was distinctly different from either BM or granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell harvests. CB contained a defined population of brightly staining CD34+ cells with low side scatter. These CD34 (bright) cells comprised a mean of 14.5 +/- 2.5% of the CB CD34+ cells, whereas < 1% of BM CD34+ cells has been shown to be CD34- bright. Eighty-five to ninety percent were negative for three antigens expressed at an early stage of stem cell maturation: CD38, HLA-DR and LFA-1. Fifty-five percent of these CD34 (bright) cells did not express the CD45RA isoform, an additional marker of immaturity. The antigen-bright cells also lacked lineage-specific antigens including CD33, CD56, CD19, CD10 and CD7 as well as CD71. Approximately 46% were Thy-1+, and 40% expressed c-kit receptors. These data suggest that, by phenotypic criteria, CB may be a particularly enriched source of primitive hematopoietic precursors.