Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
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Biol. Blood Marrow Transplant. · Dec 2004
Randomized Controlled Trial Comparative Study Clinical TrialA randomized trial comparing the combination of granulocyte-macrophage colony-stimulating factor plus granulocyte colony-stimulating factor versus granulocyte colony-stimulating factor for mobilization of dendritic cell subsets in hematopoietic progenitor cell products.
The ability of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) administration to increase the content of blood leucocytes and hematopoietic progenitor cells (HPCs) is well established, yet the effect of these cytokines on immune function is less well described. Recent data indicate that plasmacytoid dendritic cells (DC2) may inhibit cellular immune response. We hypothesized that administration of the combination of G-CSF and GM-CSF after chemotherapy would reduce the type 2, or plasmacytoid, DC2 content of the autologous blood HPC grafts compared with treatment with G-CSF alone. ⋯ A third cohort of patients received chemotherapy followed by the sequential administration of G-CSF and the addition of GM-CSF 6 days later. Grafts from these patients had a markedly reduced DC2 content compared with those from patients treated either with G-CSF alone or with the concomitant administration of both cytokines. These data, and recent data that cross-presentation of antigen by DC2 cells may induce antigen-specific tolerance among T cells, suggest that GM-CSF during mobilization of blood HPC grafts may be a clinically applicable strategy to enhance innate and acquired immunity after autologous and allogeneic HPC transplantation.
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Biol. Blood Marrow Transplant. · Dec 2004
Favorable effect on acute and chronic graft-versus-host disease with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anemia.
Between August 1989 and November 2003, 33 patients at our center with acquired aplastic anemia underwent bone marrow transplantation (BMT) from HLA-identical sibling donors with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies (MoAb) for conditioning. The median age at BMT was 17 years (range, 4-46 years). Before BMT, 58% were heavily transfused (>50 transfusions), and 42% had previously experienced treatment failure with antithymocyte globulin-based immunosuppressive therapy. ⋯ No unexpected early or late infectious or noninfectious complications were observed. We conclude that the conditioning regimen containing cyclophosphamide and anti-CD52 MoAb is well tolerated and effective for acquired aplastic anemia with HLA-matched sibling donors. The favorable effect on the incidence and severity of GVHD is noteworthy in this study and warrants further investigation.
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Biol. Blood Marrow Transplant. · Nov 2004
Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation.
We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 micromol/L/min per dose (range, 1000-1300 micromol/L/min per dose; SD +/-13%) based on the first-dose PK determination. ⋯ Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386-1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation.
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Biol. Blood Marrow Transplant. · Oct 2004
Clinical TrialEarly prediction of molecular remission by monitoring BCR-ABL transcript levels in patients achieving a complete cytogenetic response after imatinib therapy for posttransplantation chronic myelogenous leukemia relapse.
Imatinib induces a high complete cytogenetic response (CCR) rate in relapsed chronic myelogenous leukemia. By analyzing minimal residual disease (MRD) under the levels of CCR, we tried to assess the molecular response after imatinib therapy. By using real-time quantitative reverse transcriptase-polymerase chain reaction (Q-RT-PCR), MRD was evaluated in 23 patients (3 in cytogenetic relapse, 6 in chronic phase, 9 in accelerated phase, and 5 in blast crisis) who were treated with standard-dose imatinib for relapsed chronic myelogenous leukemia after allogeneic stem cell transplantation. ⋯ The BCR-ABL/ABL ratios were similar in 2 groups at 3 months but were significantly different at 6 months (median, 0.0000012 for MR and 0.00022 for CCR; P =.003). The probability of a subsequent MR was significantly higher in patients with a lower BCR-ABL/ABL ratio at 6 months (100% for <0.0001 versus 33% for >/=0.0001; P =.006) or a greater reduction in the level between 3 and 6 months (log-reduction >/=1.0;, 100%; <1.0, 17%; P =.003). Q-RT-PCR is a reliable method for monitoring MRD: the early trends in the BCR-ABL/ABL ratio may be clinically useful in discriminating patients who will achieve an MR from those who will remain in CCR.
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Biol. Blood Marrow Transplant. · Oct 2004
A CD8 DE loop peptide analog prevents graft-versus-host disease in a multiple minor histocompatibility antigen-mismatched bone marrow transplantation model.
Donor CD8(+) T cells can be potent mediators of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation to either major histocompatibility complex (MHC) class I-or multiple minor histocompatibility antigen-mismatched recipients. To develop small molecular inhibitors of CD8(+) T-cell activity, theoretical structural analysis of the human CD8 alpha molecule was previously used to identify potential functional surface epitopes that interact with the MHC class I molecule. The DE loop (p71-78) was identified as such a target region, and a panel of synthetic cyclized peptide mimics of this region were tested for their inhibitory effects on cytotoxic T lymphocyte activity in human cell-mediated lympholysis assays. ⋯ BR mice that had been challenged with CBA lymphocytes and simultaneously treated with 1109. These cells could not generate secondary proliferative responses in vitro upon stimulation with CBA splenocytes but could respond to third-party C57BL/6 stimulation. Thus, the 1109 peptide has potential application in the prevention of CD8-mediated GVHD development.