Rapid immune reconstitution and complete donor chimerism after non-myeloablative allogeneic peripheral blood stem cell transplantation (NMSCT) in pediatric patients (PTS) with malignancy
BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION(2006)
摘要
Background: Experience with NMSCT for pediatric cancer is limited. Compared to adults, children and adolescents have less immune depletion and improved reconstitution after chemotherapy, which might increase the risk of graft rejection or mixed chimerism. On the other hand, preserved host thymic function might enhance donor-derived immune recovery. We postulated that pre-transplant immune depletion followed by T cell replete NMSCT would facilitate donor engraftment and enhance post-transplant immune reconstitution. Methods: We piloted a novel regimen in 21 pediatric pts (median age 14, range 4–21) with high-risk hematologic malignancies and sarcomas. Fludarabine-based induction chemotherapy was administered for disease control and targeted CD4 count reduction. Pre-transplant conditioning consisted of cyclophosphamide (1200 mg/m2/day) and fludarabine (30 mg/m2/day) × 4 days plus melphalan (100 mg/m2 × 1 dose in sarcoma pts). Grafts consisted of G-CSF mobilized unmodified peripheral blood stem cells from 5-6/6 HLA-matched first-degree relatives (median CD34 dose 11.7 × 106/kg, range 4.4–19.1; median CD3 dose 416 × 106/kg, range 228–815). Cyclosporine was used for GVHD prophylaxis. Results: Induction therapy dramatically reduced CD4 counts. Donor-derived engraftment was rapid. Median time to achieve an absolute neutrophil count >500 cells/μL was post-transplant day (D+) 9 (range, 8–11). Full donor lymphoid chimerism (≥95% by VNTR-PCR on CD3 sorted peripheral blood) was achieved in all pts (18/21 D + 14; 21/21 D + 28). Immune recovery was brisk and sustained. CD4, CD8, and NK cell numbers exceeded those at study entry by D + 28. Serum IL-7 levels were inversely correlated with CD4 counts. B-cell counts approached entry values by D + 100. Substantial numbers of naive (CD45RA+/CD62L+) CD4+ and CD8+ T cells were detected on D + 28, suggestive of early recovery of thymic function. Conclusions: Targeted pre-transplant immune depletion and NMSCT results in rapid, sustained donor-derived engraftment and immune reconstitution in pediatric pts with malignancy. Early immune recovery includes naive T cell subsets and B cells. Despite potential obstacles in pediatric pts, NMSCT conditioning can induce rapid engraftment and immue reconstitution, which may allow application of this novel platform to direct allogeneic anti-tumor immune responses in high-risk childhood cancers (Table 1).Table 1Immune Depletion and Recovery (Mean Cell Counts/μL)PrePostD + 0D + 28D + 60D + 100D + 180CD430415627394376313413CD83442264561684635544Naive CD469352012364100118Naive CD81304987192137206169B cell115341294106200NK cell871111274222154130Data represent mean cell counts/μL; Pre: entry; Post: after induction; D+: post-transplant day. Open table in a new tab Data represent mean cell counts/μL; Pre: entry; Post: after induction; D+: post-transplant day.
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关键词
complete donor chimerism,rapid immune reconstitution,transplantation,pediatric patients,non-myeloablative
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