Publication Date:
2004-11-16
Description:
Limited cell dose within a single UCB graft provides the rationale for multiple UCB unit transplantation. Our single institution phase I study testing the safety and efficacy of multiple UCB unit infusion targeted a nucleated cell dose of minimum ≥ 5x107cells/kg, and patients were transplanted with 3-5 unrelated UCB units. Seven adult patients (median 56 years; range 20–69) with advanced hematologic malignancies (4 AML, 1 ALL, 2 NHL) were enrolled and treated with non-myelablative conditioning including Fludarabine 150mg/m2, Cyclophosphamide 2gm/m2, and ATGAM 60mg/kg. UCB grafts were not T-depleted. All UCB units were 1-2 HLA antigen mismatched with the patient, and HLA matching between units was not required. The patients were transplanted sequentially and received a median infused total nucleated cell dose: 5.4x107/kg (range 4.2–8.9), CD3+: 1.4x107/kg (range 1.4–3.4), and CD34+: 2.2x105/kg (range 1.9–5.3). Three of the 7 patients demonstrated UCB donor engraftment while 3 patients had autologous recovery, and one patient died prior to engraftment (day=56). Mixed lymphocyte culture (MLC) was performed including proliferation and cytokine production in order to evaluate impact of graft-graft and patient-graft immune reactivity on donor engraftment. Cryogenically preserved pre-transplant patient and corresponding UCB graft samples were thawed for MLC with readouts including proliferation (CFSE staining) and cytokine production (cytometric bead assay-CBA)(Becton Dickinson, Franklin Lakes, NJ) including pro-inflammatory TH1 cytokines (IFN-γ, TNF-α, IL-2) and anti-inflammatory TH2 cytokines (IL-10, IL-5, IL-4). We hypothesize that increased proliferation and a strong TH1 response may be detrimental to engraftment which was confirmed by preliminary analysis (n=4). We observed higher rates of proliferation as well as higher TH1 cytokine production within the MLC of patients who did not attain donor engraftment. Table 1: TH1 Cytokine Output and Proliferation of Patient and Graft Mixed Lymphocyte Cultures Patient Number Number of UCB Units Donor Engraftment IFNγ(pg/mL) TNFα (pg/mL) IL-2(pg/mL) % Proliferation Pt #1 5 No 940 226 79 16 Pt #2 3 No 234 56 46 20 Pt #3 3 Yes 32
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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