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Clinical Trial
. 2015 Jul 1;125(7):2677-89.
doi: 10.1172/JCI81229. Epub 2015 Jun 8.

VSports手机版 - Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts

Marie Bleakley, Shelly Heimfeld, Keith R Loeb, Lori A Jones, Colette Chaney, Stuart Seropian, Ted A Gooley, Franziska Sommermeyer, Stanley R Riddell, Warren D Shlomchik
Clinical Trial

VSports最新版本 - Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts

Marie Bleakley et al. J Clin Invest. .

Abstract

Background: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT) VSports手机版. In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively. .

Methods: In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN V体育安卓版. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution. .

Results: All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell-replete grafts V体育ios版. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years. .

Conclusion: Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory. VSports最新版本.

Trial registration: ClinicalTrials. gov (NCT 00914940) V体育平台登录. .

Trial registration: ClinicalTrials. gov NCT00914940 VSports注册入口. .

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Figures

Figure 7
Figure 7. GVHD in recipients of TN-depleted PBSC HCT and the contemporary standard myeloablative PBSC HCT cohort.
Cumulative incidences of (A) aGVHD and (B) cGVHD. Cumulative incidences of time to discontinuation of (C) systemic corticosteroids and of (D) all immunosuppression in recipients of TN-depleted and T cell–replete PBSC grafts.
Figure 6
Figure 6. Transfer of CMV-specific T cells with TN-depleted HCT.
(A and B) pp65NLV-specific T cells were detected by MHCI-tetramer staining of peripheral blood samples from HLA-A*0201+ CMV+ donors and in their respective recipients after HCT. (A) The time course of expansion of pp65NLV tetramer+ cells (right y axis, solid lines, absolute number of CD8+ pp65NLV+ T cells/μl in recipient peripheral blood at days 28, 56, and 80 after HCT) in relation to blood CMV copy number (left y axis, dashed lines) for 3 representative patients. Data shown at time 0 (black triangles) are from donor blood (D) (CD8+ pp65NLV+ T cells/μl). The 3 patients shown in A are representative of a total of 7 patients; the data for all 7 are shown in B. (B) The percentage of pp65NLV tetramer+ cells among CD8+ T cells and absolute numbers of pp65NLV tetramer+ CD8+ T cells in peripheral blood. (C) Expression of CD27 and CD28 on pp65NLV tetramer+ cells (blue overlay) and total CD8+ cells (red underlay) from 3 representative patients at day 56 and IL-2 and IFN-γ production on day 56 in response to pp65 peptide stimulation (gated on CD8+ cells).
Figure 5
Figure 5. Quantitative immune reconstitution.
(A–G) Absolute numbers of (A) CD8+CD3+ T cells, (B) CD4+CD3+ T cells, (C) CD56+CD16+CD3– NK cells, (D) CD19+ B cells, (E) CD8+ TN, (F) CD4+ TN, and (G) Tregs. Error bars indicate the median value and interquartile range. The gray shading shows the normal range for each respective subset. H shows numbers of signal-joint TRECs (sjTRECs) per 106 PBMCs.
Figure 4
Figure 4. Survival, DFS, relapse, and NRM.
The probabilities of (A) NRM, (B) overall survival and DFS, (C) relapse among all patients, and (D) relapse among patients in CR1, without minimal residual disease, or in CR2, CR3, and/or with residual disease.
Figure 3
Figure 3. GVHD.
(A) Cumulative incidences of aGVHD by grade. (B) aGVHD organ involvement. Clinical severity of (C) GI aGVHD and (D) skin aGVHD. (E) Histopathological severity of GI GVHD on endoscopic biopsy samples. (F) Incidence of cGVHD.
Figure 2
Figure 2. Engraftment and chimerism.
Cumulative incidence of (A) neutrophil and (B) platelet engraftment. Percentage donor chimerism in sorted (C) CD33+ myeloid cells and (D) CD3+ T cells.
Figure 1
Figure 1. Consort diagram of phase II nonrandomized clinical trial.
Number of patients assessed for eligibility and excluded or allocated to the trial, treated, followed, and analyzed. Patients with AML, ALL, or MDS could be allocated to nonmyeloablative HCT or to less intensive, non-TBI myeloablative HCT if the attending physician determined that their disease status required less intensive conditioning or if the patient had significant co-morbidities. Patients who were allocated to standard HCT with cyclophosphamide TBI conditioning, rather than the TN depletion trial, included patients who refused consent or lacked insurance coverage to participate in a clinical trial, those who were precluded from participating for logistical reasons, and those who did not meet eligibility criteria.
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VSports - References

    1. Pidala J, Djulbegovic B, Anasetti C, Kharfan-Dabaja M, Kumar A. Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev. 2011;(10):CD008818. doi: 10.1002/14651858.CD008818.pub2. - DOI - PMC - PubMed
    1. Koreth J, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301(22):2349–2361. doi: 10.1001/jama.2009.813. - DOI - PMC - PubMed
    1. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340–352. doi: 10.1038/nri2000. - DOI - PubMed
    1. Gooley TA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363(22):2091–2101. doi: 10.1056/NEJMoa1004383. - DOI - PMC - PubMed
    1. Flowers ME, et al. Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood. 2002;100(2):415–419. doi: 10.1182/blood-2002-01-0011. - DOI - PubMed

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