Adoptive immunotherapy with donor lymphocyte infusionsafter allogeneic HPC transplantation

Baron, Frédéric; Béguin, Yves

doi:10.1046/j.1537-2995.2000.40040468.x

Cited by 25 publications

(26 citation statements)

References 87 publications

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“…In addition, tumor cells resistant to standard doses of chemotherapy are unlikely to be completely eliminated by tolerable higher-intensity doses of chemo-radiotherapy alone (5). Moreover, donor alloreactivity against tumor cells has been recognized as a major factor in the success of HSC transplantation (6)(7)(8)(9)(10). This graft-versus-leukemia (GVL) effect may be so potent that leukemia relapses after standard allogeneic transplantation can be effectively [70% long-term complete remission (CR) in chronic myeloid leukemia (CML)] treated with donor lymphocyte infusions (DLI) (10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, donor alloreactivity against tumor cells has been recognized as a major factor in the success of HSC transplantation (6)(7)(8)(9)(10). This graft-versus-leukemia (GVL) effect may be so potent that leukemia relapses after standard allogeneic transplantation can be effectively [70% long-term complete remission (CR) in chronic myeloid leukemia (CML)] treated with donor lymphocyte infusions (DLI) (10)(11)(12)(13)(14)(15)(16)(17). Taken together, these findings suggested that the potential for cure after allogeneic HSC transplantation could be obtained by induction of host-versus-graft tolerance with low-dose highly immunosuppressive regimens, allowing in a second step the implantation of donor T and natural killer (NK) (18,19) cells (DLI) to eradicate host tumor cells (3,5,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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Nonmyeloablative Stem Cell Transplantation with CD8-Depleted or CD34-Selected Peripheral Blood Stem Cells

Baron

Baudoux

Frère

et al. 2002

Journal of Hematotherapy & Stem Cell Research

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To decrease the incidence of graft-versus-host disease (GVHD) observed after nonmyeloablative stem cell transplantation (NMSCT), we studied the feasibility of CD8-depleted or CD34-selected NMSCT followed by CD8-depleted preemptive donor lymphocyte infusion (DLI) given in incremental doses on days 40 and 80. Fourteen patients with high-risk malignancies and an HLA-identical sibling (n 5 8) or alternative donor (n 5 6) but ineligible for a conventional transplant were included. Nonmyeloablative conditioning regimen consisted in 2 Gy total body irradiation (TBI) alone, 2 Gy TBI and fludarabine (previously untreated patients) or cyclophosphamide and fludarabine (patients who had previously received $12 Gy TBI). Patients 1-4 (controls) received unmanipulated peripheral blood stem cells (PBSC) and DLI and patients 5-14 CD8-depleted or CD34-selected PBSC followed by CD8-depleted DLI. Post-transplant immunosuppression was carried out with cyclosporine A (CsA) and mycophenolate mofetil (MMF). Initial engraftment was seen in all patients, but 1 patient (7%) later rejected her graft. The actuarial 180-day incidence of grades II-IV acute GVHD was 75% for patients 1-4 versus 0% for patients 5-14 (p 5 0.0019). Five of 14 patients were in complete remission (CR) 180 days after the transplant and 6/14 had partial responses. The 1-year survival rate was 69%, and nonrelapse and relapse mortality rates were 16 and 18%, respectively. We conclude that CD8-depleted or CD34-selected NMSCT followed by CD8-depleted DLI is feasible and considerably decreases the incidence of acute GVHD while preserving engraftment and apparently also the graft-versus-leukemia (GVL) effect. Further studies are needed to confirm this encouraging preliminary report. 301

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nonmyeloablative Stem Cell Transplantation with CD8-Depleted or CD34-Selected Peripheral Blood Stem Cells

Baron

Baudoux

Frère

et al. 2002

Journal of Hematotherapy & Stem Cell Research

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“…The power of the GVL effect and its apparent mediation by donor lymphocytes led several groups to infuse donor lymphocytes (DLI) in patients with relapsed leukemia after HSCT (6)(7)(8)(9)(10)(11)(12). The induction of durable remissions by DLI demonstrated that the GVL effect is capable of erad-…”

Section: Introduction Tmentioning

confidence: 99%

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Baron

Béguin

2002

Journal of Hematotherapy & Stem Cell Research

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment for selected hematological malignancies. Its curative potential is largely mediated by an immune-mediated destruction of malignant cells by donor lymphocytes termed graft-versus-leukemia (GVL) effect. However, because of its toxicity, conventional allogeneic HSCT is restricted to younger and fitter patients. These observations led several groups to set up new (less toxic) transplant protocols (nonmyeloablative stem cell transplantation or NMSCT) based on a two-step approach: first, the use of immunosuppressive (but nonmyeloablative) preparative regimens providing sufficient immunosuppression to achieve engraftment of allogeneic hematopoietic stem cells and, in a second step, destruction of malignant cells by the GVL effect. Preliminary results showed that NMSCT were feasible with a relatively low transplant-related mortality (TRM), even in patients older than 65 years. In addition, strong antitumor responses were observed in several hematological malignancies as well as in some patients with renal cell carcinoma. After discussing the mechanisms and efficacy of the GVL effect as well as the rationale for NMSCT strategies, this article reviews the first results of ongoing clinical trials. Innovative modalities that may permit amplification of the GVL effect while minimizing the risk of GVHD are discussed. Because the benefits of NMSCT over alternative forms of treatment remain to be demonstrated, this strategy should be restricted to patients included in clinical trials. 243

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“…[1][2][3] Their efficacy has provided powerful evidence supporting the existence of a graft-versus-malignancy effect. Most of the patients reported in the literature had either chronic myeloid leukemia (CML) or acute leukemia , both myeloid or lymphoid.…”

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confidence: 99%

“…Most of the patients reported in the literature had either chronic myeloid leukemia (CML) or acute leukemia , both myeloid or lymphoid. [2][3] The efficacy of post-allo-SCT DLIs seems most apparent in CML patients, where the impact of the T-cell dose on outcome (ie development of GVHD and response) has been demonstrated. [4][5] Experience with DLIs in Hodgkin's lymphoma (HL) remains scarce, [6][7][8] and the very existence of a graft-versusHodgkin's effect remains controversial.…”

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confidence: 99%

Donor leukocyte infusions in relapsed Hodgkin's lymphoma following allogeneic stem cell transplantation: CD3+ cell dose, GVHD and disease response

Anderlini

Acholonu

Okoroji

et al. 2004

Bone Marrow Transplant

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Summary:Nine patients with advanced Hodgkin's lymphoma (HL) who had undergone allogeneic stem cell transplantation (allo-SCT) received donor leukocyte infusions (DLIs) for treatment of persistent or progressive disease (PD). A total of 15 DLIs were performed, with four patients receiving more than one DLI. In four patients, prior salvage chemotherapy was administered. The median CD3 þ cell dose administered was 77.5 Â 10 6 /kg (range 5-285). GVHD developed in all but one patient. The response rate was 4/9 (44%). Three of these four responders developed GVHD and 3/4 had received chemotherapy. No correlation was observed between CD3 þ cell dose infused and disease response. At the latest follow-up, three patients are alive and six have expired (PD n ¼ 3, nonrelapse mortality n ¼ 3). The median response duration was 7 months (range 4-9), with one response currently ongoing. These data suggest that DLIs for immunotherapy of recurrent HL have significant activity, although they frequently leads to GVHD. The small sample size does not allow any conclusion as to whether chemotherapy administration increases the chance of response. The CD3 cell dose infused does not seem to correlate with disease response. from both matched related and unrelated donors. 1-3 Their efficacy has provided powerful evidence supporting the existence of a graft-versus-malignancy effect. Most of the patients reported in the literature had either chronic myeloid leukemia (CML) or acute leukemia , both myeloid or lymphoid. 2-3 The efficacy of post-allo-SCT DLIs seems most apparent in CML patients, where the impact of the T-cell dose on outcome (ie development of GVHD and response) has been demonstrated. [4][5] Experience with DLIs in Hodgkin's lymphoma (HL) remains scarce, 6-8 and the very existence of a graft-versusHodgkin's effect remains controversial. Because of the paucity of data, the impact (if any) of the T-cell dose on clinical outcome has been uncertain. In this study, we review our experience with DLIs as adoptive immunotherapy in HL patients in the treatment of post-allo-SCT relapse. Patients and methodsOver a 5-year period (January 1999-January 2004), 51 patients underwent allografts from a matched related or unrelated donor for refractory or relapsed HL at our center. In all, 25 of them (49%) had persistent or progressive disease (PD) after allo-SCT. All patients in this group who received one or more DLI (with or without preceding salvage chemotherapy) for the management of PD following allo-SCT are included in this study. The treatment plan for the patients was approved by our institution's Institutional Review Board (IRB), and all patients provided written informed consent.The conditioning regimen for these patients included in all but one case fludarabine with melphalan or cyclophosphamide. One patient received busulfan-based conditioning. Three patients received antithymocyte globulin as part of their preparative regimen. There was no manipulation of the stem cell product infused. GVHD prophylaxis consisted of tacrolimus and me...

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Adoptive immunotherapy with donor lymphocyte infusionsafter allogeneic HPC transplantation

Cited by 25 publications

References 87 publications

Nonmyeloablative Stem Cell Transplantation with CD8-Depleted or CD34-Selected Peripheral Blood Stem Cells

Nonmyeloablative Stem Cell Transplantation with CD8-Depleted or CD34-Selected Peripheral Blood Stem Cells

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Donor leukocyte infusions in relapsed Hodgkin's lymphoma following allogeneic stem cell transplantation: CD3+ cell dose, GVHD and disease response

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