CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation

Mohty, Mohamad; Bagattini, S.; Chabannon, Christian; Faucher, Catherine; Bardou, Valérie‐Jeanne; Bilger, Karin; Vey, Norbert; Gaugler, Béatrice; Stoppa, Anne‐Marie; Coso, Diane; Ladaique, Patrick; Olive, Daniel; Viens, Patrice; Blaise, Didier

doi:10.1016/j.exphem.2004.07.020

Cited by 31 publications

(22 citation statements)

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“…124 A correlation between CD8+ T-cell dose and survival was previously observed after Flu/TBI2 125 but high CD8+ and CD34+ cell doses may also correlate with GvHD. 122,126 Clearly, graft composition is a potentially modifiable determinant of outcome, though additional data are required.…”

Section: Predictors Of Outcome and Personalized Approachesmentioning

confidence: 99%

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reshef

Porter

2015

Bone Marrow Transplant

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AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. ( Bone Marrow Transplantation THE RATIONALE FOR RIC IN AMLTraditional myeloablative transplants are effective in part due to a potent immunologic GVL effect independent of the conditioning regimen. The GVL response has been repeatedly demonstrated in allo-SCT 1,2 and through the use of DLI. 3,4 The ability to harness GVL yet minimize toxicity is highly relevant in AML, which is common in older patients and often incurable with chemotherapy alone. In 2013, AML was the most common indication for allo-SCT, 35% of AML transplants were in patients over age 60 and over 40% were performed with reduced-intensity conditioning (RIC) regimens (data from CIBMTR-Center for International Blood and Marrow Transplant Research).Data from animal models 5,6 and clinical observations regarding GVL activity [1][2][3][4]7 facilitated the development of RIC regimens. The success of initial attempts to use low-dose (2 Gy) TBI alone as conditioning was hindered by frequent graft rejections. The addition of fludarabine to low-dose TBI promoted engraftment with encouraging outcomes. [8][9][10][11][12] This supported a conceptual shift in allo-SCT away from dose intensity toward less myelotoxic regimens that rely on a potent GVL response. EFFICACY-IS THERE AN IDEAL CONDITIONING REGIMEN?The definition of RIC has been a moving target. The term 'reduced intensity' describes regimens characterized by lower rates of toxicities compared with myeloablative transplants. RIC regimens can be further classified as non-myeloablative when they result in minimal cytopenias. These regimens presumably have minimal or no direct effect on leukemic cells, relying solely on the GVL response. 13 The CIBMTR defines a RIC regimen ...

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Section: Predictors Of Outcome and Personalized Approachesmentioning

confidence: 99%

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reshef

Porter

2015

Bone Marrow Transplant

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“…21 Although CD41 T cells are generally regarded as helper cells in the induction and maintenance of CD81 T-cell immunity, 22 they can also exert direct cytolysis in antitumor and antipathogen immunity. 12,23 Clinical application of CD81 TCD DLI induced conversion to donor hematopoiesis and disease remission in patients with relapsed malignancies and was associated with a lower incidence of opportunistic infections in the absence of severe GVHD.…”

Section: Introductionmentioning

confidence: 99%

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Stevanović

Bergen

Luxemburg-Heijs

et al. 2013

Blood

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Key Points• GVHD after HLA-DPB1-mismatched CD41 DLI after TCD-alloSCT is mediated by allo-reactive HLA-DPB1-directed CD41 T cells.• Viral infections after TCDalloSCT can induce HLA class II on nonhematopoietic tissues, making them targets for CD41 T cells in GVHD.CD81 T cell-depleted (TCD) donor lymphocyte infusion (DLI) after TCD allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with a reduced risk of graft-versus-host disease (GVHD) while preserving conversion to donor hematopoiesis and antitumor immunity, providing a rationale for exploring CD41 T cell-based immunotherapy for hematologic malignancies. Here, we analyzed the clinical course and specificity of T cell immune responses in 2 patients with acute myeloid leukemia (AML) who converted to full-donor chimerism but developed severe acute GVHD after prophylactic CD41 DLI after 10/10-HLA-matched, but HLA-DPB1-mismatched TCD-alloSCT. Clonal analysis of activated T cells isolated during GVHD demonstrated allo-reactivity exerted by CD41 T cells directed against patient-mismatched HLA-DPB1 molecules on hematopoietic cells and skin-derived fibroblasts only when cultured under inflammatory conditions. At the time of CD41 DLI, both patients contained residual patient-derived T cells, including cytomegalovirus (CMV)-specific T cells as a result of CMV reactivations.Once activated by CMV antigens, these CMV-specific T cells could stimulate HLA-DPB1-specific CD41 T cells, which in turn could target nonhematopoietic tissues in GVHD. In conclusion, our data demonstrate that GVHD after HLA-DPB1-mismatched CD41 DLI can be mediated by allo-reactive HLA-DPB1-directed CD41 T cells and that ongoing viral infections inducing HLA class II expression on nonhematopoietic cells may increase the likelihood of GVHD development. This trial is registered at http://www.controlled-trials.com/ISRCTN51398568/LUMC as #51398568. (Blood. 2013;122(11):1963-1973 IntroductionIn allogeneic hematopoietic stem cell transplantation (alloSCT), T-cell depletion of the graft efficiently prevents the occurrence of severe acute graft-versus-host disease [GVHD]) 1,2 but also adversely affects posttransplant antitumor and antipathogen immunity.1-3 Early intervention with donor lymphocyte infusion (DLI) after T cell-depleted (TCD)-alloSCT may prevent relapse of the malignancy and improve immune reconstitution against pathogens but is frequently associated with reintroduction of GVHD. 4,5 Therefore, exploration of treatment strategies to improve the balance between graft-versus-leukemia (GVL) reactivity and antipathogen immunity and GVHD is warranted.To minimize the risk of GVHD, patients are preferably transplanted with stem cell grafts from HLA-matched sibling or unrelated donors (URD).6 HLA matching is generally performed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles (10/10 match) but not for HLA-DPB1. Therefore, 70% to 80% of URD alloSCT are HLA-DPB1-mismatched. 6,7 In contrast to HLA class I, constitutive expression of HLA class II molecules is mainly confined to normal...

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“…Various studies analyzing graft T-cell composition have not convincingly demonstrated any particular cellular component as reproducibly having either deleterious or beneficial effects on transplant outcomes. [21][22][23][24] In their study of 63 RIC transplant patients, Cao and colleagues reported improved freedom from progression, overall survival and attainment of full donor T-cell chimerism with higher CD8 + cell doses, with no correlation between CD8 + dose and GVHD and no significant effect of CD3 + or CD4 + subsets on any of these outcomes. 21 In contrast, Mohty + or CD34 + subsets on these outcomes (of note, TNC dose was not reported in this study).…”

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confidence: 99%

Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34 ⁺ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation

Martin

Nikiforow

et al. 2016

Haematologica

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© Ferrata Storti Foundation P.S. Martin et al. 500haematologica | 2016; 101(4) nificant impact on transplant outcomes in the RIC setting. However, relatively few studies have reported on productrelated outcome data in RIC transplants. These studies have primarily focused on CD34 + cell dose, most reporting that higher CD34 + cell doses are associated with more rapid engraftment with a variable effect on the incidence of graft-versus-host disease (GVHD) and survival outcomes. [1][2][3][4][5] Gomez-Almaguer and colleagues reported on 138 recipients of RIC hematopoietic stem cell transplants, showing that higher CD34 + doses correlated with improved overall survival. 6 A CIBMTR registry analysis of 1054 RIC hematopoietic stem cell transplant recipients found that lower CD34 + doses correlated with increased transplant-related mortality and decreased overall survival. 7 In contrast, Remberger and colleagues reported that higher CD34 + doses were actually associated with higher relapse rates and lower overall survival. 8 Relative to CD34 + cell dose, total nucleated cell (TNC) dose has been less frequently studied. However, in the limited number of studies that have examined TNC, a trend toward improved survival outcomes with higher TNC dose, independently of CD34 + dose, has been found. 9,10 The current study examines the impact of both TNC and CD34 + cell dose on major transplant outcomes in a cohort of 705 consecutive patients undergoing RIC allogeneic peripheral blood hematopoietic stem cell transplantation. MethodsWe analyzed data from 705 consecutive patients with hematologic malignancies undergoing RIC utilizing granulocyte colonystimulating factor-mobilized donor peripheral blood mononuclear cells as a graft source. Patients who underwent either in vivo T-cell depletion with antithymocyte globulin or ex-vivo T-cell depletion were excluded from the study. All patients had at least 3 years of follow-up after their transplant. All patients provided consent to the use of protected health data for research, as approved by a common institutional review board of the Dana-Farber/Harvard Cancer Center. Definitions and end-pointsNeutrophil engraftment was defined as the first day of an absolute neutrophil count >500/mL on three consecutive measurements. Platelet recovery was defined as the first day of two consecutive measurements of >20,000/mL (unsupported). Acute and chronic GVHD were graded by consensus grading criteria and their cumulative incidence was calculated through day +200 after hematopoietic stem cell transplantation. Chronic GVHD was defined clinically by treating physicians utilizing standard criteria ultimately supplanted by NIH Consensus Conference recommendations.11 Relapse was defined as disease recurrence documented by morphological, histological or radiographic means. Treatmentrelated mortality was defined as death while in continuous remission. Progression-free survival was defined as the time from transplantation to relapse or death from any cause, and overall survival was defined as ...

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CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation

Cited by 31 publications

References 30 publications

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reduced-intensity conditioned allogeneic SCT in adults with AML

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34 ⁺ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation

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CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation

Cited by 31 publications

References 30 publications

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reduced-intensity conditioned allogeneic SCT in adults with AML

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34 + cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation

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Infused total nucleated cell dose is a better predictor of transplant outcomes than CD34 ⁺ cell number in reduced-intensity mobilized peripheral blood allogeneic hematopoietic cell transplantation