BACKGROUND Brentuximab vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma. METHODS We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS At a median follow-up of 24.9 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.7 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P = 0.03). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.72 [95% CI, 0.44 to 1.17]; P = 0.19). All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity. CONCLUSIONS A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.)
Mixed hematopoietic chimerism can be induced in mice receiving allogeneic bone marrow transplantation (BMT) after nonmyeloablative host conditioning with depletion T cells with of anti-T cell monoclonal antibodies (mAbs), low-dose (3 Gy) total-body irradiation (TBI), and local thymic irradiation (7 Gy). These mice are specifically tolerant to donor and host antigens. When nontolerant donor T cells are given to chimeras several months after BMT, full donor-type chimerism develops, but graft-vs.-host disease (GVHD) does not occur. The induction of such lymphohematopoietic GVH reactions without GVHD could provide an approach to separating graft-vs.-leukemia (GVL) from GVHD in patients with hematologic malignancies. To make the nonmyeloablative conditioning regimen described above more cytoreductive for such malignancies, we have now modified it by replacing TBI with cyclophosphamide (CP). Treatment with anti-CD4 and anti-CD8 mAbs on day -5, 200 mg/kg CP on day -1, and 7 Gy thymic irradiation on day 0 was only slightly myelosuppressive and allowed fully major histocompatibility complex (MHC)-mismatched (with or without multiple minor antigen disparities) allogeneic bone marrow to engraft and establish long-term mixed chimerism in 40 to 82% of recipients in three different strain combinations. The administration of nontolerant donor spleen cells at 5 weeks or at 5, 8, and 11 weeks posttransplant was capable of eliminating host hematopoietic cells, leading to full or nearly full donor chimerism in six of six and two of four chimeric animals in two different strain combinations. No clinical evidence of GVHD was observed in any recipients of these donor leukocyte infusions (DLI). These studies demonstrate that induction of mixed chimerism with nonmyeloablative conditioning followed at appropriate times by DLI might allow lymphohematopoietic GVH reactions, and hence GVL effects, to eliminate chronic hematologic malignancies without causing clinically significant GVHD.
Following bone marrow transplantation, delayed donor leukocyte infusions (DLIs) can induce graft-versus-leukemia (GVL) effects without graft-versus-host disease (GVHD). These antitumor responses are maximized by the presence of host hematopoietic antigen-presenting cells (APCs) at the time of DLI. Using a tumor-protection model, we demonstrate here that GVL activity following administration of DLIs to established mixed chimeras is dependent primarily on reactivity to allogeneic MHC antigens rather than minor histocompatibility or tumorassociated antigens. CD8 ؉ T-celldependent GVL responses against an MHC class II-negative tumor following delayed DLI require CD4 ؉ T-cell help and are reduced significantly when host APCs lack MHC class II expression. CD4 ؉ T cells primed by host APCs were required for maximal expansion of graft-versus-host reactive CD8 ؉ T cells but not their synthesis of IFN-␥. In contrast, the GVL requirement for CD4 ؉ T-cell help was bypassed almost completely when DLI was administered to freshly irradiated recipients, indicating that the host environment is a major factor influencing the cellular mechanisms of GVL. IntroductionFollowing allogeneic bone marrow transplantation (BMT), donor T-cell alloreactivity can be co-opted to generate powerful antitumor activity, an effect termed the graft-versus-leukemia (GVL) response. 1,2 The GVL effect is associated with the presence of graft-versus-host disease (GVHD) and is linked to the degree of major MHC disparity and the presence of T cells within the graft, indicating that graft-versus-host (GVH) alloreactive donor T cells are important for this effect. 3 We have previously shown that administration of delayed donor leukocyte infusion (DLI) to established mixed chimeras (MCs; in which hematopoietic elements from both the donor and recipient are present) produces dramatically improved GVL effects compared with those seen following delayed DLI to full chimeras (FCs). 4 Host hematopoietic antigen-presenting cells (APCs) expressing MHC class I molecules are necessary for this optimization of GVL effects in MCs. 4 The importance of host APCs in inducing GVL has recently been confirmed in freshly irradiated mice, 5 and previous studies have shown their importance in inducing GVHD under such conditions. 6,7 The marked overlap of GVL and GVHD limit the wider application of allogeneic BMT, especially in those individuals who lack an HLA-identical donor. However, GVL can be achieved without GVHD by administration of DLI to established MCs that lack proinflammatory stimuli from recent conditioning. 4,8 A precise definition of the mechanisms that underlie the GVL effect of DLI in MCs will be important for the rational development of this strategy for achieving maximal GVL effects without GVHD in humans. Using a tumor protection model, we demonstrate here that GVL responses of DLI are due to alloresponses against recipient MHC antigens. We also demonstrate a requirement for CD4 ϩ T-cell help in generating maximal CD8 ϩ T-cell-mediated GVL activity against MH...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.