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Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies.

ABSTRACT: Unmanipulated haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) has been an established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of treatment failure for patients with relapsed/refractory disease or with very high-risk gene mutations such as TP53, TET2, and DNMT3a. In this study, we aimed to establish the tolerance and efficacy of prophylactic donor lymphocyte infusion (DLI) with G-CSF-primed peripheral blood progenitors for prevention of relapse in these very high-risk patients after haplo-PBSCT. The prophylactic DLI was given at a median of 77 days after transplantation in 31 of 45 consecutive patients with very high-risk leukemia/lymphoma. The median dose of CD3+ cells for infusion was 1.8?×?107/kg. The 100-day incidences of acute graft-versus-host disease (GVHD) grades 2-4 and 3-4 after DLI were 55.3% and 10.2%. The 2-year incidences of chronic GVHD and severe chronic GVHD were 52.0% and 18.2%. The 2-year incidences of non-relapse mortality and relapse were 33.1% and 32.5%. The 2-year probabilities of overall survival and relapse-free survival were 40.1% and 31.9%. Poor-risk gene mutations (p?=?0.029), disease in non-remission status prior to transplantation (p?=?0.005), and donors older than 40 years of age (p?=?0.043) were associated with relapse after DLI. In multivariate analysis, disease in non-remission status prior to transplantation was an independent risk factor of relapse (hazard ratio?=?4.079; p?=?0.035). These data showed the feasibility of the prophylactic DLI in the haplo-PBSCT setting and the anti-leukemic efficacy in very high-risk leukemia/lymphoma.

SUBMITTER: Gao XN

PROVIDER: S-EPMC6334751 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:Relapse of hematologic malignancies is the primary cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HCT). Treatment for post-HCT relapse using donor lymphocyte infusion (DLI) has limited utility, particularly in the setting of acute leukemia, and can result in the development of graft-versus-host disease (GVHD). The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies, with limited expression in normal tissues. In this pilot trial, we assessed safety and feasibility of a WT1 peptide-loaded donor-derived dendritic cell (DC) vaccine given with DLI designed to enhance and direct the graft-versus-leukemia effect. Secondary objectives were to evaluate immunologic and clinical responses. A total of 5 subjects, median age 17 years (range, 9 to 19 years), with post-HCT relapse were enrolled. Disease subtypes included acute lymphoblastic leukemia (n = 3), acute myelogenous leukemia (n = 1), and Hodgkin lymphoma (n = 1). Successful vaccine production was feasible from all donors. DC vaccination and DLI were well tolerated. One recipient developed grade 1 skin GVHD not requiring systemic therapy. The most common adverse events included grade 1 reversible pain and pruritus at the vaccine injection and delayed-type hypersensitivity (DTH) skin testing sites. There were no grade 3 or higher adverse events related to the research. Immune responses consisted of ELISpot response in 3 recipients and positive DTH tests to WT1 peptide cocktail in 2 subjects. Our study provides 1 of the first attempts to apply tumor-specific vaccine therapy to the allogeneic setting. Preliminary results show the DC-based vaccination is safe and feasible after allogeneic HCT, with a suggestion that this approach can be used to sensitize the repopulated allogeneic-donor immune system to WT1. Future directions may include testing of vaccination strategies in the early post-transplantation setting for relapse prevention.

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Donor lymphocyte infusion for prevention of relapse after unmanipulated haploidentical PBSCT for very high-risk hematologic malignancies.

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