Evolving Therapeutic Options for Chronic Graft-versus-Host Disease

Despite improvements in prevention and treatment of acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor-, patient-, and transplant-related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid-refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.     

Tju103和CTLA4-Ig诱导MHC半相合小鼠骨髓移植耐受比较

目的：观察Tju103和CTLA4—Ig各自对MHC半相合小鼠骨髓移植免疫耐受的诱导。方法：半相合供鼠T细胞与受鼠抗原、Tju103(或CTLA4—Ig)共育后与骨髓细胞混合移植，观测移植后受情况。结果：A．单纯照射组：全部小鼠于照射后11d内死于造血衰竭；B．白血病CTX治疗组：全部小鼠于接种白血病细胞后16—23d死于白血病；C．单纯移植组：全部小鼠于移植后21d内死于移植物抗宿主病(GVHD)；D．CsA预防组：5只小鼠于移植后8—22d死亡，1只死于白血病，各有2只死于GVHD和感染，5只活过30d；E．Tju103处理组：4只小鼠于移植后9～26d死亡，2只死于GVHD，各有1只死于白血病和感染，6只活过30d；F．CTLA4—Ig处理组：2只小鼠于移植后17—26d死亡GVHD，8只活过30d。结论：Tju103和CTLA4—Ig均明显延长生存期，降低GVHD发生和严重程度，CTLA4—Ig保留有抗感染和移植抗白血病(GVL)作用，而Tju103没有。     

The potential role of lactoferrin and derivatives in the management of infectious and inflammatory complications of hematology patients receiving a hematopoietic stem cell transplantation

Abstract: Human lactoferrin is a natural defense protein belonging to the innate immune system present in several body fluids and secretions, as well as in the secondary granules of polymorphonuclear neutrophils. Lactoferrin and its derivatives have pleiotropic functions including broad-spectrum anti-microbial activity, anti-tumor activity, regulation of cell growth and differentiation, and modulation of inflammatory as well as humoral and cellular immune responses. This is the reason why much research has addressed the potential therapeutic activity of these molecules in different clinical settings, especially regarding infectious diseases and uncontrolled inflammatory conditions. In patients with hematological malignancies treated with a hematopoietic stem cell transplantation (HSCT), morbidity and mortality due to infections and uncontrolled inflammation remains high, despite many advances in supportive care. These life-threatening complications are a result of the damage caused by the conditioning regimens to the mucosal barrier, and the innate and adaptive, humoral, and cellular immune defenses. These complications necessitate the continued exploration of new treatment modalities. Systemic and probably local levels of lactoferrin are decreased following HSCT. Therefore, the use of lactoferrin, or short peptide derivatives that retain the cationic N-terminal moiety that is essential for the anti-microbial and anti-inflammatory activity, may prove to be a promising versatile class of agents for managing the complications that arise from HSCT.     

Graft versus host disease following transfusion of normal blood products to patients with malignancies

A patient undergoing treatment with cytotoxic chemotherapy for Hodgkin's disease developed graft versus host disease (GVHD) following a transfusion of packed red cells. This is the 28th reported patient with a malignancy who did not have a bone marrow transplant and developed GVHD after transfusion of normal blood or blood products. All patients had received cytotoxic chemotherapy prior to acquiring GVHD. The underlying malignancies included lymphoma, acute leukemia, neuroblastoma, rhabdomyosarcoma, and glioblastoma. Twenty-three of the 28 patients died of GVHD. The incidence of transfusion-related GVHD in this patient population is low but the illness is often fatal as treatment is largely ineffective. Transfusion-related GVHD can be prevented by irradiating all blood products with 1500 rad prior to administration.     

Low-Dose Anti-T Lymphoglobulin as Prophylaxis for Graft-versus-Host Disease in Unrelated Donor Transplantations for Acute Leukemias and Myelodysplastic Syndromes

Chronic graft-versus-host disease (cGVHD) is a major complication after stem cell transplantation (HSCT). Several randomized studies already demonstrated that anti-T lymphoglobulin (ATLG) is effective in preventing GVHD after myeloablative unrelated and HLA-identical sibling transplants. However, the issue of doses and the potential increase of relapses still remain unsolved. Here we report data on 190 patients with acute leukemia and myelodysplastic syndrome who underwent an unrelated HSCT with low-dose ATLG (15 to 30 mg/kg) given at an earlier timing (days –6 to –2). HSCT was performed from HLA 10/10 (n?=?62, 33%), 9/10 (n?=?91, 48%), 8/10 (n?=?30, 16%), and <8/10 (n?=?7, 4%) identical unrelated donor. Peripheral blood was the stem cell source in 42% (n?=?80). Median follow-up was 51 months. Grades II to IV and III to IV acute GVHD were 26% and 9%, respectively, and 2-year overall and moderate to severe cGVHD were 23% and 14%, respectively. The 3-year incidences of relapse and nonrelapse mortality were 26% and 18%, respectively. The rates of 3-year overall survival (OS), disease-free survival (DFS), and GVHD-free and relapse-free survival (GRFS) were 60%, 56% and 44%, respectively. Factors such as younger donor, good performance status, and early disease were associated with better outcome in terms of OS, DFS, and GRFS. Our data indicate that doses of ATLG lower that those used in randomized clinical trials can be used for GVHD prevention, even in the adult setting, without clear increases in relapse and infections; these findings need to be further validated by a prospective randomized study.     

Risk Factors for Severe Acute Graft-versus-Host Disease in Donor Graft Composition

Acute graft-versus-host disease (aGVHD) is 1 of the main major complications of post–hematopoietic stem cell transplantation (HSCT). Identifying patients at risk of severe aGVHD may lead to earlier intervention and treatment, resulting in increased survival and a better quality of life. We aimed to identify biomarkers in donor grafts and patient plasma around the time of transplantation that might be predictive of aGVHD development. We build on our previously published methods by using multiplex assays and multicolor flow cytometry. We identified 5 easily assessable cellular markers in donor grafts that combined could potentially be used to calculate risk for severe aGVHD development. Most noteworthy are the T cell subsets expressing IL-7 receptor-α (CD127) and PD-1. Additionally, we identified a potential role for elevated tumor necrosis factor-α levels in both graft and patient before HSCT in development of aGVHD.     

Impact of amino acid substitution at residue 9 of HLA‐A2 on the development of acute GVHD in Korean pediatric patients receiving unrelated hematopoietic stem cell transplantation

Incompatibility of human leukocyte antigen (HLA) alleles between donors and recipients of unrelated hematopoietic stem cell transplantation (UHSCT) increases the risk of acute graft‐versus‐host disease (GVHD). We evaluated the positional effect of amino acid substitutions in HLA molecules on severe acute GVHD in Korean pediatric recipients of UHSCT. All of 64 donor–recipient pairs were serologically matched for HLA‐A, ‐B, and ‐DR loci. Only substitution at residue 9 resulting from an HLA‐A*02 polymorphism was significantly associated with the risk of severe acute GVHD in patients (OR = 7.0, P = 0.033) on multivariate analysis. Recipients of this mismatched HLA also showed shortened overall survival (HR = 9.7, P < 0.001) and increased risk for transplant‐related mortality (HR = 9.1, P = 0.027). Structural modeling showed that the amino acid substitution could alter the peptide preference of the ligand‐binding pocket. A single amino acid substitution at position 9 was a major predictor of severe acute GVHD in Korean pediatric patients.     

喘可治对小鼠异基因骨髓移植中移植物抗宿主病效应的影响

<正>喘可治注射液(简称CKZ)主要成分为淫羊藿、巴戟天提取物,临床传统用于治疗哮喘。前期研究结果显示,喘可治具有复杂的免疫调节作用,影响T细胞的活化、细胞因子分泌(TH1/TH2平衡)、增殖和凋亡等行为,具有一定双向调节功能,即免疫反应过强时抑制免疫应答,免疫反应过弱时     

Pathophysiology of gastrointestinal acute graft-versus-host disease and the potential role of glucagon-like peptide 2

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic haematopoietic cell transplantation, with gastrointestinal (GI) tract involvement (GI aGVHD) being one of the leading causes of morbidity and mortality. Whilst systemic steroids are the standard first-line treatment for aGVHD, approximately 50% of patients become steroid refractory (SR), which is associated with poor outcomes. Existing options for SR-GVHD are limited, and there is a significant unmet need for new non-immunosuppressive treatment approaches in patients with GI aGVHD. Here, we review newer concepts in the pathogenesis of GI aGVHD and present the evidence for the role of glucagon-like peptide 2 (GLP-2) in maintaining and protecting GI epithelial cells, including the enterocytes, intestinal stem cells and Paneth cells, which are direct targets of aGVHD. Finally, we discuss the therapeutic rationale for GLP-2 treatment as a tissue regeneration approach and the potential use of the novel GLP-2 analogue apraglutide as an adjunctive treatment for GI aGVHD.