Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.     

Efficacy of the interleukin-2 receptor antagonist basiliximab in steroid-refractory acute graft-versus-host disease

Acute graft-versus-host disease (aGVHD) occurs in up to 80% of patients who undergo allogeneic stem cell transplantation (SCT) and contributes significantly to transplant-related mortality (TRM). We conducted a prospective phase II trial to assess the efficacy and feasibility of treating steroid-refractory aGVHD with basiliximab, a chimaeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor. Basiliximab was administered intravenously at a dose of 20 mg on days 1 and 4. Twenty-three patients were enrolled between October 1999 and July 2004. We found a primary overall response rate of 82.5% with four patients (17.5%) showing a complete response and 15 patients (65%) a partial response. Six patients were again treated successfully with an IL-2 receptor antagonist because of recurrence of aGVHD. The rates of infections, chronic GVHD, malignancy recurrence and 1-year TRM following immunosuppression with basiliximab were comparable with those found with other treatment modalities for aGVHD. We conclude that basiliximab is efficient and feasible for steroid-refractory aGVHD and merits further evaluation.     

Diagnosis and manifestations of chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) is an immunoregulatory post-transplant disorder which shares features of autoimmunity and immunodeficiency. This chapter describes the major recommendations of the National Institutes of Health (NIH) consensus process on chronic GVHD conducted in 2004 and 2005 with respect to new guidelines for the diagnosis and staging of GVHD. Acute and chronic GVHD were redefined to emphasize the central importance of distinct diagnostic manifestations differentiating the two entities, rather than time of onset post-transplant. The diagnosis of chronic GVHD requires, at a minimum, the presence of at least one diagnostic clinical sign of chronic GVHD or the presence of at least one distinctive clinical manifestation confirmed by biopsy or other relevant tests in the same or another organ. Diagnostic criteria include signs and symptoms which are sufficient alone to establish the diagnosis of chronic GVHD. They can involve the skin and appendages, mouth, eyes, female genitalia, esophagus, lungs, and connective tissues. The NIH consensus project also generated a chronic GVHD scoring system and suggestions for overall grading of severity of chronic GVHD. The expectation is that the provisional guidelines described here will be widely used and refined with additional observer experience.     

A metalloproteinase inhibitor prevents acute graft-versus-host disease while preserving the graft-versus-leukaemia effect of allogeneic bone marrow transplantation

We examined the effect of a hydroxamic acid-based matrix metalloproteinase inhibitor (KB-R7785), which we previously demonstrated to have a potent ameliorating effect on acute graft-versus-host disease (GVHD), and on the graft-versus-leukaemia (GVL) effect of allogeneic bone marrow transplantation (BMT). KB-R7785 was administered to (C57BL/6 x BALB/c) F1 (CBF1) mice that had been inoculated with IgE-producing B53 hybridoma cells of BALB/c origin as a model tumour, along with or without transplantation of C57BL/6 (B6) bone marrow cells and spleen cells (BMS). Administration of KB-R7785 without BMS significantly prolonged the survival of B53-inoculated CBF1 mice by inhibiting the infiltration of B53 cells into the liver and spleen. Transplantation of B6 BMS without KB-R7785 resulted in the death of most recipients due to acute GVHD while efficiently eliminating B53 cells. Administration of KB-R7785 along with B6 BMS resulted in a 50% survival of B53-inoculated CBF1 mice over 50 d without histological manifestations of acute GVHD or residual B53 cells. These results indicate the beneficial effects of KB-R7785 that inhibit tumour infiltration and prevent acute GVHD while preserving the GVL effect of allogeneic BMT.     

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.     

Advances in understanding the pathogenesis of graft-versus-host disease

Acute graft-versus-host disease (GVHD) remains a major complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The emergence of different immuno-prophylaxis strategies, such as post-transplant cyclophosphamide or anti-thymocyteglobulin has reduced the incidence of acute GVHD in recent years. The biology of the acute GVHD we observe in the clinic may change due to the use of novel immuno-stimulatory agents, including immune checkpoint inhibitors or anti-neoplastic immune-modifiers, like lenalidomide, given before or after allo-HSCT. Here we discuss the recent advances in our understanding of acute GVHD with a focus on early events of the disease, including tissue damaging factors, innate immune cells, costimulatory pathways, immune cell signalling, immuno-regulatory cell types, biomarkers of GVHD and regenerative approaches. New insight in the pathogenesis of acute GVHD has revealed the role of pro-inflammatory intracellular signalling, defects in intestinal tissue regeneration and anti-bacterial defence, as well as a reduced diversity of the microbiome, which will be the basis for the development of novel therapies.     

Sirolimus for the treatment of multi-resistant pure red cell aplasia

Patients with relapsed, refractory or advanced stage B non-Hodgkin lymphoma (NHL) continue to have a dismal prognosis. This review summarises current and novel cellular and immunotherapy for these high-risk populations, including haematopoietic stem cell transplant, bispecific antibodies, viral-derived cytotoxic T cells, chimeric antigen receptor (CAR) T cells, and natural killer (NK) cell therapy, as discussed at the 6th International Symposium on Childhood, Adolescent and Young Adult Non-Hodgkin Lymphoma on September 26th–29th 2018 in Rotterdam, the Netherlands, and explores the future of NK/CAR NK therapies.     

Cyclosporin A versus methotrexate,followed by rescue with folinic acid as prophylaxis of acute graft-versus-host disease after bone marrow transplantation

Summary Fifty-seven patients undergoing bone marrow transplantation were randomly assigned to receive either cyclosporin A (CsA, n=26) or methotrexate, followed by rescue with folinic acid (MTX + FA, n=31) as prophylaxis for graft-versus-host disease (GVHD). All patients but one receiving CsA had evidence of sustained engraftment, and there was no difference between the two groups on the day in which marrow engraftment was documented. Oropharyngeal mucositis was of similar incidence and severity in the two groups. In contrast, patients receiving CsA showed higher renal and hepatic toxicity rates than those treated with MTX + FA. Severe-to-moderate acute GVHD (grades II–IV) was documented in 12 patients receiving CsA and in 12 treated with MTX + FA. The cumulative incidence of this complication was similar in both groups (46.1% and 38.7%). Similarly, there was no difference in the incidence of chronic GVHD. The leukemic relapse rates were also comparable, as well as the estimated probability of survival, which was 55% in patients treated with MTX + FA and 41% in those who were given CsA. We conclude that MTX + FA is as effective as CsA in the prevention of GVHD, with the additional advantage of reduced renal and hepatic toxicities.     

The TNFd4 allele is correlated to moderate-to-severe acute graft-versus-host disease after allogeneic stem cell transplantation

Certain cytokine gene polymorphisms may be associated with severe acute graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. The present study analysed 196 patients and their donors for TNF-308, TNFd, IL-10-1064 and IL-10-1082 gene polymorphisms. Serum analysis of tumour necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10) levels during conditioning therapy was also performed. Among patients with sibling donors, the TNFd allele 4 was significantly correlated with acute GVHD grades II-IV (P < 0.01). Acute GVHD grades II-IV were more common among patients homozygous for the IL-10-1064 allele 13 (P = 0.02). Patients homozygous for the TNF-308 allele (AA) correlated with higher TNF-alpha serum levels during conditioning (P = 0.02).     

Evaluation of prognostic factors among patients with chronic graft-versus-host disease

Background

Chronic graft-versus-host disease (cGVHD) is a major complication after allogeneic stem cell transplantation with an adverse effect on both mortality and morbidity. In 2005, the National Institute of Health proposed new criteria for diagnosis and classification of chronic graft-versus-host disease for clinical trials. New sub-categories were recognized such as late onset acute graft-versus-host disease and overlap syndrome.

Design and Methods

We evaluated the prognostic impact of the new sub-categories as well as the clinical scoring system proposed by the National Institute of Health in a retrospective, multicenter study of 820 patients undergoing allogeneic stem cell transplantation between 2000 and 2006 at 3 different institutions. Patients were retrospectively categorized according to the National Institute of Health criteria from patients’ medical histories.

Results

As far as the new sub-categories are concerned, in univariate analysis diagnosis of overlap syndrome adversely affected the outcome. Also, the number of organs involved for a cut-off value of 4 significantly influenced both cGVHD related mortality and survival. In multivariate analysis, in addition to NIH score, platelet count and performance score at the time of cGVHD diagnosis, plus gut involvement, significantly influenced outcome. These 3 variables allowed us to develop a simple score system which identifies 4 subgroups of patients with 84%, 64%, 43% and 0% overall survival at five years after cGVHD diagnosis (score 0: HR=15.96 (95% CI: 6.85–37.17), P<0.001; score 1: HR=5.47 (95% CI: 2.6–11.5), P<0.001; score 2: HR=2.8 (95% CI: 1.32–5.93), P=0.007).

Conclusions

In summary, we have identified a powerful and simple tool to discriminate different subgroups of patients in terms of chronic graft-versus-host disease related mortality and survival.     

Treatment of steroid refractory acute and chronic graft-versus-host disease with daclizumab

Competitive inhibition of interleukin 2-dependent lymphocytes by daclizumab demonstrates some beneficial effects in the treatment of graft-versus-host disease (GVHD). Sixteen patients with steroid refractory GVHD received daclizumab (1 mg/kg BW) on d 1, 2 (-5), 7, 14 and 21. Twelve patients suffered from grade III-IV acute GVHD and four patients from extensive chronic GVHD. Responses were observed in nine patients (six acute, three chronic GVHD). Fourteen out of 16 patients acquired infections during daclizumab treatment and three deaths were infection related. Daclizumab demonstrates limited activity and is associated with an increased incidence of infectious complications.     

MAGIC biomarkers of acute graft-versus-host disease: Biology and clinical application

Acute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation and is the primary cause of early non-relapse mortality (NRM) after transplant. GVHD of the gastrointestinal (GI) tract fuels the systemic inflammatory reaction and consequently is the principal driver of mortality. Recently, the MAGIC algorithm probability (MAP) that is computed from two biomarkers of GI GVHD has been validated to accurately predict risk of NRM throughout the course of early acute GVHD. This review focuses on the biology, clinical evidence, and practical application of the biomarkers in the measurement of acute GVHD.     

Management of acute graft-versus-host disease

Acute graft-versus-host disease (GvHD) is a frequent complication of allogeneic haemopoietic stem cell transplantation (HSCT) and donor lymphocyte infusions (DLI). Its incidence and severity depends on several factors, such as prophylaxis method, donor/recipient matching, intensity of the conditioning regimen and composition of the graft. Significant progress has been made in recent years in understanding the pathogenesis of the disease, and some of these advances have been translated into clinical trials. First-line treatment of acute GvHD is based on corticosteroids, and produce sustained responses in 50-80% of patients depending on the initial severity. Non-responders are offered second-line therapy, with combinations of immunosuppressive agents, but 1-year survival is 30% in most large trials. New strategies explored include infusion of expanded mesenchymal stem cells (MSC), down regulation of antigen-presenting cells (APC) and suicide gene transduced T cells. Acute GvHD is complicated by severe immunodeficiency causing life-threatening infections. To date, GvHD has not been differentiated from the graft-versus-leukaemia effect. The present review will discuss some of these aspects.     

The effect of therapeutic bronchoalveolar lavage in combination with glucocorticoids on children with acute exogenous lipoid pneumonia

Background

Exogenous lipoid pneumonia (ELP) is a rare disease caused by the inhalation of oily materials in the alveoli with the pathological characterization by the presence of laden-lipid macrophages in the respiratory specimens. At present, the treatment norm for ELP has not well defined, and so the aim of this study is to evaluate the effect of bronchoalveolar lavage in combination with glucocorticoids on children with ELP.

Methods and Materials

We retrospectively reviewed 17 children with a confirmed history of exogenous oily materials aspiration, admitted to the First Affiliated Hospital of Guangzhou Medical University from June 2012 to December 2021. Clinical features, blood investigations, tomographic evaluations, therapeutic bronchoalveolar lavage and glucocorticoids use were carried out at the beginning of therapy and throughout a follow-up period.

Results

The included children are the median age of 2 years. Fever, dypnea and tachypnea were the most common symptoms. The most common radiological features were airspace consolidations (15, 93.75%). Chest CT scans showed areas of consolidation with air bronchogram (15, 93.75%), poorly defined centrilobular nodules (13, 81.25%), areas of ground-glass attenuation (11, 68.75%) and ‘crazy-paving’ pattern (6, 37.5%) in the both lower, right middle lung lobes. Neutrophil percentage of peripheral blood and bronchoalveolar lavage fluid exhibited a significantly higher than the normal range. After treatment with multiple bronchoalveolar lavages and local administration of budesonide during the hospital stay, taken by oral prednisolone (1 ~ 2 mg/kg) after discharge, all of children became asymptomatic and presented normal radiological imagings in the follow-up period.

Conclusion

The most frequently findings in the CT scan of ELP were consolidations and ground-glass attenuation in the both lower and right middle lung lobes. Multiple bronchoalveolar lavages in combination with oral prednisolone for children who had a confirmed history of exogenous oily substances ingestion were an efficient and safe for the clearance of oily materials from the lung and the prevention of fibrosis. This strategy contributed to reducing the damage of ELP in children patients.     

Rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease

We prospectively evaluated the safety and efficacy of the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of corticosteroid-refractory chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation. Seven patients were treated with 375 mg/m² rituximab weekly for 4 consecutive weeks. Rituximab was well tolerated with no severe toxicity observed during treatment. At 1 year, 3 patients showed a partial response to rituximab therapy, 3 had stable disease, and 1 had progressive disease. Rituximab allowed a reduction in the dose of steroids in 4 patients. Responsive manifestations included mild to moderate skin and oral lesions, and immune hemolytic anemia, and thrombocytopenia. Severe manifestations involving the skin, fascia, and eye did not respond to treatment. These observations suggest that rituximab therapy may be effective for select patients with corticosteroid-refractory chronic GVHD that is not advanced.     

An in vivo model of human skin acute graft-versus-host disease: transplantation of cultured human epidermal cells and dermal fibroblasts with human lymphocytes into SCID mice

The ability of mixed epidermal cell-lymphocyte reactions to detect allogeneic reactivities in an in vivo model was investigated by developing an in vivo model of acute graft-versus-host disease (GVHD), using SCID mice with a C.B-17 background in which human skin structures were generated by transplantation of cultured human epidermal cells (HEC) with dermal fibroblasts (HDFC). Suspensions containing cultured HEC and HDFC from a single donor were mixed with autologous peripheral blood mononuclear cells (PBMNC) or with PBMNC from unrelated individuals, and were injected into the flanks of C.B-17-SCID mice. Ten and 21 days after injection, subcutaneous nodules generated in the mice were examined histologically and immunohistochemically. Cystic structures developing after injection of HEC and HDFC without human PBMNC showed normal epidermislike tissue. Human skin generated in SCID mice injected with HEC and HDFC with auto-PBMNC showed no graft-versus-host reaction (GVHR) histologically, whereas those mice injected with PBMNC from siblings that shared an HLA haplotype showed mild GVHR. Human skin in SCID mice injected with HEC and HDFC with histoincompatible unrelated PBMNC showed moderate to severe GVHR. The severity of GVHR paralleled the dose of unrelated PBMNC, and GVHR was prevented by peroral treatment with cyclosporine A. Immunohistochemically, inflammatory cells infiltrating human cutaneous tissue formed in the SCID mice were stained by an anti-human CD45RO antibody that reacts with human T cells but not with murine lymphocytes, and most T cells were stained by an anti-human CD8 antibody recognizing HLA class I antigens. These findings are similar to those in clinical skin graft-versus host disease (GVHD) observed in patients undergoing allogeneic bone marrow transplantation. This experimental system should be useful as an in vivo model of human skin GVHD.     

Safety and Long-Term Efficacy of Sirolimus Eluting Stent in ST-elevation Acute Myocardial Infarction: The REAL (Registro REgionale AngiopLastiche Emilia-Romagna) Registry

Summary Background: Limited data are available for sirolimus eluting stent (SES) implantation in patients with ST-segment elevation myocardial infarction (STEMI). Aim: to confirm the safety and effectiveness of SES in patients with STEMI in a real-world scenario (multicentric registry). Methods: From July 2002 to June 2004, clinical and angiographic data of 1617 patients with STEMI treated with primary percutaneous coronary intervention (PCI) have been collected. Patients were prospectively followed for the occurrence of major adverse cardiac events (MACE): death, reinfarction and target vessel revascularization (TVR). Results: Overall, 205 patients received SES (12.5%, SES group) and 1412 received bare metal stent (87.5%, BMS group) in the infarct related artery. Compared with the BMS group, SES patients were younger, had more often diabetes mellitus, anterior localization and less cardiogenic shock at admission. The angiographic characteristics in the SES group showed longer lesions and smaller diameter of vessels. After a median follow-up of 396 days, there was no significant difference in the rate of stent thrombosis (1% in the SES group vs 1.5% in the BMS group, p=ns). The incidence of MACE was significantly lower in the SES group compared to BMS group (HR 0.62 [95% CI: 0.4–0.95]; p=0.03), principally due to the lower rate of TVR (HR 0.41 [95% CI: 0.2–0.85]; p=0.01). Conclusions: Utilization of SES in the setting of primary PCI for STEMI, in our “real world” registry, was safe and improved the 1-year clinical outcome compared to BMS reducing the need of TVR.     

Diagnosis and management of acute graft-versus-host disease

A joint working group established by the Haemato-oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft-versus-host disease. This guideline includes recommendations for the diagnosis and grading of acute graft-versus-host disease as well as primary treatment and options for patients with steroid-refractory disease. The goal of treatment should be effective control of graft-versus-host disease while minimizing risk of toxicity and relapse.     

Hepatitis E infection in adults with primary immunodeficiency with or without immunoglobulin replacement therapy

BackgroundIn a context of secondary immunodeficiency, hepatitis E virus (HEV) infection can be responsible for chronic liver disease.Materials and methodsWe investigated HEV infection in patients with primary immunodeficiency treated (or not) with immunoglobulin (Ig) replacement therapy (IgRT) in France, a country with a high seroprevalence of HEV. In a nationwide study of individuals with primary immunodeficiency, 533 patients (349 and 184 receiving IgRT or not, respectively) were tested for HEV RNA and anti-HEV antibodies. In addition, 23 batches of five different commercially available immunoglobulin preparations were screened for anti-HEV IgG.ResultsThree of the 533 patients displayed markers of a recent HEV infection (HEV RNA in one case, and anti-HEV IgG and IgM in two) but no evidence of chronic liver disease. The overall seroprevalence of HEV was 50% (266 out of 533), with values of 68% and 16% in patients receiving IgRT or not, respectively (p<0.001). Anti-HEV IgG were detected in all batches of immunoglobulin preparations, although the titer varied from 3 to 127 IU/g IgG. Seroconversion was observed in 15 of the 22 (68%) patients tested before and after IgRT.DiscussionNo cases of chronic HEV-related disease were detected among patients with primary immunodeficiency and hypogammaglobulinemia, whether they received IgRT or not. This confirms that patients with primary immunodeficiency have a low risk of chronic infection despite a seroprevalence close to that observed in the French general population and that IgRT, which confers a high HEV seroprevalence, might play a key role in protection against chronic infection.     

老年急性髓系白血病的治疗现状

急性髓系白血病（AML）随着年龄的增长发病率逐渐升高。由于老年AML患者化疗完全缓解率低,治疗相关死亡率高,长期生存率低,预后差,尚缺乏统一有效的治疗策略。本文就目前老年AML治疗现状作简单综述,探讨传统化疗、造血干细胞移植及新的靶向药物在老年AML治疗中的应用。