Transfusion-associated Graft-versus-host Disease Research Articles

Application Development of Blood Irradiation Indicator -Review

Transfusion-associated graft-versus-host disease (TA-GVHD) is known as one of common complications of blood transfusion. The blood irradiation is generally accepted as a proven method to prevent from this disease, for the reason that it makes lymphocytes inactivated in blood products. The blood irradiation indicator provides a guarantee of proper radiation dose, thus improving the transfusion safety. Though widely used in developed countries for decades, the blood irradiation indicator is still in the initial stage in our country. In this review, the action principle, applications and applied value of the blood irradiation indicator are summarized briefly.

Colorimetric detection of low dose gamma radiation based on the aggregation of gold nanoparticles and its application for the blood irradiation

To develop a simple and sensitive sensor for gamma radiation is of great importance not only for public safety, but also for rational utilization of ionizing radiation. In this study, a simple and sensitive method for colorimetric detection of low dose gamma radiation has been developed based on the single-strand DNA modified AuNPs (ssDNA-AuNPs), which were synthesized by immobilizing the sulfhydryl ssDNA on the surface of AuNPs. After the gamma radiation, the colors of ssDNA-AuNPs changed from wine-red to blue-purple gradually, and this can be easily distinguished by the naked eyes. Over a range from 0 to 30 Gy, a good linear relationship between the ratio of absorbance at 625 nm to that at 521 nm (A625/A521) in the UV–vis spectrum and radiation dose was obtained. The detection limit was as low as 0.5 Gy. The colorimetric mechanism was ascribed to the generation of hydroxyl radical during the gamma radiation. As a result, ssDNA was cut off and released from the AuNPs. Then the salt effect caused the aggregation leading to the distinct color change. The capability of the method has also been demonstrated for anti-radiation efficiency comparison of different radioprotectors. In addition, lymphocytes irradiation expriment indicated that the ssDNA-AuNPs prepared in this work can be successfully used for an indicator during blood irradiation to avoid transfusion associated graft vs. host disease (TA-GVHD).

Prevention of Transfusion-Associated Graft-Versus-Host Disease With Blood Product Irradiation: The Past, Present, and Future.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a disease with a very high mortality rate. In this report, we discuss TA-GVHD from a historical perspective, highlight the pathogenesis of TA-GVHD, and emphasize the importance of blood product irradiation, which is a very effective means to prevent this disease. We summarize the current recommendations in different patient populations from different countries and review recent developments, such as alternatives for the use of radioactive materials. We also speculate on future directions.

P224 Diversity of alleles and haplotypes of HLA class I and class II in Saudi population

Aim Human Leukocyte Antigens (HLA) play an important role in host immune responses to infectious pathogens, bone marrow and organ transplantation, cancer and autoimmune diseases. HLA association studies have shown that homozygosity was associated with worse clinical outcomes of transfusion associated-graft versus host disease (TA-GvHD). Here we conducted a retrospective study of HLA class I and class II genes homozygosity at allelic and haplotype levels in patients and healthy donors genotyped from 2012 to 2016 in a tertiary hospital at the capital of Saudi Arabia. Methods About 2773 cases were retrospectively analyzed for HLA-A, -B, -C -DRB1 and DQB1 homozygosity at allelic and haplotype levels. HLA molecular typing was performed using a commercial Sequence-Specific oligonucleotides (SSO) kit and following the manufacturer instructions (rSSO; One Lambda, Canoga Park, CA). Statistical analysis was done with Fisher’s exact test (two-tailed). The analysis was performed on Stata package. Results In contrast to other populations, we were able to identify only 46 HLA class I and 18 class II alleles demonstrating a very low genetic diversity in Saudi population. A total of 15 HLA-A, 20 HLA-B, 11 HLA-C, 13 HLA-DRB1 and 5 HLA-DQB1 alleles have been identified. In class I, the highest homozygosity is found in locus C followed by A and B (21.3% > 17.1% > 15.5%; p 20.3%; p Conclusions We found low genetic diversity of both class I and II alleles and haplotype in Saudi population which would have a significant impact in shaping the transplantation practices, transfusion associated graft versus host disease practices and host-pathogen interactions in the population.

Prevention of transfusion-associated graft-versus-host disease with pathogen-reduced platelets with amotosalen and ultraviolet A light: a review.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a serious complication of blood component transfusion therapy, caused by donor T lymphocytes. γ-Irradiation or pathogen inactivation methods, capable of inactivating proliferating T cells in blood components, should be selected to prevent TA-GVHD. This review summarizes the published evidence to support the use of pathogen-reduced platelets with amotosalen (150 μm) and ultraviolet A light (UVA, 320-400 nm, 3 J/cm2 ) for preventing TA-GVHD. Available literature on the use of pathogen-reduced platelets to prevent TA-GVHD was reviewed. Observational studies, animal models, in vitro studies and mechanistic studies of pathogen-reduced platelets with amotosalen and UVA light showed that inactivation of T cells are equal or even superior to γ-irradiation. Pathogen-reduced platelets with amotosalen and UVA light can be used as a measure to prevent TA-GVHD.

Photochemical inactivation of lymphocytes by riboflavin with visible light for TA-GVHD prevention

Transfusion-associated graft-versus-host disease (TA-GVHD) is a life-threatening complication caused by the input of a number of immunocompetent allogeneic lymphocytes. This study focus on the photochemical effects of riboflavin excited by visible light (RB+L) treatment on human lymphocytes, to study the feasibility of using RB+L treatment to prevent adverse immune reactions caused by transfused lymphocytes. 100μM riboflavin was added to lymphocyte suspensions. After exposure to 400–580nm visible light with a total energy of 40J/mL, cells were cultured and the ability of proliferation and cytokine secretion were assayed upon stimuli. Meanwhile, lymphocytes were also treated by gamma-irradiation as parallel to testify the inactivation effect of RB+L. Results showed that γ-irradiation and RB+L treated cells showed a decline in cell viability. After stimulation of phytohemagglutinin (PHA) or anti-CD3 together with anti-CD28, proliferative ability of RB+L treated cells was strongly inhibited when compared to untreated cells. The inhibitive rates of proliferation in RB+L group were also higher than those of cells treated by γ-irradiation. Results of CFSE assays also illustrated hardly any cell division of RB+L and γ-irradiation treated lymphocytes. Besides low level productions of IL-4 and IL-12, cytokine production of TNF-α, IFN-γ and IL-10 by incubation with PHA or IL-1β, IL-2, IL-6, IL-8, IL-10, TNF-α and IFN-γ stimulated by anti-CD3 plus anti-CD28 were suppressed after treatment of RB+L significantly. It was suggested that RB+L/γ-irradiation treatment induced cell apoptosis. These results indicated that RB+L treatment functionally inactivated lymphocytes by inhibiting cell proliferation and cytokine production. RB+L might be an alternative for TA-GVHD prevention.

Study of CD69 antigen expression and integrity of leukocyte cellular membrane in stored platelet concentrates following irradiation and treatment with Mirasol® PRT System.

Leukocytes in transfused blood components, particularly residual lymphocytes, have been shown to contribute to the occurrence of various adverse reactions. One of the most severe is transfusionassociated graft versus host disease (TA-GvHD) following transfusion of blood components contaminated with immunocompetent T lymphocytes. Irradiation is a routine method for protection against TA-GvHD. According to the literature, some pathogen reduction methods have also been proven effective for the inactivation of T lymphocytes, and so they may be considered as an alternative to irradiation. Comparison of CD69 antigen expression and the integrity of the leukocyte cellular membrane in stored platelet concentrates (PCs) following irradiation with the Gammacell 3000 Elan (Nordion Inc., Ottawa, Canada) and treatment with the Mirasol® Pathogen Reduction Technology (PRT) System (Terumo BCT, Lakewood, USA). The study included seven experiments. For each experiment we used 3 PCs, for Mirasol® PRT System treatment (M), for Gammacell 3000 Elan irradiation (R), and for the control (C). 7-amino-actinomycin D (7-AAD, Becton Dickinson, Franklin Lakes, USA) permeability was used to determine lymphocyte viability while CD69 antigen expression was the marker of lymphocyte activation. Analyses of 7-AAD and CD69 antigen expression were performed in a FACS Canto I flow cytometer (Becton Dickinson, USA). During 6 storage days, viable lymphocyte count decreased to 28% (p = 0.001) in the Mirasol® PRT System treated PCs and to 65% (p = 0.004) in the irradiated PCs. A statistically significant increase in CD69 expression in the irradiated PCs was observed; 1.3-fold on day 3 and 1.5-fold on day 6. In the Mirasol ® PRT System treated PCs, no statistically significant increase was observed. The in vitro results suggest that the Mirasol® PRT System is as effective as irradiation due to donor leukocyte inactivation capacity.

Anti-CD3 Antibody Ameliorates Transfusion-Associated Graft-Versus-Host Disease in a Chemotherapy-Based Mouse Model With Busulfan and Fludarabine

ABSTRACT To establish a transfusion-associated graft-versus-host disease (TA-GVHD) mouse model with busulfan and fludarabine for effective treatment evaluation. BALB/c (H-2d) mice were injected with busulfan (15 mg/kg) and fludarabine (30 mg/kg) twice a day for 4 days. The mice were transfused with 10 6 T cell-depleted bone marrow (TCD-BM )and cells in different groups 3 days after chemotherapy: syngeneic BALB/c, MHC minor mismatch DBA/2 (H-2d), or MHC major mismatch C57BL/6(H2-b). Recipient BALB/c mice were injected with either blood only or blood+splenocyte. TA-GVHD was monitored in terms of body weight loss, clinical scores, and survival. Dexamethasone (50 mg/kg), cyclophosphamide (50 mg/kg), cyclosporine A (30 mg/kg), and anti-CD3 (1 mg/kg) were injected to each group to examine the treatments. Blood transfusion alone is insufficient to induce TA-GVHD in a chemotherapy-based mouse model. A MHC-mismatched TA-GVHD model can be induced by splenocyte and blood transfusion. This MHC-mismatched TA-GVHD model was resistant to dexamethasone treatment. Treatment based on anti-CD3 monoclonal antibody slightly ameliorated TA-GVHD. Treatment effectiveness was associated with T-cell depletion following activation by anti-CD3. Busulfan and fludarabine chemotherapy regimen can be used to establish a TA-GVHD mouse model. Anti-CD3 monoclonal antibody is a potential alternative to treat TA-GVHD.

Phase II Study of Prophylactic Non-Irradiated Granulocyte Transfusions in AML Patients Receiving Induction Chemotherapy

Background: Patients with Acute Myeloid Leukemia (AML) experience profound neutropenia; infections remain the leading cause of morbidity and mortality. Transfusion of functional non-irradiated allogeneic granulocytes may treat or prevent infections in AML patients, and may also have anti-leukemic benefits. Study Design: Patients free of infection, with a diagnosis of AML or high-risk myelodysplastic syndrome undergoing induction or first-salvage therapy were eligible. Allogeneic Granulocyte Transfusions (GTs) were administered to neutropenic (<0.5 × 109/L) patients every 3-4 days until sustained ANC recovery, initiation of new therapy, or completion of 6 weeks on study. Results: 45 patients enrolled with a median age of 67 years (range 23-83); 27 (60%) were male. Five patients (11%) never received a GT, due to donor screening failure and/or donor unavailability. 119 donors donated 156 granulocyte concentrates to the remaining 40 patients. The median number of GTs transfused per patient was 3 (range 1-9). All patients experienced >1 neutropenic fever, with an average of one infectious episode per patient. Other adverse reactions were urticaria/pruritis (n=1), rash (n=1), and hypotension (n=1). Response to leukemiadirected therapy included complete remission in 50%, overall response rate of 70%, and 8-week mortality of 8%. Median overall survival was 15 months, with 51% 1-year survival. Conclusion: Administration of non-irradiated functional allogeneic GTs to neutropenic MDS/AML patients is safe and feasible. No transfusion-associated graft-versus-host-disease (TA-GVHD) was reported and no increased toxicity was described, including among the 10% receiving subsequent allogeneic stem cell transplant. The favorable patient outcomes within this diverse group of primarily elderly AML are notable.

Pathogen Inactivated Platelet Components Used without Leukofiltration, or Gamma Irradiation Show Comparable Therapeutic Efficacy and Safety to Gamma Irradiated and Non-Leukofiltered Conventional Products for the Support of HSCT Patients in Hong Kong

▪Introduction: Depending on the conditioning intensity and graft source, mosthematopoietic stem cell transplant(HSCT) patients invariably experience a cytopenic phase of at least 2-3 weeks and require transfusion support until engraftment. All transfused blood components post-transplant need to be gamma irradiated to prevent transfusion associated graft versus host disease (TA-GVHD). Platelet component (PC) manufacturing methodologies differ around the globe. Currently, Hong Kong HSCT patients are supported with individual platelet rich plasma (PRP) PCs without leukocyte filtration (NLF), tested by short-term aerobic cultures for bacterial contamination (STABC), and gamma irradiated. When new PC manufacturing methodologies are considered for adoption, it is important to assess the immediate and longer term effects on transfused patients. Amotosalen+UVA light (A-UVA) pathogen reduction technology (INTERCEPT™ Blood System, Cerus Corporation, Concord, CA) inactivates bacteria, viruses, parasites and leukocytes by efficient covalent adduct modification of DNA and RNA. Treatment with A-UVA prevents TA- GVHD in an animal model, inhibits clonal T cell proliferation, prevents allogeneic antigen stimulation in mixed lymphocyte reactions, and inhibits transcription mediated cytokine production and early activation antigen expression (Corash et al, BMT 2004). The common strategy of prescribing gamma irradiated PC only for suspected "high risk" patients is sub-optimal, as failure to identify recipients at risk for TA-GVHD was responsible for 50% of reported cases (Kopolovic et al. Blood 2016). Treatment of PC with A-UVA addresses two key issues for HSCT patients: bacterial contamination, and universal prevention of TA-GVHD. Here, we compared the clinical support of HSCT patients with conventional PCs (C-PC) vs. an equivalent HSCT group supported with A-UVA PCs (I-PC) using a sequential patient cohort design within a single HSCT clinical center.Methods: I-PCs were prepared from 5 pooled ABO-matched, NLF buffy coat PCs in platelet additive solution and treated with A-UVA replacing gamma irradiation and bacterial detection. C-PCs were prepared from 5 ABO-matched, STABC-negative, NLF PRP PCs, and treated with gamma irradiation. Each patient could receive up to 5 PC transfusions. The primary efficacy endpoint was the 1-hour corrected count increment (CCI) and the primary safety endpoint was the proportion of patients (P) with acute transfusion reactions (ATR). Follow-up data on mortality, hematopoiesis engraftment, and immune status were collected up to 100 days post HSCT.Results: Patient demographics and type of HSCT were similar between patient cohorts. 33 patients received 76 A-UVA PCs and 31 patients received 89 C-PCs. The mean days of platelet support (p=0.618) and mean 1-hour CCIs per patient averaged for all transfusions were comparable (p=0.296) between the I- PC and conventional C-PC cohorts (Table). The proportion of patients with AEs was lower (p=0.021) for the I-PC group (Table), and no related SAEs were observed during the entirety of trial. Survival at 100 days post HSCT and rates of remission were similar between the cohorts (Table). The ATR rate trended lower, although not significantly different (p=0.296), in the I- PC group (Table). Follow-up data showed that the patients had comparable neutrophil and platelet engraftment (Table) with comparable immune system reconstitution by 100 days post HSCT. No cases of TA-GVHD were observed in either cohort.Conclusions: A-UVA-treated PCs prepared without LF, gamma irradiation, and bacterial detection can replace C-PCs for support of HSCT patients resulting in comparable post transfusion CCI responses and short and intermediate term clinical outcomes, while offering additional protection against transfusion transmitted bacteria and emerging or untested pathogens. [Display omitted] DisclosuresSim Pui Yin:Cerus Corporation: Other: Investigator sponsored trial. Leung Yuk Yan:Cerus Corporation: Other: Investigator sponsored trial. Lam Chun Kit:Cerus Corporation: Other: Investigator sponsored trial. Tsoi Wai:Cerus Corporation: Other: Investigator sponsored trial. Lee Cheuk:Cerus Corporation: Other: Investigator sponsored trial. Lie Kwok Wai:Cerus Corporation: Other: Investigator sponsored trial. Huang:Cerus Corporation: Employment. Rico:Cerus Corporation: Employment. Lin:Cerus corp: Employment. Corash:Cerus Corporation: Employment. Stassinopoulos:Cerus Corporation: Employment.

Treatment Use Study of Platelet Components Treated with Amotosalen and Ultraviolet a Light in Response to Emerging Arboviruses in Puerto Rico - True Study Final Results

▪Background: In 2014, epidemic chikungunya virus (CHIKV) emerged in Puerto Rico, concurrent with endemic dengue (DENV). The Department of Health mandated blood donation quarantine for 72h pending follow-up donor contact for infectious symptoms. The American Red Cross (ARC) halted local platelet collections and began importing blood components. Imported platelet components (PCs) from the continental U.S. were used to supply hospitals in the Caribbean. An alternative strategy is local PC production with amotosalen +UVA (A-UVA) pathogen reduction (PR) technology (INTERCEPT™ Blood System, Cerus Corporation, Concord, CA) as utilized by the French Transfusion Service in the Overseas Territories, including the Caribbean since 2007. The major logistical advantage of such a strategy is earlier PC availability to hospitals since there is no need to wait for the results of bacterial culture, or transport of PCs from the continental U.S. A-UVA technology inactivates bacteria, viruses, parasites and leukocytes by efficient covalent adduct modification of DNA and RNA, thus addressing risks of bacterial contamination and reducing the risk of transfusion-transmitted infection (TTI). Treatment with A-UVA also prevents transfusion associated graft vs. host disease (TA-GVHD) in an animal model, inhibits clonal T cell proliferation, prevents allogeneic antigen stimulation in mixed lymphocyte reactions, and inhibits transcription mediated cytokine production and early activation antigen expression (Corash et al, BMT 2004) and is recognized by the AABB as a replacement for gamma irradiation in the prevention of TA-GVHD.Aims: A treatment use clinical study (TRUE) was conducted in Puerto Rico under the Investigational Device Exemption (IDE) early/expanded access regulations while the INTERCEPT Premarket approval (PMA) application was under review by the Food and Drug Administration (FDA). The objective of the TRUE study was to provide early access to INTERCEPT to reduce the risk of TTIs during the ongoing CHIKV/DENV epidemic.Methods: A prospective, open label, single arm, treatment use, multi-center study was conducted involving 7 hospitals and the ARC. Apheresis (Trima® or Amicus® collectors) leukocyte-reduced PR PCs, suspended in 100% plasma without gamma irradiation, bacterial contamination testing, or the need for CMV serology were produced. Safety outcome measures included all adverse events (AEs), serious adverse events (SAEs) and acute transfusion reactions. Patients were transfused with study PCs according to local practices for as long as clinically indicated.Results: 90 patients (55.6% male, mean age 67.2 y) were transfused with 256 PR PCs (2.8 ± 3.5/patient). The vast majority of the patients were hematology oncology patients (76.7%). Most patients (81.1%) received 1 transfusion cycle (transfusion support without > 5 days between transfusions) with 2 PR PCs (40.0%), while 32.2% received 1 PR PC, and 25.6% received between 3-10 PR PCs. Mean duration of platelet support was 14.7 days. Thirty-three unrelated AEs were reported in 26 patients. Nineteen patients (21.1%) had unrelated SAEs (including 17 deaths [18.9%]). Two febrile non-hemolytic reactions and one allergic transfusion reaction were reported and deemed unrelated to INTERCEPT by the investigators. No suspected cases of CHIKV or DENV infections or other TTIs were reported. Reported AEs were within the expected spectrum of co-morbidity and mortality for patients of similar age with advanced hematology-oncology diseases.Conclusions: The INTERCEPT Blood System was rapidly deployed in response to the CHIKV and DENV epidemic with replacement of bacterial detection, gamma irradiation and the need for CMV serology. No PR PC related AEs were reported. INTERCEPT was approved in late 2014 by the FDA to treat Amicus apheresis PCs suspended in platelet additive solution and in 2016 for Trima PCs suspended in 100% plasma. The importance of this proactive technology is highlighted by the recent emergence of Zika virus (ZIKV). FDA has recently requested that all blood establishments in Puerto Rico and in certain counties in Florida cease collecting blood immediately until investigational donor screening test for ZIKV RNA is implemented or until they implement the use of an approved or investigational pathogen reduction technology. DisclosuresRico:Cerus Corporation: Employment. Stramer:Cerus Corporation: Other: fee for service study with Cerus Corporation. Benjamin:Cerus corp.: Employment. Cartagena:Cerus Corporation: Other: fee for service study with Cerus Corporation. Arroyo:Cerus Corporation: Other: fee for service study with Cerus Corporation. Robles:Cerus Corporation: Other: fee for service study with Cerus Corporation. Carlo:Cerus Corporation: Other: fee for service study with Cerus Corporation. Vera:Cerus Corporation: Other: fee for service study with Cerus Corporation. Solivan-Ortiz:Cerus Corporation: Other: fee for service study with Cerus Corporation. Huang:Cerus Corporation: Employment. Koontz:Cerus Corporation: Employment. Berry:Cerus Corporation: Employment. Corash:Cerus Corporation: Employment.

ПОСТТРАНСФУЗИОННАЯ РЕАКЦИЯ ТРАНСПЛАНТАТ ПРОТИВ ХОЗЯИНА

Transfusion-associated graft-versus-host disease (TA-GvHD) is a very rare but potentially lethal complication occurring after blood components transfusion. Goal of the article: to analyze the literature describing this complication. TA-GvHD can develop due to several factors: quantity and viability of lymphocytes, contained in the transfused blood component, responsiveness of the patient's immune system to replantation of donor lymphocytes and degree of immunological HLA-homology between the donor and the recipient. History and epidemiology of this fatal syndrome, its pathogenesis, clinical manifestations, diagnostics and therapy have been reviewed. It has been shown that the main prevention techniques include abstaining from blood components transfusion collected from close relatives and using special irradiation modes, suppressing proliferation of the donor's lymphocytes. Conclusion: Doctors performing blood components transfusion should note that post-transfusion reaction development in the variant of graft-versus-host might develop in order to provide timely diagnostics and to start the specific treatment of this complication.

Evaluación de la eficacia de un irradiador terapéutico para la irradiación de concentrados eritrocitarios, en Oaxaca, México

La enfermedad injerto contra hospedero asociada a la transfusión (EICH-AT) es una reacción postransfusional grave debido al injerto de linfocitos residuales (LR) presentes en los componentes sanguíneos. El objetivo de este trabajo fue evaluar la eficacia del irradiador terapéutico THERATRON® Phoenix™ (cobalto 60) del Centro de Oncología y Radioterapia de Oaxaca, México, para eliminar la capacidad de proliferación de los LR en concentrados eritrocitarios (CR). Para este fin, se obtuvieron siete concentrados eritrocitarios de donadores de sangre seleccionados según los criterios de las normas oficiales nacionales, los cuales fueron irradiados a 2520 cGy; y se cuantificaron parámetros para evaluar la conservación del potencial terapéutico de los concentrados eritrocitarios (hemoglobina, hematocrito, hemólisis e hiperkalemia) y de efectividad para inactivar a los LR (número, viabilidad y capacidad proliferativa). El irradiador preservó la calidad e incrementó la seguridad transfusional de estos componentes sanguíneos al eliminar la capacidad proliferativa de los LR, y el análisis de costo-efectividad demostró su eficiencia para este proceso. Tomando como base estos resultados, se proponen estos parámetros como control de calidad para la validación de irradiadores terapéuticos y/o de rayos X para la irradiación de concentrados eritrocitarios, así como la difusión de este servicio en todo el país, con la finalidad de reducir la incidencia de la enfermedad injerto contra hospedero asociada a la transfusión.

Transfusion-Associated Graft-Versus-Host Disease with a Non-fatal Course.

Graft-versus-host disease (GVHD) is a clinical syndrome ascribed to the inflammatory reaction mounted by the donor cells against the host organs [1]. Transfusion associated graft-versus-host disease (TA-GVHD) is a rare and a fatal complication of the transfusion of non-irradiated cellular blood components in susceptible recipients [2]. It has low incidence of 0.1–1 % in susceptible recipients with an extremely high mortality rate of 87–100 % [3]. The underlying pathogenesis of this dreaded condition is due to the donor T-cells that engraft, proliferate and mediate a cellular immune response against host tissues, resulting in damage to skin, liver, gastrointestinal tract and bone marrow [2]. The existence of an atypical TA-GVHD, which does not follow a fatal course and exhibit all the manifestations of GVHD, has been suggested. English literature describes only two such published cases [4, 5]. The relative rarity of atypical TA-GVHD interested us to present this case report.

Use of non-irradiated blood components in Campath (alemtuzumab)-treated renal transplant patients.

The prevention of transfusion-associated graft-versus-host disease (TA-GvHD) through the irradiation of components is key as there is no effective treatment. Universal leucodepletion reduces but may not eliminate TA-GvHD; therefore, irradiation is still recommended. In 2010, Campath (alemtuzumab) was added as an indication for irradiation but was not implemented everywhere. To identify any cases of TA-GvHD in our Campath-conditioned renal transplant patients, who were transfused with non-irradiated components. Retrospective study of Campath-conditioned renal transplant patients transfused with non-irradiated components. In those transfused up to 9 months following Campath who survived to 1-year follow-up, TA-GvHD was excluded. For patients not followed-up for a full year, we reviewed medical records for features of TA-GvHD. For patients transfused after 9 months following Campath, survival of at least 3 months following last transfusion excluded TA-GvHD. Six hundred and forty-seven Campath-conditioned renal transplant patients were transfused; 616 were transfused within 9 months following Campath; 601 were alive at 1 year, excluding TA-GvHD. Twelve died and three were not followed-up for a full year, but a review of medical records excluded TA-GvHD. The 31 patients transfused 9 months or longer following Campath were all alive 6 months following the last transfusion, excluding TA-GvHD. Despite receiving non-irradiated components, none of the 647 Campath-conditioned renal transplant patients developed TA-GvHD. Further reviews to replicate our data could enable change to guidance, at least in UK where components are leucodepleted, as an unnecessary requirement for irradiated components has both clinical delay and cost implications.

Granulocyte Transfusions at Appropriate Doses Improve Survival in Hematological Patients with Febrile Neutropenia

Introduction. The granulocyte transfusions (GTXs) are used to booster antimicrobial drugs in severely neutropenic hematological patients. However, the optimal GTX dose and the actual efficacy of this practice are debated.Methods. We retrospectively evaluated the infection-attributable mortality (IAM, i.e. the mortality at 30 days after the last GTX) in 84 consecutive patients with hematological malignancies receiving GTXs (January 2009- December 2014). The indications for GTXs were i) presence of absolute neutrophil count (ANC) <0.5 x 10^9/l ii) fever with evidence of bacterial or fungal infections or symptoms of infections and iii) unresponsiveness to appropriate antimicrobial therapies for at least 48 hours.Results. Among 84 patients, 101 infectious episodes requiring GTXs were recorded (422 transfusions in total). Patients characteristics are summarized in Table I. Bacterial infections were documented in 94 episodes (Klebsiella pneumonia in 35 cases, Escherichia coli in 16 and Pseudomonas aeruginosa in 13), invasive fungal infections (IFI) in 34 cases (including 18 pulmonary aspergillosis and 14 candidemia); 8 cases were considered as FUO. The infection was mono-microbial in 60 cases and poly-microbial in 33. Sepsis occurred in 67 cases. The overall IAM was 26.7 % (27 deaths among 101 infective episodes). At univariate analysis we failed to detect statistical association between IAM and several evaluated variables, either patient-related (age, sex, diagnosis, status of disease, allo-HSCT, aplasia duration) or infection-related (bacterial infection or IFI, sepsis, XDR, G-SCF concurrent administration) or GTX-related (number of GTXs received, PMN /Kg/course, PMN/Kg/day of neutropenia). However, when we grouped patients according to the value of the median dose of PMN per transfusion, we found that patients receiving 1.5 - 3 x 10^8/kg (GTXs A) had a lower IAM than patients receiving less than 1.5 (GTXs B) or more than 3 x 10^8 /kg (GTXs C) (15,7%, 35,3% and 44,4%, for GTXs A, B and C, respectively, p=0,014 at chi-square test). The dose's cut off were derived from the Guide to the preparation, Use and Quality assurance of Blood Components of the European Committee on Blood Transfusion (16th Edition). If the analysis was carried out by pooling together GTXs B and C, the association between PMN dose and IAM was even more pronounced (p value =0.006 at Fisher test for GTXs A versus GTXs B+C). At Kaplan-Meier analysis, the median survival was 59 days for GTXs A-patients and 30 days for GTXs B+C-patients (p =0,010). When patients with bacterial of fungal infections were separately evaluated, the effect of PMN dose on IAM was confirmed in bacterial (n=54, p=0,008) but not in fungal (n=23, p=0,588) infections. We then introduced the PMN dose (GTXs A or GTXs B+C) in a Cox proportional-hazards regression model together with variables with p<0.1 at univariate analysis (sepsis) or other clinically relevant factors (Allo-HSCT, age over 60 years, disease status categorized as onset/remission or relapse/resistance ). The PMN dose was the unique variable significantly associated with IAM (HR=3,0; 1,1-8,0 95% CI, p=0,020).Conclusions. These findings suggest that appropriate GTX doses can improve the post-infection survival of severely neutropenic hematological patients. Transfusion-related immunomodulation, leukostasis or transfusion-associated GVHD may underlie the detrimental effect of high PMN doses and deserve to be better explored.Table 1Clinical characteristics of 84 patients treated with GTXs. A total of 101 courses were recorded.CharacteristicsAge (years, median value range)46 (20-74)Male/Female54/30Underlying disease (n, %)Acute myeloid leukemiaLymphomaAcute lymphoblastic leukemiaMyelodysplastic syndromeMultiple myelomaChronic lymphocytic leukemia63 (75%)12 (14%)5 (6%)2 (3%)1 (1%)1 (1%)Disease status at PMN transfusion (n, %)OnsetRelapse/resistanceComplete remission49 (48,5%)41 (40.5%)11 (10.8%)Duration of neutropenia (days, median value, range)18 (3-79)Site of infection (n, %)Sepsis LungBowelOthersMultiples (≥3 involved sites)67 (66.3%)22 (21.9%)4 (3.9%)8 (7.9%)4 (4%)Allo-HSCTYes No21(20.7)80(79.2)Transfusions per course (median value, range)4 (1-14)PMN x 108/kg/course (median value, range)8.78 (0.53-53.23)PMN x 108/kg/transfusion (median value, range)2.11 (0.46-7.34) DisclosuresNo relevant conflicts of interest to declare.

Pathogenesis and Prevention of Transfusion-Associated Graft-versus-Host Disease

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The disease is fulminant and fatal in most patients. TA-GVHD is caused by transfused alloreactive donor T lymphocytes that attack host tissue, including skin, liver, gastrointestinal tract and bone marrow. Most patients are immunocompromised, but immunocompetent patients can also be involved. Irradiation of blood components is generally recommended to prevent the onset of TA-GVHD for susceptible recipients. This review focus on pathogenesis and prevention of TA-GVHD.

Guidelines for the diagnosis and management of adult aplastic anaemia.

Sally B. Killick (Writing Group Chair), Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe, Anna Wood (BCSH Task Force Member), Judith C.W. Marsh on behalf of the British Society for Standards in Haematology. The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Northern Genetics Service, Newcastle upon Tyne, St Bartholomew’s Hospital, Barts Health NHS Trust, London, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, Addenbrooks Hospital, University of Cambridge, Cambridge, Leeds Teaching Hospitals, Leeds, Kings College Hospital NHS Foundation Trust, London, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Great Ormond Street Hospital for Children NHS Foundation Trust, London, West Hertfordshire NHS Trust, Watford.

Linear accelerator based blood irradiation for pediatric oncology practice in limited resource setting: Illumination and innovation.

e21001 Background: Blood Component Irradiation is the only proven method of preventing Transfusion associated graft versus host disease (TA-GVHD). The option of dedicated blood product irradiator i...

Preventing transfusion-associated graft-versus-host disease: state of the art

Preventing transfusion-associated graft-versus-host disease: state of the art Loren D Fast Division of Hematology/Oncology, Rhode Island Hospital and Warren Alpert School of Medicine at Brown University, Providence, RI, USA Abstract: The transfer of pathogens and the induction of immune responses are deleterious consequences that can result from the transfusion of blood products. Transfusion-associated graft-versus-host disease (TA-GVHD), the most severe immune consequence, occurs when recipient immune responses are incapable of effectively eliminating donor leukocytes, permitting unabated responses of the donor T lymphocytes. Currently, prevention of TA-GVHD is routinely accomplished by exposing blood products to &gamma;-irradiation in order to prevent donor T cell proliferation. Alternative protocols are being developed to meet the challenges associated with the use of &gamma;-irradiation. Use of pathogen reduction protocols, which interfere with nucleic acid replication by modifying nucleic acids, are increasing. Comparison of pathogen reduction protocols with &gamma;-irradiation have found that both protocols are equally effective in preventing T lymphocyte proliferation and GVHD responses when testing in both in vitro and in vivo models. The potential use of pathogen reduction protocols to treat whole blood prior to separation into its components could provide a cost-effective method for preventing TA-GVHD in the future. Keywords: blood transfusion, GVHD, pathogen reduction, irradiation