Haemopoietic Stem Cell Transplant Patients Research Articles

COVID-19 outcomes in haemopoietic stem cell transplant recipients in Western Australia: the value of vaccination and antiviral therapy.

Coronavirus-19 (COVID-19) mortality rates among haemopoietic stem cell transplant (HSCT) patients are high, ranging between 20% and 40%. We prospectively evaluated the mortality outcomes of COVID-19 in Western Australian HSCT patients. A total of 32/492 (6.5%) HSCT recipients contracted COVID-19 during the study, of whom 30/32 (94%) developed mild or asymptomatic disease. Two allogeneic HSCT patients were hospitalised for severe COVID-19; one patient died. Stringent healthcare, social isolation practices, aggressive vaccination programmes and rapid access to COVID-19 antivirals may have promoted mild COVID-19 illness in Western Australian HSCT patients, resulting in one of the lowest COVID-19 mortality rates in HSCT recipients worldwide.

Centre-based comparison of double versus single prevention strategy on transfusion-transmitted cytomegalovirus in at-risk haemopoietic stem cell transplant patients and a state survey on cytomegalovirus-seronegative ordering practises.

Universal leucocyte depletion reduces the risk of transfusion-transmitted cytomegalovirus; however, many clinicians still prescribe cytomegalovirus seronegative units. Our retrospective study aims to confirm the low risk of transfusion-transmitted cytomegalovirus with leucocyte depletion alone and demonstrate the ongoing variability in cytomegalovirus seronegative transfusion prescribing. Over a 9-year period (July 2009-July 2018), occurrences of transfusion transmitted cytomegalovirus in cytomegalovirus seronegative donor/recipient haemopoietic stem cell transplant pairs were compared at one allogeneic haemopoietic stem cell transplant centre providing cytomegalovirus seronegative blood products and leucocyte depletion (double prevention) versus another providing leucocyte depletion only (single prevention). Retrospective chart audit identified patient demographics, blood product exposure and cytomegalovirus infection by polymerase chain reaction. A separate audit examined cytomegalovirus seronegative blood product ordering in a broader range of hospital types. We identified 122 and 66 cytomegalovirus-negative donor/recipient haemopoietic stem cell transplant pairs using double and single transfusion prevention strategy respectively. Transfusion exposure to red cells and pooled platelets was similar, although more apheresis platelets were used in the double prevention group. The cytomegalovirus infection rate was 3 (2.4%) and zero in the double and single prevention groups respectively. Cytomegalovirus seronegative unit ordering was not limited to hospitals with obstetric or neonatal populations, suggesting ongoing reliance of cytomegalovirus seronegative units outside this population. The analysis suggests a double prevention strategy does not provide additional protection against transfusion-transmitted cytomegalovirus. There is ongoing variability in the acceptance of leucocyte depletion alone despite the low risk of cytomegalovirus infection.

Mass Cytometry Reveals the Broad Effect of CMV Reactivation on Adaptive and Innate Immune Recovery in HSCT Patients Undergoing Adoptive T Cell Therapy for Viral Infections

Introduction. Adoptive cell therapy (ACT) with virus specific T cells (VST) has been shown to be safe and effective in controlling viraemia in recipients of haemopoietic stem cell transplant (HSCT). Long term engraftment has been demonstrated in some studies but the fate of the transferred cells is not well understood. We hypothesised that the clinical effect of ACT is mediated by interaction of transferred cells with a wide range of innate and adaptive immune cells present in the recipient at the time of ACT treatment. In order to better understand the interaction of stem cell donor-derived and adoptively transferred third-party cells, we sought to apply immune profiling by mass cytometry.Methods. Longitudinal samples from healthy individuals and collected pre- and post-donor derived and third party ACT in HSCT recipients were assessed with a 37 marker panel to identify canonical immune subsets. Cryopreserved peripheral blood mononuclear cells were thawed in batches and stained with metal-labelled antibodies and markers for DNA content and viability. Samples were acquired on the Helios upgraded CyTOF2 mass cytometer. Following sample QC and normalisation of files, viable cells were manually gated to 75 canonical populations with cell subsets enumerated and represented graphically for each sample using visualised t-stochastic neighbour embedding (ViSNE). Cell subsets were expressed as percent of total cells as well as absolute cell number (x109/L) using lymphocyte and monocyte counts from an automated whole blood analyser. This approach was taken to incorporate the large numerical changes that occur in the early months post-HSCT. Mass cytometry data was analysed with unsupervised and supervised clustering algorithms to identify immune signatures. Significance of microarray (SAM) was used to identify the cell subset changes that contributed to the differences in clusters. t-stochastic neighbour embedding (tSNE) and principal component analysis (PCA) were used to correlate immune signatures with clinical variables including patient, transplant and donor baseline characteristics and post-transplant outcomes (including CMV reactivation and disease, acute GVHD, relapse and death).Results. A total of 104 samples from 9 healthy donors and 27 HSCT recipients who received ACT on phase I and II clinical trials were available for analysis. ViSNE revealed highly detailed relationships of the 75 cell subsets within individuals longitudinally and between patients. Unsupervised clustering on all patients and time points and the healthy individuals revealed three distinct immunological signatures (Figure 1). Healthy individuals (signature A) were clearly distinguished from all patients and no patient developed a normal immune profile over the timeframe of the study (up to 6 months post HSCT). In a subset of samples from HSCT recipients a distinct immune phenotype was seen (signature C), characterised by increased CD8+ subsets (CD8em, CD8emra (both of these with and without PD1), CD8+CD57+, CD8+CD31+), NK cell subsets (CD16-, NKp46loCD56lo), NKT cells and plasmacytoid dendritic cells. Of the clinical parameters assessed, signature C was most strongly correlated with CMV reactivation. Signature B showed lower cell numbers overall and included patients with acute GVHD treated with corticosteroids and patients in whom CMV reactivation progressed to CMV disease.Conclusion. Mass cytometry and sophisticated analysis reveal an unprecedented level of detail about the relationships of immune subsets to one another at single time points and their changes over time. This approach identifies distinct global immune signatures involving changes to multiple immune subsets in patients undergoing HSCT and ACT. We have identified an immune signature associated with CMV reactivation that indicates a broader effect of CMV reactivation on immune recovery than previously recognised. As this study was not randomised and did not include a control group who were not treated with ACT, further investigation is required to define the contribution of ACT to the observed immunological changes. This global approach to immunological assessment has the potential to improve understanding of the dynamics of immunological recovery post HSCT. [Display omitted] DisclosuresGottlieb:Indee: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Factors affecting attitudes on the decision to commence nasogastric tube feeding in haemopoietic stem cell transplant patients: a systematic review

Nutritional status has been linked to clinical outcomes in patients with cancer, and those being treated with haematopoietic stem cell transplant (HSCT) have a significant potential for prolonged periods of poor oral nutrition. This article explores factors affecting the provision of timely nasogastric tube feeding. A preliminary literature search identified a growing evidence-base for the choice and timing of nutritional support therapy. However, existing evidence and personal experience suggest that the use of nasogastric tubes to feed patients is often resisted by both health professionals and patients. This is the first systematic review to explore factors affecting attitudes on the decision to commence nasogastric tube feeding. Wide variation in practice already exists. Therefore, a better understanding of factors that affect the attitudes of health professionals and patients towards nutritional support therapy can facilitate the delivery of optimal nutritional care. The results provide a new perspective on how to achieve the best possible outcomes for patients.

TNFR2 Is Expressed Preferentially By Late Differentiated CD8 T-Cells and Can be Triggered By TNFR2-Specific Ligand to Induce Cell Death of Recently Activated Antigen-Specific T Cells: A Possible Role of TNFR2 in T-Cell Deflation

Recent evidence suggests that Tumor Necrosis Factor (TNF) can selectively kill antigen-specific autoreactive CD8+ T-cells through engagement with TNF Receptor 2 (TNFR2) (1). Within the immune system, TNFR2 expression is restricted to subsets of T-cells, a profile which is in marked contrast to the ubiquitous pattern of expression of TNFR1. However, the spectrum and physiological significance of TNFR2 expression by CD8+ T-cell subpopulations is unknown.In this study we analysed the expression of TNFR2 by CD8 T-cell subsets isolated from normal healthy donors by flow cytometry. In addition, in order to understand the physiological significance of TNFR2 expression on recently activated T cells, we further studied expression on CMV-specific CD8 T-cells which expanded in stem cell transplant patients in response to episodes of CMV reactivation. The expression of TNFR2 was compared to that of other common gamma chain receptors including IL2R and IL7R, and to the expression of a receptor for inflammatory cytokine IL6.TNFR2 expression was found to increase during differentiation of CD8+ T cells. In particular, TNFR2 expression was seen on 6.5% of naïve, 14.6% of central memory, 37.9% of effector memory and 45.2% of CD45RA-revertant effector memory (TEMRA) CD8+ T cells. In contrast, common gamma chain cytokine receptor expression was skewed towards less differentiated T-cell subsets. For example, IL-7R was expressed by 63% of central memory populations but only 18.4% of the TEMRA subset. Comparable expression of IL2R was 12.1% on TCM and 2% on TEMRA. Of interest, IL-6 receptor expression was predominantly expressed by naïve CD8 T-cells (69.5%). In support of these results, we went on to show that expression of TNFR2 was inducible on primary T cells following activation with anti-CD3 and IL-2 in vitro. Healthy CMV seropositive donors had a larger median number of CD8+ T cells expressing TNFR2 (53%) in comparison to CMV seronegative donors (15%), (p<0.0001), consistent with the known accumulation of differentiated T-cells within CMV seropositive individuals.The expression of TNFR2 was then examined on CMV-specific CD8 T-cells which were undergoing acute expansion in response to viremia in six haemopoietic stem cell transplant patients. The expansion of CMV-specific CD8 T-cells was accompanied by an increase in the intensity of TNFR2 expression which later decreased during the retraction of antigen-specific T-cells during resolution of viremia. In order to explore the functional significance of TNFR2 expression, T-cells isolated from healthy donors were treated with recombinant TNFR2-specific ligand. This induced cell loss ranging from 13% to 60% of all CD8 T-cells in relation to untreated control cells, with selective depletion of the TNFR2+ population. A similar proportion of CMV-specific T-cells from transplant patients were eliminated by ex vivo stimulation of TNFR2.In conclusion our work shows that TNFR2 expression increases during differentiation of CD8+ T cells. In addition, we were able to utilize virus-specific T cells from SCT patients to show that expression is increased during the acute response to stimulation with antigen. We also provide evidence that TNFR2 activation can lead to the partial elimination of antigen-specific CMV-specific T-cells and it may thus play an important role in the ‘deflation’ of a pathogen-specific T-cell immune response following resolution of infection. These data suggest that TNFR2 expression may act as a ligand to signal activation-induced cell death in late differentiated populations of CD8+ T cells. Further investigations are required to assess the molecular pathways of TNFR2 signalling that are activated following receptor ligation in vivoand whether or not these are disrupted in disorders associated with chronic CD8+ T cell lymphproliferation.(1) L. Ban et al, PNAS 2008, 105: 3644 DisclosuresNo relevant conflicts of interest to declare.

Management of cytomegalovirus infection in haemopoietic stem cell transplantation

● Cytomegalovirus (CMV) infection and CMV diseaseshould be diagnosed according to established, interna-tionally accepted, standardized criteria (Grade 1C).● Risk-adapted patient assessment should inform clinicalmanagement (Grade 1B).● All potential haemopoietic stem cell transplantation(HSCT) recipients should be tested for the presence ofCMV IgG antibody at diagnosis (Grade 1C).● Once optimum human leucocyte antigen (HLA) match-ing has been performed, a CMV IgG-negative donorshould be chosen for a CMV IgG-negative recipient anda CMV IgG-positive donor should be chosen for a CMVIgG-positive recipient when possible (Grade 1A).● Donors or recipients who are initially found to be CMVIgG-negative should be retested pre-transplant toexclude primary CMV infection (Grade 1C).● Apparent CMV seroconversion in potential allograftrecipients who have received unscreened blood productsshould be actively investigated to exclude passive acqui-sition of antibody (Grade 1C)● Any CMV IgG-negative HSCT recipient transplantedfrom a CMV IgG-negative donor who develops CMVinfection post-transplant must be reported to the SeriousHazards of Transfusion (SHOT) scheme (Grade 1C).● Primary prophylaxis with ganciclovir is not generallyrecommended as toxicity outweighs efficacy in HSCTpatients (Grade 1B).● Primary prophylaxis with aciclovir or valaciclovir canbe deployed but only in conjunction with appropriatemonitoring of CMV in blood (Grade 1B).● Valaciclovir or valganciclovir are valid treatmentoptions for secondary prophylaxis with appropriatemonitoring of CMV in blood (Grade 1C).● Intravenous immunoglobulin is not recommended forprophylaxis of CMV infection (Grade 1A).● Real time quantitative polymerase chain reaction (PCR)is the preferred choice for monitoring CMV DNA levelsin HSCT patients (Grade 1B).● All diagnostic laboratories should deploy the CMVinternational standard to allow viral loads to becompared between centres (Grade 1C).● Monitoring of CMV load should be undertaken atleast weekly for the first 3 months post-HSCT (Grade2C).● CMV viral load monitoring should continue for 6-12 months if the patient has chronic graft-versus-hostdisease (GvHD) or prolonged T-cell immunodeficiency(Grade 1B).● Each transplant centre should have a risk-adapted policydetailing threshold values for treatment of CMV infec-tion, taking into account patient factors and PCR meth-odology (Grade 2C).● Ganciclovir is recommended as first line pre-emptivetherapy for CMV in HSCT patients (Grade 1A).● Oral valganciclovir is a valid alternative when gastroin-testinal absorption is normal or only minimallyimpaired (Grade 1A).● Foscarnet is recommended as an alternative first-lineagent if neutropenia is present or for ganciclovir treat-ment failure (Grade 1A).

Intensive care unit experience of haemopoietic stem cell transplant patients

Previous research at our institution (1988-1998) established an intensive care unit (ICU) and hospital mortality between 70% and 80% in haemopoietic stem cell transplant (HSCT) patients requiring ICU admission. This study explored mortality in a more contemporary cohort while comparing outcomes to published literature and our previous experience. Retrospective chart review of HSCT patients admitted to ICU between December 1998 and June 2008. Of 146 admissions, 53% were male, with a mean age of 44 years, an Acute Physiologic and Chronic Health Evaluation II score of 28 and Sepsis Organ Failure Assessment score of 11. Fifty-six per cent had graft versus host disease (GVHD), with respiratory failure (67%) being the most common admission diagnosis. All but one received mechanical ventilation. The ICU and hospital mortality were 42% (72% 1988-1998 cohort) and 64% (82% 1998-1998 cohort) respectively. The 6- and 12-month survivals were 29% and 24% respectively for the 1998-2008 cohort. Dying in ICU was independently predicted by fungal infection (P= 0.02) and early onset of organ failure (P < 0.001), while GVHD (P= 0.04) predicted survival. Mortality at 12 months was independently predicted by the acute physiology score (P= 0.002), increasing number of organ failures (P= 0.001), and cytomegalovirus positive serology (P= 0.005), while blood stream infection (P= 0.003), an antibiotic change on admission to the ICU (P= 0.007) and a diagnosis of non-Hodgkin lymphoma (P= 0.02) predicted survival. Our study found that acute admission of HSCT patients to the ICU is associated with improved survival compared to our previous experience, with organ failure progression a strong predictor of ICU outcome, and specific disease characteristics contributing to long-term survival.

Incidence and relationship of human cytomegalovirus infection and human herpesvirus 6 infection in pediatric patients after hemopoietic stem cell transplantation

To study the incidence of human cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6) infection in pediatric patients with hemopoietic stem cell transplantation (HSCT), and to explore the relationship between CMV and HHV-6 infection in pediatric patients with HSCT. Pediatric patients with HSCT in hemotology center of Beijing Children's Hospital were enrolled into this study from June 2007 to October 2009. Peripheral blood were collected every week after HSCT, and Fluorescent quantitation PCR and conventional PCR were used to detect CMV DNA load in serum and HHV-6 DNA in peripheral blood respectively. Genetic typing was conducted on HHV-6. Fifty two pediatric patients with HSCT were enrolled into this study, and six hundreds and thirty six specimens were collected totally. CMV DNA was detected in fifty two specimens from twenty cases. The median time was 56 days after HSCT. The incidence of CMV infection was 38.5% (20/52) in all HSCT patients and 47.6% (20/42) in allogene HSCT patients. The incidence of late CMV infection was 22.2% (6/27) in allogene HSCT. Three patients died of CMV infection,and two died of CMV interstitial pneumonia. HHV-6 DNA was detected in thirty three specimens from fourteen cases. The median time was 23 days after HSCT. The incidence of HHV-6 infection was 26.9% (14/52)in all HSCT patients and 31% (13/42) in allogene HSCT patients. The genotype of HHV6 was all type B. HHV-6 DNA was positive in six of twenty cases with CMV infection. The incidence of co-infection was 30% (6/20). There was a substantial incidence of CMV and HHV6 infection after HSCT. The relationship between earlier HHV6 infection and later CMV infection in pediatric patients with HSCT need further study.

Analysis of Circulating Microrna Expression Profile In Patients Transplanted From Matched Unrelated Donors (MUD) Identifies mir203 as a Putative Marker of aGVHD

AbstractAbstract 2308 Introduction:Allogeneic haemopoietic-stem-cell transplantation (HSCT) is the treatment of choice for many malignant and non-malignant disorders. Despite the recent advances in post-transplant immunosuppressive therapy, Graft-versus-Host Disease (GVHD) still represents the major life-threatening complication, developing in a substantial number of HSCT patients and resulting in poor outcome. Recent studies have indicated that microRNAs (miRNAs) circulate in a stable, cell-free form in the bloodstream and that the abundance of specific miRNAs in plasma or serum can serve as biomarkers of cancer and other diseases. We examined plasma microRNA (miRNA) expression levels from patients transplanted from matched unrelated donor (MUD) to assess their clinical application for diagnosing and monitoring GVHD. Methods:Having obtained an informed consent, we collected plasma samples from 11 patients who received unmanipulated HSCT from MUDs. After HSCT, 5 of 11 patients developed acute GVHD. Blood samples were collected serially at day +30, +60, +90, +150 after HSCT. MicroRNAs were isolated from the peripheral blood (PB) plasma using a modified mirVana™ miRNA Isolation Kit (Ambion Inc). The miRNAs expression profile was examined using a quantitative PCR-method (TaqMan ® Human microRNA cards, Applied Biosystems) that allows the analysis of 384 human miRNAs by low density array technology. Plasma samples of normal subjects have been included in the study. Relative quantification of miRNA expression was calculated with the 2-ΔΔCt method. The data were normalized respect to hsa-mir-122 and relative to a calibrator sample (average of normal subjects plasma samples). Results:Initial analysis showed that miRNAs are stable and detectable in all plasma samples from MUD transplanted patients. Among the 384 mirRNAs analyzed we identified a panel of mirRNAs that may have a predictive role for GVHD. Among these, we have identified mir203 which is upregulated in patients prior to the onset of GVHD and its expression decreases upon therapy. Mir203 acts downregulating SOCS3, the endogenous regulator of cytokine signaling through JAK-STAT3 which is involved in the activation of the immune response. The importance of SOCS3 in the pathogenesis of GVHD has been recenly demonstrated (Hill et al. Blood, 2010) confirming the potential regulatory role of mir203 in this disease. Of interest, the evaluation of mir203 expression levels at day +30 after HSCT is able to clearly classify the patients who will develop GVHD from those who will not (p-value<0.01). Conclusions:Profiling of mir203 in a wider and heterogeneous group of patients receiving allo-HSCT is ongoing to extend and confirm the present findings. Although preliminary, these results indicate that the detection of circulating miRNAs might provide new complementary markers of GVHD. In particular the elevated plasma level of mir203 at day +30 after HSCT may be used to predict the risk of developing GVHD. Disclosures:No relevant conflicts of interest to declare.

PC-FACS

PC-FACS

Pentraxin-3: An Easily Measurable Soluble Factor to Improve Post-Transplant Graft Versus Host Disease Monitoring and Management.

Abstract 2217Poster Board II-194 Introduction:Allogeneic haemopoietic-stem-cell transplantation (HSCT) is the treatment of choice for many malignant and non-malignant disorders. Despite the recent advances in post-transplantat immunosuppressive therapy, Graft-versus-Host Disease (GVHD) still represents the major life-threatening complication, developing in a substantial number of HSCT patients and resulting in poor outcome. The basis of GVHD pathophysiology are still poorly understood and its current diagnosis depends mainly on clinical manifestations and invasive biopsies. Specific biomarkers for GVHD would facilitate the early and accurate recognition of this invalidating disease as well as the monitoring of patient response to adopted anti-GVHD pharmacological treatment. With the aim to explore new reliable markers for predicting and monitoring GVHD course, we focused on pentraxin-3 (PTX-3), an acute-phase protein, that has been shown to play a crucial role in orchestrating inflammatory immune responses. Patients and Methods:Having obtained an informed consent, we collected plasma samples from 46 patients who received unmanipulated HSCT and from 9 healthy donors (HD) volunteers. After HSCT, 25/46 patients developed skin GVHD (18 acute GVHD and 7 chronic GVHD), while 21/46 never experienced it. Concerning GVHD patients, blood samples were collected at the day of GVHD onset/ flare, before the beginning of GVHD-specific drug therapy. PTX-3 plasma levels were monitored by ELISA assays. Results:Patients who did not develop GVHD after HSCT showed augmented PTX-3 plasma levels (mean=3.3 ng/ml, range=1.1-8.6 ng/ml) if compared to HD (mean=1.2 ng/ml, range=0.3-2.5 ng/ml, p<0.01). Interestingly, we observed a strong increase of PTX-3 plasma levels in patients with acute GVHD (mean=42.2 ng/ml, range=6.7-218.2 ng/ml) or with flair-ups of chronic GVHD (mean=15.8 ng/ml, range=9-44.3 ng/ml). The increase of PTX-3 levels in patients with acute and active chronic GVHD was statistically significant (p<0.01 and p<0.05 respectively) when compared to both HD and HSCT patients without GVHD. Conclusions:These preliminary results suggest that PTX-3 plasma levels increase very rapidly in patients experiencing active GVHD, thus candidating PTX-3 as an easily measurable soluble factor useful to corroborate clinical observations in a disease in which signs and symptoms are often protean. Further studies are needed to clarify if PTX-3 could represent a good diagnostic and/or prognostic factor rapidly indicating therapy responsiveness. Disclosures:No relevant conflicts of interest to declare.

Prophylactic infusion of cytomegalovirus-specific cytotoxic T lymphocytes stimulated with Ad5f35pp65 gene-modified dendritic cells after allogeneic hemopoietic stem cell transplantation

AbstractCytomegalovirus (CMV) and its therapy continue to contribute to morbidity and mortality in hemopoietic stem cell transplantation (HSCT). Many studies have demonstrated the feasibility of in vitro generation of CMV-specific T cells for adoptive immunotherapy of CMV. Few clinical trials have been performed showing the safety and efficacy of this approach in vivo. In this study, donor-derived, CMV-specific T cells were generated for 12 adult HSCT patients by stimulation with dendritic cells transduced with an adenoviral vector encoding the CMV-pp65 protein. Patients received a prophylactic infusion of T cells after day 28 after HSCT. There were no infusion related adverse events. CMV DNAemia was detected in 4 patients after infusion but was of low level. No patient required CMV-specific pharmacotherapy. Immune reconstitution to CMV was demonstrated by enzyme linked immunospot assay in all recipients with rapid increases in predominantly CMV-pp65 directed immunity in 5. Rates of graft-versus-host disease, infection, and death were not increased compared with expected. These results add to the growing evidence of the safety and efficacy of immunotherapy of CMV in HSCT, supporting its more widespread use. This study was registered at www.anzctr.org.au as #ACTRN12605000213640.

Gut Toxicity During Hemopoietic Stem Cell Transplantation May Predict Acute Graft-Versus-Host Disease Severity in Patients

Graft-versus-host disease (GVHD) is the primary complication of allogeneic, hemopoietic, stem cell transplantation (HSCT). Murine models suggest that gut toxicity, induced by the intensive chemotherapy preceding hematopoietic stem cell infusion, aggravates systemic GVHD. In HSCT patients gut toxicity correlates with chemotherapy intensity. The present study investigates acute GVHD severity and intestinal toxicity in patients undergoing allogeneic HSCT. In 38 patients intestinal permeability was assessed before and after chemotherapy (on days -1, +4, +7 and +14 as related to the stem cell infusion). Cumulative acute GVHD (days 0-100) and clinical intestinal toxicity (days 0-14) were evaluated in parallel. Patients with mild, acute GVHD (grades 0-I) had better-preserved intestinal barrier function (P=0.04) and less pronounced cumulative clinical intestinal toxicity (P=0.02) compared with patients with more severe acute GVHD (grades II-IV). Gut toxicity predicts acute GVHD severity. Therefore, gut protective strategies may diminish GVHD severity in allogeneic HSCT patients.

Development of an acuity measurement tool specific to haematology and haemopoietic stem cell transplant patients

The lack of recognition, within New South Wales (NSW), of the degree of complexity involved in the management of Haematology/Stem Cell Transplant (SCT) patients have long been a source of frustration for nurses working in this area. This is largely attributable to the inadequacy of existing generic tools to accurately quantify specific haematology/ST patient acuity. This lack of accurate information has led, over time, to the erosion of staffing levels, inappropriate skill mix and unsafe patient/staff ratios.

Fungal CNS infections in patients with hematologic malignancy

Various fungal agents can cause CNS infections. CNS fungal infections may present as a mass (i.e., brain abscess) typically in the course of aspergillosis or zygomycosis, or may primarily involve the meninges (i.e., meningitis), as can be observed in patients with candidiasis or cryptococcosis. Most commonly, fungal brain abscesses are due to aspergillosis. CNS aspergillosis is observed particularly in acute leukemia and allogeneic hemopoietic stem cell transplantation patients. Usually, aspergillosis is localized in the lungs and secondarily spreads to the brain; only in few cases does it develop as solitary localization of CNS. In these conditions, diagnosis is very difficult because signs and symptoms can be completely aspecific. Diagnosis can often be performed only through aggressive procedures (i.e., stereotactic puncture). Zygomycetes are the second most frequent cause of brain abscesses. CNS involvement is higher than in the course of invasive aspergillosis, and this fungal complication is also characterized by a high mortality rate. In vitro and in vivo studies demonstrated that only posaconazole and lipid formulations of amphotericin B present some possibility of success in the treatment of zygomycosis, but the pharmacologic approach should always be associated with surgery. Among molds, other agents (i.e., Fusarium and Scedosporium) may also be responsible for fungal abscess. More rarely during the course of a hematologic malignancy, a meningeal candidiasis or cryptococcosis may be observed. This review mainly focuses on the epidemiology, clinical manifestations, diagnosis and management strategies of all cases of CNS fungal infections in hematologic patients.

Effects of a relaxation breathing exercise on fatigue in haemopoietic stem cell transplantation patients

Our purpose was to investigate the effect of a relaxation breathing exercise on fatigue in allogenic haemopoietic stem cell transplantation patients. Exercise is a promising approach in ameliorating the fatigue associated with cancer and its treatment. A randomized design with control, experimental groups being assessed pre- and postintervention. Thirty-five patients were randomly selected, with 18 assigned to an exercise group and 17 to a control group. The exercise intervention lasted for 30 minutes every day for six weeks. It consisted of physical exercise combined with relaxation breathing exercise. Fatigue was measured by the revised version of the Piper Fatigue Scale. The exercise group had a greater decrease in fatigue than the control group. These findings indicate that a relaxation breathing exercise would improve fatigue in allogenic haemopoietic stem cell transplantation patients. A relaxation breathing exercise by a nurse can improve fatigue in allogenic haemopoietic stem cell transplantation patients.

Effects of a Relaxation Breathing Exercise on Anxiety, Depression, and Leukocyte in Hemopoietic Stem Cell Transplantation Patients

This study was performed to investigate the effects of a relaxation breathing exercise on anxiety, depression, and leukocyte count in patients who underwent allogenic hemopoietic stem cell transplantation. Thirty-five patients were randomly selected, with 18 assigned to an exercise group and 17 assigned to a control group. The exercise intervention was applied to the exercise group for 30 minutes every day for 6 weeks. It consisted of physical exercises combined with relaxation breathing. Anxiety was measured by the State-Trait Anxiety Inventory and depression was measured by the Beck Depression Inventory. The total number of leukocytes was calculated from total and differential counts of peripheral white blood cells. The exercise group had a greater decrease in anxiety and depression than did the control group, but the total number of leukocytes did not significantly differ between the two groups. These findings indicate that a relaxation breathing exercise would improve anxiety and depression levels in patients who undergo allogenic hemopoietic stem cell transplantation, but would not affect the number of leukocytes.

Haemopoietic stem cell transplants: the impact of haemorrhagic complications

Acute graft-versus-host disease (GVHD) is the most important complication of allogeneic haemopoietic stem cell transplantation (HSCT), increasing susceptibility to haemorrhage and risk of early mortality. We evaluated 807 allogeneic HSCT patients to assess both the association between bleeding and GVHD, and the influence of haemorrhagic complications on clinical outcome. Up to 55% of patients with grade III–IV GVHD experienced bleeding, compared with 23% of patients with grades 0–l. Furthermore, 45% of patients receiving non-HLA-identical transplants suffered haemorrhage, whereas only 23% of patients receiving transplants from HLA-identical donors experienced bleeding. This can be explained by the higher incidence of severe GVHD among recipients of non-HLA-identical transplants. Our findings also demonstrated that haemorrhagic complications - particularly bleeding from the GI tract - markedly increase patient mortality. An ongoing, multi-centre, randomised, double-blind trial is currently investigating the efficacy and safety of recombinant factor VIIa (rFVIIa; NovoSeven®) in the treatment of HSCT-associated bleeding. The trial will examine the ability of three dose levels of rFVIIa to reduce - or even eliminate entirely - the incidence and severity of haemorrhage following such procedures. A total enrolment of 100 patients is anticipated, and preliminary data are expected at the end of 2003.

Plasma concentration monitoring of busulfan: does it improve clinical outcome?

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

Haemorrhagic cystitis: incidence and risk factors in a transplant population using hyperhydration.

Haemorrhagic cystitis (HC) is the syndrome of haematuria and symptoms of lower urinary tract irritability in the absence of bacterial infection. We report a low incidence of HC (18.2%) in 681 haemopoietic stem cell transplant patients, using a prophylactic regimen of hyperhydration and forced diuresis. The incidence of grade 3-4 disease is 3.4%. There was a marked difference in incidence between allogeneic and autologous transplant populations, 24.2% vs. 3.5% (P<0.0005). Busulphan conditioning, acute GVHD, interstitial pneumonitis and use of methotrexate and cyclosporin immune suppression were associated with significantly increased incidence of HC in the allogeneic population. This may reflect the numerous factors that contribute to the greater immunosuppression and consequent increased risk for HC in allogeneic transplantation.