UK Transplant Centres Research Articles

CFTR Modulators and Lung Transplantation: Factors to Consider - A UK Transplant Centre Experience

<h3>Purpose</h3> Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are drugs that act on the defective CFTR protein in people with cystic fibrosis (pwCF), resulting in improved CFTR protein function and thus improved CF symptoms. Evidence is increasing of their positive impact on extra-pulmonary features of CF, which remains problematic in pwCF post-lung transplantation (LTx). Elexacaftor/tezacaftor/ivacaftor (ele/tez/iva) was licensed in the UK in August 2020. It has been debated since if ele/tez/iva has a role post-LTx for ongoing non-pulmonary CF symptoms. We aim to highlight the practical issues faced when considering this drug in the post-LTx CF population in a single large UK LTx unit. <h3>Methods</h3> Retrospective analysis of electronic records of pwCF post-LTx with ongoing extra-pulmonary manifestations considered for initiation of ele/tez/iva August 2020-2021, including demographics, potential benefits, contraindications and outcomes. <h3>Results</h3> 5 pwCF with LTx have been discussed with their CF physicians to consider initiating ele/tez/iva (some had more than one problem):- sinus (n = 2); bowels (n = 2); weight (n = 2); other (n = 2). All were at least 12 months post-LTx (median 42 months; range 21-191 months). Discussions were initiated by the patient in 1 case, the CF team in 2, and transplant team in 2. 3 were not initiated - 1 due to potential side effects on mental health and 2 were contraindicated with deranged liver tests and ongoing bowel symptoms. 2 were initiated on ele/tez/iva. Of these, one is on tacrolimus, needed no immunosuppression adjustment, but stopped due to drop in FEV1 (CT and biopsy negative for features of rejection) which recovered. The other is on sirolimus, needed significant reduction in immunosuppression (9mg to 4mg) and remains on ele/tez/iva. <h3>Conclusion</h3> Extra-pulmonary manifestations of CF are varied and continue post-LTx. With increasing evidence supporting using CFTR modulators to manage extra-pulmonary symptoms, it is important to establish the role these drugs can have in the post-LTx CF population, but also the potential risks. Our experience so far shows mixed results and that discussion between CF and transplant physicians, with patient involvement is vital to ensure correct decisions are taken. Randomised controlled trials are needed to ensure modulator use in pwCF post-LTx is supported by robust evidence.

Incidence and outcomes of post-transplant lymphoproliferative disease after 5365 solid-organ transplants over a 20-year period at two UK transplant centres.

Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication of solid-organ transplantation (SOT). We present the incidence and outcomes of PTLD in a cohort of 5365 SOT recipients over a 20-year period at two UK transplant centres. With a median follow-up of 7.7years, 142 of 5365 patients have developed PTLD. Cumulative incidence was 18% at five years after multivisceral transplant and 1%-3% at five years following the other SOT types. Twenty-year cumulative incidence was 2%-3% following liver and heart transplantation and 10% following kidney transplantation. Median overall survival (OS) following SOT was 16years, which is significantly reduced compared with the age-adjusted UK population. There is relatively high early mortality following diagnosis of PTLD and only patients surviving two years regained a longer-term survival approaching the non-PTLD SOT cohort. Of 90 patients with monomorphic PTLD, diffuse large B-cell lymphoma, 66 were treated with first-line rituximab monotherapy and 24 received first-line rituximab plus chemotherapy. Up-front rituximab monotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes before and after treatment remains high with both treatment approaches. Multivariate analysis of all 90 monomorphic PTLD patients identified an International Prognostic Index (IPI) of 3+ as the strongest pretreatment variable associating with inferior one-year OS.

Incidence and Outcomes of Post-Transplant Lymphoproliferative Disease after 5365 Solid Organ Transplants over a 20 Year Period at 2 UK Transplant Centres

Background:Post-transplant lymphoproliferative disease (PTLD) confers a high morbidity and mortality in a vulnerable population. We present the epidemiology and outcomes of PTLD in a large UK cohort of solid organ transplant (SOT) recipients who were transplanted over a 20-year period.Methods:This is a retrospective study of 5365 SOT recipients who had their first transplant between 2000 and 2021 at two UK transplant centres (Addenbrooke's Hospital and Papworth Hospital). We reviewed the records of all patients and found 142 who subsequently developed PTLD. For each type of transplant, we calculated the incidence rate of PTLD and cumulative incidence using a competing risk of death model.Survival was compared with the age-adjusted life expectancy of the UK population using the National life tables and a landmark analysis was performed to compare overall survival (OS) of PTLD patients from the date of diagnosis with the background survival of the transplant population. To compare treatment outcomes, a subset of 90 cases of monomorphic PTLD, DLBCL subtype were identified. 66 were treated with first-line Rituximab monotherapy and 24 received first-line R-Chemotherapy. Demographics, treatment response, and survival data were analysed with univariate and multivariate analysis to identify covariates associated with death in the first year post diagnosis of PTLD.Results:With a median follow-up time of 5.3 years, 142 of 5365 solid organ transplant recipients have developed PTLD (56/1965 kidney, 22/1428 liver, 12/327 simultaneous kidney-pancreas (SPK), 21/113 multivisceral (MVT), 10/778 heart, 15/503 bilateral lung, 3/148 single lung and 3/85 heart and lung). The incidence rate of PTLD was highest in the first year post-transplant in lung and MVT recipients. Cumulative incidence (shown in Figure 1) was 18% at 5 years post-MVT and 1-3% at 5 years following the other SOT types. Cumulative incidence was lowest for liver and heart transplants and was 10% at 20 years post-kidney transplantation.Median OS following SOT was 16 years which is significantly reduced compared with the age-adjusted UK population. There is a relatively high early mortality rate following diagnosis of PTLD and only patients surviving two years post diagnosis regained a similar longer-term survival to the non-PTLD SOT cohort.Treatment with rituximab monotherapy (RM) is now a standard of care for monomorphic PTLD 1. Outcomes for monomorphic patients were compared between those treated with RM (n=66, median follow-up 2.2 y) and R-Chemotherapy (n=24, median follow-up 5.2 y). The two groups were well matched for age and IPI. Of the 66 RM patients, 22 (33%) achieved complete remission with RM and required no further treatment. A further 18 (27%) patients achieved remission following further treatment with chemotherapy/surgery/CTL. 6/66 (9%) patients died of progressive disease (PD), 9/66 (14%) died pre-remission of non-PTLD causes and 11/66 (17%) died in remission of unrelated causes. In the R-Chemotherapy group, 22 patients received R-CHOP and 2 received R-CVP (n=24). 8 (33%) patients are alive and in remission after first line treatment and a further 3 patients (13%) after second line treatment. 2/24 (8%) patients died of PD, 4/24 (17%) died pre-remission of non-PTLD causes and 7/24 (30%) died post-remission of unrelated causes. There is no significant difference in OS between the two groups. Only a minority of deaths were due to PD and death from non-lymphoma causes pre and post remission remain considerably higher than non-PTLD SOT patients up to 2 years post treatment (Figure 1). Multivariate analysis of all 90 monomorphic PTLD patients identified IPI3+ as the strongest pre-treatment variable associating with inferior 1 year OS. Interestingly IPI3+ did not retain this significance when R-chemo patients were analysed alone.Conclusion:With this large SOT dataset we have mapped the cumulative incidence of PTLD over a 20 year period and highlight transplanted organ-specific differences in PTLD incidence over time. Treating monomorphic DLBL patients first-line with RM rather than R-chemotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes pre- and post-treatment remains high with both treatment approaches, with poor OS compared with age-matched non-PTLD SOT recipients.1Trappe et al. Lancet Oncol; 2012 13(2):196-206 [Display omitted] DisclosuresSantarsieri: Janssen: Honoraria. Uttenthal: Roche: Other; Takeda: Other; Jazz: Other. Follows: Janssen, Abvie, Roche, AZ: Other.

P-74: Change in CMV Infection Rates Over Time at a UK Transplant Centre

P-74: Change in CMV Infection Rates Over Time at a UK Transplant Centre

Does CMV Status Affect Morbidity and Survival Following Heart Transplantation? A Large Multicentre Retrospective Study

<h3>Purpose</h3> Cytomegalovirus (CMV) infection following heart transplant is associated with increased morbidity and mortality. We evaluated the impact of CMV status on long term survival at all centres in the UK, each employing different approaches to managing CMV. <h3>Methods</h3> Adult patients undergoing heart transplantation and surviving >30 days between 1987 and 2018 were included. Data obtained from NHS Blood and Transplant included CMV donor (D) and recipient (R) status, R age, R sex, centre, treated rejection episodes and survival. Patients grouped by CMV status: D-ve R-ve (DN), D+ve R-ve (PM), D+ve R+ve (DP), D-ve R+ve (RM). 5 year survival, adjusted for age, sex and centre, was compared between groups. Adjusted survival between centres was also compared. Survival data was compared using Cox-proportional hazards. Treated rejection rates between CMV groups were compared using Chi² test. <h3>Results</h3> 2675 patients were included from 6 UK transplant centres; 2 use a pre-emptive strategy, 4 use valganciclovir in PM patients and high risk R+ve patients for 3-6 months. Five year survival per group CMV DN 629/750 (83.9%), PM 440/563 (78.1%) RM 655/773 (84.7%) DP 467/592 (78.8%). Compared to DN, both PM (HR 1.43 p=0.005) and DP (HR 1.34 p=0.025) associated with significantly higher mortality. There was no survival difference between centres, p=0.127 and no difference between centres for PM (p=0.69) or DP (0.23) groups. Rates of treated rejection at 12 months were higher in PM and DP patients (p=0.0033). <h3>Conclusion</h3> This is the first multicentre evaluation of the impact of CMV status on longer term survival following heart transplant. CMV mismatch and double positive statuses were associated with higher rates of rejection and reduced survival, irrespective of CMV prevention strategy. This should be considered when counselling patients, and in adjusted survival analyses. No differences in outcomes were seen between centres, although we were unable to account for changes in individual centre practice over time.

COVID-19 in Kidney Transplant Patients From a Large UK Transplant Center: Exploring Risk Factors for Disease Severity

BackgroundThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has raised concern for the health of immunocompromised individuals, who are potentially at higher risk of more severe infection and poorer outcomes. As a large London transplant center serving a diverse patient population, we report the outcomes of SARS-CoV-2 infection in our cohort of 2848 kidney and/or pancreas transplant patients. MethodsData were obtained retrospectively for all transplant patients who attended hospital during the peak of the pandemic and had a positive nasopharyngeal SARS-CoV-2 test. ResultsSixty-six patients were found to be positive for SARS-CoV-2. Twenty percent were treated as outpatients, 59% were admitted to the general ward, and 21% required intensive care. Treatment consisted of reduced immunosuppression, antibiotics for pneumonia or sepsis, and other supportive treatments. Within our cohort, 12 patients died (18%), with an overall mortality of 0.4%. Predictive risk factors for COVID-19 severity were explored. ConclusionsSevere disease was associated with lower hemoglobin prior to COVID-19 diagnosis and lower lymphocyte count at the time of diagnosis but not age, sex, ethnicity, or preexisting comorbidities. Lower glomerular filtration rate and higher C-reactive protein were associated with more severe disease. Despite no use of hydroxychloroquine, azithromycin, antiviral, or immunomodulatory medications, our mortality rate (kidney and pancreas transplant patients) is similar to current international rates.

Early and late-onset veno-occlusive disease/sinusoidal syndrome post allogeneic stem cell transplantation - a real-world UK experience.

Classical veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication post allogeneic hematopoietic stem cell transplantation (HSCT). Before the recently revised EBMT criteria, the Baltimore and modified Seattle criteria failed to recognize the syndrome of late-onset VOD. We present real-world experience from a large UK transplant center reporting on VOD/SOS in consecutive HSCT adult patients (n = 530), transplanted for hematological cancers. We identified 27 patients treated with Defibrotide for VOD/SOS diagnosis, where detailed data were available for final analysis. Using standard definitions including EBMT criteria, around 30% (n = 8/27) of cases classified as late-onset VOD presenting at median of 46 (22-93) days but with D100 survival (63% vs 58%, Log-rank; P = 0.81) comparable to classical VOD. Hazard ratio for D100 mortality was 2.82 (95% CI: 1.74-4.56, P<.001, Gray test) with all VOD/SOS events. Twenty percent (n = 2/8) of late-onset VOD patients were anicteric and 42% (n = 8) classical VOD patients presented with refractory thrombocytopenia, while less than half met EBMT criteria for classical VOD in adults, highlighting gaps in real-world diagnostic limitations using EBMT criteria. However, challenges remain about underrecognition and difficulties related to early defibrotide access for treatment of late-onset VOD in current treatment guidelines. Our report strongly supports early Defibrotide for the treatment of severe VOD/SOS in adults regardless of time of onset.

Skin cancer screening in organ transplant centres in the United Kingdom: a national survey

Organ transplant recipients (OTRs) have up to 500-fold increased risk of keratinocyte skin cancer (KSC). International guidelines recommend at least annual skin cancer screening for OTRs. To explore the current skin cancer surveillance practice in UK transplant centres across all solid organs and the barriers to surveillance. An online survey was sent to all 59 transplant centres in the UK specialising in kidney (n = 24), pancreas (n = 10), heart and/or lung (n = 13), liver (n = 8) and intestine (n = 4) transplants. Fifty-one (86%) transplant centres responded. Twenty-eight (55%) centres provided skin cancer surveillance post-transplantation, of which 18 (64%) had a non-skin cancer specialist providing screening. Only 21 (41%) units performed a full skin examination. Eight units (29%) screened at least bi-annually in the first five years post-transplantation. Of the 23 (45%) centres that did not provide skin cancer surveillance, limitations included: reliance on patient-reported lesions (48%), lack of skin surveillance training (30%), lack of funding (48%), not a requirement in all patients (17%) and time restraints in the clinic (30%). In the UK, many transplant units do not provide skin surveillance. Collaboration between skin cancer and transplant specialists would improve surveillance rates and reduce morbidity and mortality.

Recipient Comorbidity and Survival Outcomes After Kidney Transplantation: A UK-wide Prospective Cohort Study.

Comorbidity is increasingly common in kidney transplant recipients, yet the implications for transplant outcomes are not fully understood. We analyzed the relationship between recipient comorbidity and survival outcomes in a UK-wide prospective cohort study-Access to Transplantation and Transplant Outcome Measures (ATTOM). A total of 2100 adult kidney transplant recipients were recruited from all 23 UK transplant centers between 2011 and 2013. Data on 15 comorbidities were collected at the time of transplantation. Multivariable Cox regression models were used to analyze the relationship between comorbidity and 2-year graft survival, patient survival, and transplant survival (earliest of graft failure or patient death) for deceased-donor kidney transplant (DDKT) recipients (n = 1288) and living-donor kidney transplant (LDKT) recipients (n = 812). For DDKT recipients, peripheral vascular disease (hazard ratio [HR] 3.04, 95% confidence interval [CI]: 1.37-6.74; P = 0.006) and obesity (HR 2.27, 95% CI: 1.27-4.06; P = 0.006) were independent risk factors for graft loss, while heart failure (HR 3.77, 95% CI: 1.79-7.95; P = 0.0005), cerebrovascular disease (HR 3.45, 95% CI: 1.72-6.92; P = 0.0005), and chronic liver disease (HR 4.36, 95% CI: 1.29-14.71; P = 0.018) were associated with an increased risk of mortality. For LDKT recipients, heart failure (HR 3.83, 95% CI: 1.15-12.81; P = 0.029) and diabetes (HR 2.23, 95% CI: 1.03-4.81; P = 0.042) were associated with poorer transplant survival. The key comorbidities that predict poorer 2-year survival outcomes after kidney transplantation have been identified in this large prospective cohort study. The findings will facilitate assessment of individual patient risks and evidence-based decision making.

Does CMV Status Impact on Morbidity and Survival Following Heart Transplantation? A Large Multi-Centre Retrospective UK Study

Cytomegalovirus (CMV) infection following heart transplant is associated with increased morbidity and mortality. We evaluated the impact of CMV status on long term survival at all UK centres, employing different approaches to managing CMV. Adult patients undergoing heart transplantation and surviving >30 days between March 1987 and August 2018 included. Data obtained from NHS Blood and Transplant included CMV donor (D) and recipient (R) status, age, sex, centre, treated rejection episodes and survival. Patients grouped by CMV status: D-ve R-ve (DN), D+ve R-ve (PM), D+ve R+ve (DP), D-ve R+ve (RM). 5 year survival, adjusted for age, sex and centre, was compared between all CMV groups, with individual comparisons between DN patients and other statuses. Survival between centres, adjusted for age and sex also compared. Survival data compared using Cox-proportional hazards. Rates of treated rejection between CMV groups compared using Chi2 test. 2675 patients included from 6 UK transplant centres; 2 use a pre-emptive strategy, 4 use valganciclovir in PM patients and high risk R+ve patients for 3-6 months. Five year survival per group CMV DN 629/750 (83.9%), PM 440/563 (78.1%) RM 655/773 (84.7%) DP 467/592 (78.8%). Compared to DN, both PM (HR 1.43 p=0.005) and DP (HR 1.34 p=0.025) were associated with significantly higher mortality. There was no survival difference between centres, p= 0.127, and no difference between centres for PM (p=0.69) or DP (0.23) groups. Rates of treated rejection at 12 months were higher in PM and DP patients, difference between groups p=0.0033. To our knowledge, this is the first multicentre evaluation of the impact of CMV status on longer term survival following heart transplant. CMV mismatch and double positive statuses were associated with higher rates of rejection and reduced survival, irrespective of the CMV prevention strategy used. This should be considered when counselling patients, and in adjusted survival analyses.

Risk-adjusted survival in liver transplant patients assessed and managed by a non-transplanting centre: South West Liver Unit experience

BackgroundLiver transplant services remain a scarce resource not reflective of geography or burden of liver disease within the UK. To address geographical concerns in the South West (SW), a devolved...

P1.37: Incidence and outcomes of exfoliative rejection at a UK transplant centre

P1.37: Incidence and outcomes of exfoliative rejection at a UK transplant centre

P1.38: The Dental Health of patients referred for Small Bowel and Multivisceral Transplantation to a UK transplant centre

Introduction: Dental care during pre-transplant workup is important to reduce potential sources of infection, following immunosuppression to prevent graft rejection. This study documents the prevalence of oral abnormalities and recommended treatment of patients assessed for small bowel and multivisceral transplantation. Methods: We present a case series of 57 patients who underwent assessment for small bowel and multivisceral transplantation in a single centre in the UK (Cambridge) over the time period 2015–2018. This is a retrospective review of their formal assessment in a maxillofacial clinic and subsequent outcomes. Results: Of all patients assessed, 18(32%) required no treatment or crown and polish only; 12(21%) required at least one filling; 27(47%) required at least one tooth extraction and 6(10.5%) required full dental clearance. Of the 28 patients accepted and listed for transplantation, 11(39%) required no treatment or crown and polish only; 4(14%) required at least one filling; 13(46%) required at least one tooth extraction and 4(14%) required full dental clearance. Conclusion: This is the first reported study of the dental health of patients referred for small bowel and multivisceral transplantation. Overall these patients have poorer dental health compared with published data for patients referred for liver transplantation1 and over half of those accepted for transplantation required procedural intervention prior to listing. Many patients have intestinal failure at the time of referral. We hypothesise that long-term use of hypertonic fluids may partly account for the poor results described and that patients with intestinal failure should be considered for regular dental review and timely intervention. 1 J Appl Oral Sci. 2012 Mar-Apr;20(2):241–5.

Impact of Donor Hepatectomy Time During Organ Procurement in Donation After Circulatory Death Liver Transplantation: The United Kingdom Experience

No data exist to evaluate how hepatectomy time (HT), in the context of donation after cardiac death (DCD) procurement, impacts short- and long-term outcomes after liver transplantation (LT). In this study, we analyze the impact of the time from aortic perfusion to end of hepatectomy on outcomes after DCD LT in the United Kingdom. An analysis of 1112 DCD donor LT across all UK transplant centers between 2001 and 2015 was performed, using data from the UK Transplant Registry. Donors were all Maastricht Category III. Graft survival after transplantation was estimated using Kaplan-Meier method and logistic regression to identify risk factors for primary nonfunction (PNF) and short- and long-term graft survivals after LT. Incidence of PNF was 4% (40) and in multivariate analysis only cold ischemia time (CIT) longer than 8 hours (hazard ratio [HR], 2.186; 95% confidence interval [CI], 1.113-4.294; P = 0.023) and HT > 60 minutes (HR, 3.669; 95% CI, 1.363-9.873; P = 0.01) were correlated with PNF. Overall 90-day, 1-, 3-, and 5-year graft survivals in DCD LT were 91.2%, 86.5%, 80.9%, and 77.7% (compared with a donation after brain death cohort in the same period [n = 7221] 94%, 91%, 86.6%, and 82.6%, respectively [P < 0.001]). In multivariate analysis, the factors associated with graft survival were HT longer than 60 minutes, donor older than 45 years, CIT longer than 8 hours, and recipient previous abdominal surgery. There is a negative impact of prolonged HT on outcomes on DCD LT and although HT is 60 minutes or longer is not a contraindication for utilization, it should be part of a multifactorial assessment with established prognostic donor factors, such as age (>45 y) and CIT (>8 h) for an appropriately selected recipient.

Predictors of Response in Patients Receiving CD34-Selected Stem Cell Infusions without Conditioning to Correct Graft Failure Following Allogeneic Stem Cell Transplantation

▪Introduction: Graft failure (GF) is an infrequent but serious complication of following matched related or unrelated donor peripheral blood stem cell transplantation. Although infusion of CD34+-selected stem cells without additional conditioning is currently one strategy to treat this complication, few studies have reported predictors of response.Methods: We report the outcome of consecutive patients identified at two UK transplant centres between 1999 and 2017 who had primary or secondary GF after an allogeneic peripheral blood stem cell transplant and who underwent a CD34+ selected stem cell infusion without further conditioning. GF was confirmed by chimerism, bone marrow examination and exclusion of relapsed disease. Primary GF was defined by failure to ever achieve count recovery in one or more lineages (neutrophils >0.5x109/L, untransfused platelets >20 x109/L and untransfused Hb >8 g/L) post transplantation. Secondary GF was defined by loss of counts after the initial achievement of engraftment. A complete response (CR) was defined as haematological improvement (HI) in all cell lines (Hb>8g/L, platelets > 30x109/L and neutrophils > 1.5x109/L). A partial response (PR) was defined as HI within the first 30 days but not in all cell lineages. Responses were categorized as early (<30 days after infusion) versus late (>30 days); in the latter case, the role of the CD34+ infusion in count recovery was not known.Results: We identified 62 patients with GF, male:female 35:27, with a median age of 43 years (range, 10-66). Fifty-six patients (90%) had had reduced intensity conditioning. Median follow up was 6.4 years. Diagnoses included acute leukemia (n=18), non-Hodgkin's lymphoma (n=18), Hodgkin's Lymphoma (n=7), MDS (n= 6), multiple myeloma (n=3), myelofibrosis (n=2), CLL (n=2), severe aplastic anaemia (n=2), primary immunodeficiency (n=2), CML (n=1) and sickle cell disease (n=1). The original graft source was peripheral blood stem cells from a matched related donor (n=29), matched unrelated donor (n=18) and mismatched unrelated donor (n=15). Twenty-one (34%) patients had primary GF and 41 (66%) had secondary GF. Forty-three patients (69%) had GF in all 3 lineages and 19 patients (31%) had GF in 1 or 2 lineages. The median CD34+ cell dose/kg recipient weight was 3.2 x 106/kg (range, 0.47-14.2 x 106/kg) at a median of 181 days (range, 21-2718 days) following transplant. No response to CD34+ infusion was seen in 15 (24%) patients. Of the remaining 47 patients who responded (76%), 19 patients achieved a CR <30 days, 19 patients had a CR >30 days, 5 had a PR <30 days and 4 had a PR >30 days. Of those who responded, the median number of days required for neutrophil recovery was 29 days (6-1182), platelets recovery was 18 days (5-600) and haemoglobin recovery was 25 days (6-511). In a multivariate analysis, parameters significantly associated with response were CMV serostatus negative for both patient and donor (OR: 20.12, CI 95%= 1.6 - 248) and matched patient/donor sex (OR: 73, CI 95%= 3.3- 1605). Other factors including CD34+ dose, unrelated/related donor, underlying disease, disease risk score, timing of infusion, recipient/donor age, primary or secondary GF and presence or absence of GVHD did not predict for response. Overall survival (OS) for all patients at 1 and 5 years was 70% (95% CI 58-82) and 54% (95% CI 41-68) respectively. OS at 1 and 5 years was 86.4% (95% CI 75-98) and 73.6% (95% CI 54-92) in patients showing a CR versus 66.7% (95% CI 35-98) and 27.8% (95% CI 3-60) in patients with PR (Figure 1). Patients showing no response had poor outcomes with OS of 33.3% (95% CI 9-58) and 22.2% (CI 95% 5-47) at 1 and 5 years. In responding patients, those who initially had GF in 1-2 lineages had 5-year OS of 93.8% (95% CI 82-99) versus GF in 3 lineages who had a 5-year OS of 53% (95% CI 34-88) (Figure 2).Conclusions: This analysis represents the largest report of outcomes in patients who have received a CD34+ selected stem cell infusion without conditioning for GF. Negative donor/recipient CMV serostatus and sex matching predicted response. In responding patients, GF initially affecting <3 lineages was a predictor of better OS at 5 years. New strategies including cytokine or agonist support, or second transplant need to be investigated in partially or non-responding patients. [Display omitted] DisclosuresHough:University College London Hospital's NHS Foundation Trust: Employment.

Assessment of a Dedicated Transplant Low Clearance Clinic and Patient Outcomes on Dialysis After Renal Allograft Loss at 2 UK Transplant Centers

BackgroundLow clearance transplant clinics (LCTCs) are recommended for the management of recipients with a failing kidney transplant (RFKT) but data to support their use is limited. We conducted a retrospective study to assess management of RFKT at 2 transplant centers, 1 with a LCTC (center A) and 1 without (center B).MethodsPatients who transitioned to an alternative form of renal replacement therapy (RRT) between January 1, 2012, and November 30, 2016, were included. Patients with graft failure within a year of transplantation or due to an unpredictable acute event were excluded. Clinical data were collected after review of medical records.ResultsOne hundred seventy-nine patients (age, 48.6 ± 13.4 years, 99 [55.3%] male, and mean transplant duration 10.3 ± 7.8 years) were included. RRT counseling occurred in 79 (91%) and 68 (74%) patients at centers A and B (P = 0.003), at median 135 (61-319) and 133 (69-260) days before dialysis after graft loss (P = 0.92). Sixty-one (34.1%) patients were waitlisted for retransplantation; 18 (32.7%) nonwaitlisted patients were still undergoing workup at center A compared with 37 (58.7%) at center B (P = 0.028). Preemptive retransplantation occurred in 4 (4.6%) and 5 (5.4%) patients at centers A and B (P = 0.35). At 1 year after initiation of dialysis after graft loss, 11 (15.3%) and 11 (17.2%) patients were retransplanted (P = 0.12), and mortality was 6.6% overall.ConclusionsA dedicated LCTC improved RRT counseling and transplant work-up but did not lead to improved rates of retransplantation. Earlier consideration of retransplantation in LCTCs is required to improve RFKT outcomes.

Outcomes and Impact of Donor Lymphocyte Infusion after Reduced Intensity Conditioned-Alemtuzumab Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Mature Lymphoid Malignancies

Allogeneic hematopoetic stem cell transplantation (allo-HSCT) offers long-term remission for patients with lymphoid malignancies. In particular, reduced intensity conditioned (RIC) protocols with Alemtuzumab T-cell depletion lead to durable engraftment and reduced graft versus host disease (GvHD). However, such regimens may be associated with reduced graft-versus-lymphoma (GvL) effect and higher incidence of disease progression, leading to increased use of donor lymphocyte infusion (DLI). This study examined transplant outcomes and use of DLI in a large UK RIC-Alemtuzumab conditioned HSCT cohort.288 consecutive adult patients from three UK transplant centres (Birmingham, Glasgow, Oxford) undergoing first Alemtuzumab-based RIC HSCT for Hodgkin's lymphoma (57%), Non-Hodgkin's lymphoma (24%) and chronic lymphocytic leukemia (19%) between 2000 and 2012 were included. Overall survival (OS), current progression-free survival (CPFS), relapse incidence (RI), transplant-related mortality (TRM), incidence of GvHD and effects of DLI were analyzed.Median age was 49y (range 17-68) and 60% were male. Patients were heavily pre-treated with 58% having received ≥3 prior lines of treatment and 49% having failed a previous autograft. 55% received stem cells from an HLA-matched unrelated donor and 94% received a peripheral blood stem cell harvest. The most frequent conditioning regimen was Fludarabine, Melphalan and Alemtuzumab (FMC) (70%) and the median total Alemtuzumab dose was 50mg (range 30-100). Median duration of follow-up for survivors was 64 months.3y OS and CPFS were 53% and 50%, respectively. Factors negatively associated with OS in univariate (UV) analysis were previous autograft (p=0.01), no requirement for DLI (p=0.05), disease status not CR (p=0.05), previous treatment number ≥3 (p=0.007) and failure to engraft plts (p=0.001). On multivariate (MV) analysis, only previous autograft (HR 1.58 p=0.01) and failure to engraft plts (HR 2.3 p=0.0001) retained significance. Factors negatively associated with CPFS on UV analysis were no requirement for DLI (p=0.006), failure to engraft plts (p=0.0003) and previous treatment lines ≥3 (p=0.04). On MV analysis, no DLI remained a significant predictor of adverse CPFS (HR 1.8 p=0.01), as did failure to engraft plts (HR 1.77 p=0.005) and ≥3 treatment lines (HR 1.46 p=0.04).At 3y, the cumulative incidence of relapse and TRM was both 27%. The incidence of grade 2-4 acute GvHD (aGvHD) and extensive chronic GvHD (cGvHD) was 22% and 18%, respectively. UV predictors of RI were unrelated donor (p=0.0009), HLA mismatch (p=0.04), age > median (p=0.04) and lack of aGvHD (p=0.04). The presence of cGvHD may have been protective against relapse (p=0.08). No variables retained significance on MV modelling. UV predictors of TRM were failure to engraft plts (p=0.001), HLA mismatch (p=0.005), age > median (p=0.004), previous autograft (p=0.02), FMC conditioning (p=0.03), ≥3 previous lines of treatment (p=0.001) and development of aGvHD (p=0.04). On MV modelling, failure to engraft plt (p=0.001), HLA mismatch (p=0.03), age > median (p=0.003) and treatment number ≥3 (p=0.04) retained significance.62/288 patients received DLI; 37 receiving prophylactic DLI (pDLI) for mixed chimerism and 25 receiving therapeutic DLI (tDLI) for disease relapse. The median dose of DLI was 1x 10^6 CD3+ cells/kg (range 0.1 - 10 x 10^6). Median time from HSCT to first DLI was 10.5 months (range 3-30), to 2nd DLI 15 months (6-51) and to 3rd DLI 19 months (9-30). At 3y, OS after pDLI was 75% and after tDLI was 29%. 29/37 (78%) of pDLI and 14/25 (56%) of tDLI recipients achieved full or stable mixed chimerism. 3y RI after pDLI was 29% and after tDLI was 59% (p=0.02). Overall, the incidence of GvHD post-DLI was 32% (48% tDLI, 22% pDLI, p=ns). Median time to GvHD after last DLI was 46 days (range 17-249). There was no significant impact of post-DLI GvHD on RI (RI at 1y post DLI 18% in GvHD cohort vs 21% with no GvHD, p=ns), but GvHD increased TRM at 1y post DLI (17% in the GvHD cohort vs 3% with no GvHD, p=0.05).This is the largest series to date with long-term follow-up examining outcomes after Alemtuzumab-based RIC HSCT for mature lymphoid malignancy. Our data indicate that allo-HSCT is effective and is associated with good long term outcomes. Use of pDLI for was associated with excellent outcomes and supports use of DLI in patients developing mixed chimerism following allo-HSCT for lymphoid malignancies. DisclosuresNo relevant conflicts of interest to declare.

Hepatitis E Viraemia in Transplant Recipients

▪Introduction:Hepatitis E Virus (HEV) is one of the leading causes of acute infectious hepatitis worldwide; while usually a self-limiting, sub-clinical illness, genotype 3 HEV infection may become chronic in immunosuppressed patients such as solid organ transplant (SOT) or haematopoietic stem cell transplant (HSCT) recipients and rapid progression to cirrhosis may occur. Recent seroprevalence from screening of English blood donors shows antibody prevalence of ~13%. RNA prevalence in donors has increased in the UK from 1:2850 to 1:1460 over the past 3 years. This study examines the point-prevalence of HEV in SOT and HSCT recipients transplanted between January 2013 - December 2015 at a major UK transplant centre. Data on HEV clearance rates and risk factors for infection were collected in the patient cohort.Methods:Stored extracts of blood from patients undergoing liver transplant (OLT), renal transplant (RT) or HSCT were tested by real-time reverse-transcriptase polymerase chain reaction for HEV RNA. Samples were tested at baseline, 30, 60 and 90 days post-transplant +/- 7 days. Time points were chosen to give good coverage of the early post-transplant period whilst avoiding a patient becoming viraemic and clearing the infection between sample time points. All positive samples were sent to the Public Health England reference laboratory for verification, viral RNA genotyping and quantification. Patients with confirmed positive samples underwent further testing and evaluation of clinical parameters to determine chronology of infection, blood product exposure, organ function and histopathology results.Results:259 HSCT, 262 OLT and 349 RT patients met the inclusion criteria. Of the HSCTs there were 111 allogeneic stem cell transplants, 145 autologous transplants and 3 CD34 "top ups". The OLTs comprised 259 deceased donor, 2 live donor and 2 domino liver transplant patients. The RTs comprised 241 deceased donor, 38 live unrelated, 63 live related transplants and 1 live transplant where the relationship of the donor was unrecorded. In total 4 patients (1 HSCT and 3 OLT) were found to have HEV viraemiain our study period. This represents 0.39% of the HSCT and 1.15% of the OLT patients. All were positive with HEV genotype 3.Virologicaland clinical data regarding these patients are presented in tables below.Conclusion:Chronic HEV, genotype 3 in transplant patients is associated with significant morbidity. With the increasing incidence of HEV, immunosuppressed patients with high transfusion burden have an infection risk equivalent to 7-9 years' dietary exposure.Our results show that prevalence of HEV viraemia in OLT, RT and HSCT patients is higher than expectedbased on comparison from UK blood donors. Secondly, infection is not cleared as would be expected in the general population with 3 of the 4 patients requiring treatment to clear the virus.The source of infection for these patients is unclear; on a population wide basis HEV is usually a dietary acquired infection, with pork products carrying the greatest risk. In the transplant patient population, the risk of iatrogenic infection via infected blood products or an infected transplanted organ is an important consideration and UK guidance has recently changed so that transplant recipients receive dietary advice and HEV-negative blood to avoid infection (SaBTO2016).In this study 2 patients were found to be positive for HEV RNA in the baseline sample. One, the recipient of HSCT, did not acquire it through transfusion as testing of the transfused products that the patient had received were negative for the virus. It is not clear how the two OLT patients who tested positive acquired the virus. The absence of any positive results in the renal transplant recipients may reflect the lower transfusion burden in this patient group. Given the multiple routes of possible infection with HEV, a strategy if screening recipients for the virus in addition to screening blood and organ donors would be an effective way of detecting viral transmission via all routes. [Display omitted] [Display omitted] DisclosuresSekhar:Novartis: Research Funding.

Variations in practice in UK transplant centers: results of a related donor care survey

Variations in practice in UK transplant centers: results of a related donor care survey

Use of CMV Unselected Blood Products Does Not Increase the Risk of CMV Reactivation in Patients Undergoing Hematopoetic Stem Cell Transplant (HSCT)

Introduction: Conventionally patients receiving allogeneic HSCT (AlloHSCT) have received CMV negative blood products to obviate the risk of transfusion related CMV transmission. In the era of leucodepletion with more than log 4 reduction in blood product WBC content, the utility of this practice has been questioned and, in line with SABTO (Safety of Blood, Tissues and Organs) guidance, most UK transplant centers have adopted the policy of using unselected blood products for this patient cohort. At this center, our policy was changed to conform to recommended national practice in April 2013. This analysis was carried out to evaluate if this change has resulted in an increased incidence of CMV reactivation.Methods: 868 (M: 561; median age: F: 307; median age:) patients who received HSCT from January 1998 to November 2014 were included in analysis. Transplant types included AutoHSCT (n=384), AlloHSCT-Sibling (n=217) and AlloHSCT-MUD (n=267). Diagnosis was Ac Leukaemia (n=313), Chr Leukaemia (n=36), Myeloma (n=216), Lymphoma (n=261) or other malignancies (n=42). Commonest indication for AutoHSCT was myeloma or lymphoma. TBI based condition was used in 225 AlloHSCT and 50 AutoHSCT cases. RIC was used in 268 cases and full intensity in 215 cases (unknown in 1). Alemtuzumab or ATG was used in conditioning for 274 cases. Source of stem cell was PBSC (AutoHSCT: 363, AlloHSCT: 382), BM (AutoHSCT: 7, AlloHSCT: 97), both (AutoHSCT: 2, AlloHSCT: 9) and 8 AlloHSCT were UCB grafts.Results: 26, 345 blood PCR results were evaluated. 3100 tests were requested in AutoHSCT patients and 109 (3.6%) were positive. There were no differences in the incidence of positive CMV PCR results before and after use of CMV unselected blood products. Further analysis was limited to AlloHSCT patients. AlloHSCT patients were divided in two groups, GrpA: 1998 to 2013 and GrpB: 2013 to 2014 to evaluate the effect of using CMV unselected blood products. In AlloHSCT group, 9.1% of 23278 samples tested for CMV PCR were positive (Median log: 2.7, range: 0.3-7.3). Incidence of CMV reactivation was not different in GrpB as compared to GrpA (47.7% vs. 48.1%, p=0.93). There was no difference with gender (M: 45.8% vs. F: 53.1%, p=0.13), type of donor (Sibling: 48.6% vs. MUD: 47.9%, p=0.98), use of Alemtuzumab/ATG (50.6% vs. 45.4%, p=0.51), source of stem cells (BM: 36.4% vs. PBSC: 51.3%, p=0.07), use of TBI (43.8% vs. 52.3%, p=0.06). Higher incidence was observed with use of RIC transplant (53.2% vs. 42.3%, p=0.02) and donor-recipient CMV mismatch (NP: 24.5%, PN: 80%, PP: 90.8%, p<0.0001).Conclusion: This analysis suggests that the risk of CMV reactivation is related to the donor-recipient CMV mis-match and the transplant intensity. Use of CMV unselected blood products does not increase the risk of CMV reactivation and careful selection of donors using CMV sero-status is the key factor to reduce the risk of CMV reactivation post AlloHSCT. DisclosuresCavet:Janssen: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Somervaille:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.