Yr Post-transplantation Research Articles

Growth and survival dynamics of mesophotic coral juveniles in shallow reefs

As many degrading shallow reefs suffer from recruitment failure, mesophotic coral ecosystems have been suggested as a potential source of coral propagules promoting the recolonization of these reefs. However, whether mesophotic coral populations can repopulate shallower reefs is currently debatable. Here, we compared the response of corals settled on mesophotic (50 m) tiles and transplanted to the shallow reef (10 m), at a Nature Reserve and an unprotected site in the northern Gulf of Eilat/Aqaba, Red Sea. Mortality was substantially higher for the transplanted corals, as compared with their shallow counterparts living on the tiles, with over half of the transplanted juveniles dying 1 yr post-transplantation. Transplanted corals exhibited a 24% higher survivorship at the MPA site. We further explored the survival and growth rates of the 4 most common transplanted coral genera (Cyphastrea, Porites, Psammocora, and Stylophora). An inverse relationship between survival and growth was evident among the transplanted coral genera; Porites and Stylophora demonstrated similar net growth rates to those of their shallow-water counterparts but lower post-transplantation survivorship, while Cyphastrea and Psammocora showed the opposite trend. Although this study demonstrates the reduced plasticity of mesophotic coral juveniles to cope with shallow-water conditions, it nonetheless offers some potential to facilitate shallow-reef recovery.

P4.28: Renal function outcomes in paediatric intestinal transplant recipients

Background: Renal dysfunction after intestinal transplantation is a well recognised complication. Calcineurin inhibitors have a direct impact on the kidney with post-operative day 7 tacrolimus associated with kidney function at 1yr. Catheter related sepsis, prolonged usage of intravenous fluid, parental nutrition, diabetes and graft failure have all been associated with chronic kidney disease. Methods: Review of first-time paediatric intestinal graft recipients at a single centre between August’09-June’18. CKD was defined as Cystatin-C(CysC)>1mg/l measured at baseline, 6mths,1yr,2yr and 5yr post-transplant. Demographic and data associated with CKD post-transplantation were collected (Tac lvls at POD 7,3,6 and 12mths). Immunosuppression protocol consisted of Basiliximab induction then maintenance with tacrolimus and prednisolone +/- sirolimus. Target tacrolimus levels were between 12–15µ/L in the first 3wks, 8–12µ/L 3wks -3mths, 5–8µ/L out to1yr post transplantation. Statistical analysis was applied when appropriate, and analyses performed using SPSS. Results: 21 paediatric patients(53% male; 43%short gut syndrome, 38%paediatric intestinal pseudo-obstruction), median age of 5 yrs(4,7.8) underwent either isolated intestinal(43%), liver and intestinal(28%) or multivisceral transplantation(29%). 38% continued with tacrolimus and steroids alone, 57% sirolimus added. 4 patients required re-transplantation at a median time from first transplantation of 33.5mths (3.5,80). 4 patients died at a median time of 9.5mths(4.8,16). CysC level of all patients at baseline was 1.01(0.8,1.2), with 38% of children having evidence of pre-existing CKD (CysC lvl 1.16(1.1,1.5). There was significant association with CysC level at 6mth and Tacrolimus lvl at 3mths, r=-0.5 p=0.03. CysC lvl improved between 6mths and 1yr post transplant. No significant association was found between CKD at 6mths or 1yr and type of immunosuppression, prolonged use of intravenous fluids, parental nutrition, diabetes, graft failure, line sepsis or Tac lvl POD 7. Conclusion: Renal dysfunction is already prevalent at the time of intestinal transplantation therefore continuing close monitoring of renal function and tacrolimus levels is advisable. In our cohort renal dysfunction peaked at 6mths post transplant then improved following titration of tacrolimus level. A larger prospective study is required to identify paediatric variables that effect renal function following intestinal transplantation.

Gene Therapy for Sickle Cell Anemia Using a Modified Gamma Globin Lentivirus Vector and Reduced Intensity Conditioning Transplant Shows Promising Correction of the Disease Phenotype

▪Background: Genetic transfer of an anti-sickling β87-globin lentiviral vector (LV) into hematopoietic stem cells (HSC) followed by myeloablative transplant has cured one child with sickle cell anemia (SCA) (NEJM 2017), although it was not successful in 7 subsequent adult SCA patients, and modifications to intensify ablative conditioning, improve HSC dose, gene transfer are underway (Blood 130 Suppl 1: 527, 2017). Based upon our preclinical data (Blood 2009), we embarked upon a Reduced Intensity Conditioning (RIC) Phase I/II Pilot Study on Gene Transfer in Patients with SCA with a modified γ-Globin LV (NCT02186418), hypothesizing this approach will be safe, feasible and efficacious; Moreover, RIC will have significantly less toxicity, costs, and be implementable in many transplant centers, including those in some of the resource-poor countries, where supportive therapies for myeloablative transplants are unavailable, and where majority of SCA patients exist.Methods: Adult patients with severe SCA deemed eligible were transfused/erythrocytapheresed prior to HSC collection and transfused for 6 months post-transplant (PT) to Hb>10g/dl and HbS~30%. CD34+ HSC were collected via bone marrow harvest (BMH) and/or plerixafor mobilized Peripheral Blood Stem Collection (PBSC), selected for CD34+ cells and transduced. Patients received a single dose of IV melphalan (140mg/m2 BSA) 36hr prior to infusion of γ-globin modified (GM)-HSC. Patients were monitored for adverse events (AE), engraftment, vector copy number (VCN), modified HbF (HbF*) expression and clinical features of SCA.Results: Two SCA patients (35yo and 25yo) with HbS-β0 thalassemia genotype were treated. CD34+ HSC were collected via multiple BMH (P1) and BMH+PBSC (P2). Follow up data are available for 6 and 12mo on P1 and P2. P1 received 1x106 CD34+ cells/kgbw [vector copy number (VCN) 0.22], and P2 received 6.9x106 CD34+ cells/kgbw [VCN 0.46]. Time to neutrophil engraftment (ANC ≥ 500) was day 9 and 7 post-transplant (PT) in P1 and P2, respectively, and time to Plt recovery (Plt>50K) was day 14 PT in both. Patients included in this trial had severe disease and continued to have pre-existing chronic pain requiring significant opiates; hence ~80% of the AEs were pain events; other AEs were anticipated transient laboratory AEs associated with melphalan. Following GM-HSC infusion, both patients showed a progressive rise in HbF* (a point mutation in the γ-globin LV allows distinction from endogenous HbF by HPLC) starting from day 30 PT. Since patients had transfused HbA containing RBCs in the initial 6 months, HbF*/(HbF*+HbS) was calculated, and was 20% and 21% in P1 and P2 at day 180 PT and VCN 0.2-0.4, detected in all lineages. Integration site analysis, performed on the infused products (Day 0), at day 30 PT on P1 and P2, and on day 180 PT on P1 demonstrated highly polyclonal pattern of integration. At 1 yr PT, P1 had 20% HbF* (2.1g/dl HbF*, total Hb 10.6) with a stable VCN of 0.2-0.4 in multiple lineages in bone marrow and peripheral blood. The baseline Hb of P1 was 7.5-8.5g/dL prior to transplant. In the preceding 2 years prior to transplant, both patients were admitted for pain crises/acute chest >5-6 times/yr, and had chronic pain requiring chronic opiates. Chronic pain persisted for 4-5 months PT in P1, after which P1 has not required IV opiates, negligible oral opiates and has had no hospital visits/admissions with acute sickle events. P2 has required decreasing amounts of oral opiates for chronic back pain.Conclusions: Early results from 2 SCA adults treated with a modified γ-globin LV modified autologous HSC following RIC transplant showed excellent safety, feasibility, with minimal post-transplant toxicity, rapid count recovery, and sustained stable genetically modified cells in peripheral blood and bone marrow. The first patient shows significant clinical amelioration of the SCA phenotype at 1 year PT, with 20% vector-derived HbF (HbF*) that has caused amelioration of anemia, near elimination of chronic pain and absence of acute sickle events. The second patient, although still early post-transplant shows a similar HbF* trajectory. Additional study data will demonstrate whether this level of HbF* will provide consistent clinical benefit to patients with severe SCA. These early results, especially following a RIC transpant, are extremely promising; and if sustained, will provide a ‘transportable’ safe and feasible gene therapy for SCA. DisclosuresMalik:CSL Behring: Patents & Royalties. Quinn:Global Blood Therapeutics: Research Funding; Silver Lake Research Corporation: Research Funding; Amgen: Research Funding.

Pulmonary hypertension as a risk factor of mortality after lung transplantation.

Pulmonary hypertension (PH) is recognized as a risk factor in lung transplantation as reflected in the lung allocation score (LAS). We examined the impact of PH on outcome after lung transplantation, with special emphasis on pre- and post-capillary PH. Consecutive lung transplant recipients were evaluated according to ISHLT criteria including right heart catheterization in the period from 1992 to October 2014. Post-transplant survival was assessed according to hemodynamic characteristics: post-capillary PH (mean pulmonary arterial pressure [mPAP] ≥ 25 mmHg and pulmonary arterial wedge pressure [PAWP] > 15 mmHg), pre-capillary PH (mPAP ≥ 25 mmHg, PAWP ≤ 15 mmHg) and non-PH (mPAP < 25 mmHg). Of 518 transplant recipients, 58 (11%) had post-capillary PH. Pre-capillary PH was present in 211 (41%) and 249 (48%) non-PH. Post-capillary PH and pre-capillary PH were associated with worse 90-d outcomes after transplantation compared to non-PH (p = 0.043 and 0.003, respectively). The negative effect persisted 1 yr post-transplantation in pre-capillary PH (p = 0.037), but not in post-capillary PH (p = 0.447). Long-term survival was unaffected by hemodynamic classification. Post-capillary PH was present in 11% and pre-capillary PH in 41% of the transplant cohort. Post-capillary PH and pre-capillary PH were associated with inferior 90-d survival, but long-term survival was unaffected.

AST-to-platelet ratio index in non-invasive assessment of long-term graft fibrosis following pediatric liver transplantation.

Long-term graft fibrosis occurs in the majority of pediatric liver transplant recipients. Serial biopsies to monitor graft health are impractical and invasive. The APRI has been evaluated in pediatric liver disease, but not in the context of post-transplantation fibrosis. We aimed to investigate the validity of APRI as a predictor of long-term graft fibrosis in pediatric liver transplant recipients. This was a retrospective, observational study of a cohort of children who underwent liver transplantation at King's College Hospital between 1989 and 2003, with a relevant dataset available. Protocol liver biopsies were performed at 10-yr follow-up and fibrosis was graded using the Ishak scoring system, with S3-6 denoting "significant fibrosis." APRI was calculated concurrently with biopsy. A total of 39 asymptomatic patients (20 males; median age at transplant, 1.43 yr) underwent protocol liver biopsies at a median of 10.39 yr post-transplantation. APRI was associated with significant fibrosis (p = 0.012). AUROC for APRI as a predictor of significant fibrosis was 0.74 (p = 0.013). The optimal cutoff APRI value for significant fibrosis was 0.45 (sensitivity = 0.67; specificity = 0.79; PPV = 0.67; NPV = 0.79). APRI appears to be a useful non-invasive adjunct in the assessment of significant graft fibrosis in the long-term follow-up of pediatric liver transplant survivors.

Single-center assessment of nutritional counseling in preventing excessive weight gain in pediatric renal transplants recipients.

Post-transplantation obesity is a common complication that is associated with a higher risk for decreased allograft function and hypertension. However, the role of diet intervention on reducing post-transplantation obesity is relatively unknown. We investigated the clinical relevance of dietary counseling on the prevalence of overweight/obesity during the first two yr following renal transplantation. The computerized patient records of 42 recipients (31 males) aged 6.3 ± 4.8 yr at transplantation were reviewed. All patients systematically underwent yearly dietary assessment/counseling (motivational interviewing technique) and measurement of renal function and ABPM. At transplantation, 14.2% of patients were overweight/obese, which increased to 42.8% by two yr post-transplantation (p = 0.004). The majority of patients experienced a significant increase in BMI SDS during the first six months post-transplantation that remained sustained throughout the duration of the follow-up period (p = 0.001). By two yr post-transplantation, there were no observable differences between patients classified as having normal BMI or being overweight/obese with regard to renal function and controlled hypertension. The application of yearly tailored dietary assessment/counseling had a poor effect on preventing post-transplantation weight gain, suggesting the need for more comprehensive interventions to reduce post-transplant obesity.

The inferior impact of antibody-mediated rejection on the clinical outcome of kidney allografts that develop de novo thrombotic microangiopathy.

Antibody-mediated rejection (AMR) can induce and develop thrombotic microangiopathy (TMA) in renal allografts. A definitive AMR (dAMR) co-presents three diagnostic features. A suspicious AMR (sAMR) is designated when one of the three features is missing. Thirty-two TMA cases overlapping with AMR (AMR+ TMA) were studied, which involved 14 cases of sAMR+ TMA and 18 cases of dAMR+ TMA. Thirty TMA cases free of AMR features (AMR- TMA) were enrolled as control group. The ratio of complete response to treatment was similar between AMR- TMA and AMR+ TMA group (23.3% vs. 12.5%, p = 0.33), or between sAMR+ TMA and dAMR+ TMA group (14.3% vs. 11.1%, p = 0.79). At eight yr post-transplantation, the death-censored graft survival (DCGS) rate of AMR- TMA group was 62.8%, which was significantly higher than 28.0% of AMR+ TMA group (p = 0.01), but similar between sAMR+ TMA and dAMR+ TMA group (30.0% vs. 26.7%, p = 0.92). Overall, the intimal arteritis and the broad HLA (Human leukocyte antigens) mismatches were closely associated with over time renal allograft failure. The AMR+ TMA has inferior long-term graft survival, but grafts with sAMR+ TMA or dAMR+ TMA have similar characteristics and clinical courses.

Cardiovascular risk factors and cardiac disorders in long-term survivors of pediatric liver transplantation.

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single-center retrospective review was undertaken for patients who had a liver transplantation before 18yr of age and were >5yr post-transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty-eight patients were included in the study with a mean age at transplantation of 6.3±6.1yr and mean follow-up of 14.1±6.0yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow-up being significant risk factors. Fifty-three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p<0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.

Pulmonary function following allogeneic stem cell transplantation in childhood: a retrospective cohort study of 51 patients.

HSCT is associated with a high risk of late morbidity. The aim of this study was to evaluate the frequency, time frame, risk factors, and possible etiology of pulmonary dysfunction following allogeneic HSCT in childhood. We evaluated the pulmonary function of 51 HSCT patients (>6 yr), by including FVC and FEV1 values prior to (baseline) and annually up to five yr after HSCT. A Cox proportional hazards model was used to analyze the risk factors for a pulmonary event. Over half (59%) of the patients developed pulmonary dysfunction, mainly consisting of restrictive abnormalities. Acute GvHD (HR 4.31, 95% CI 1.47-12.63), chronic GvHD (HR 10.20, 95% CI 2.42-43.03), and an abnormal baseline pulmonary function (HR 4.82, 95% CI 1.02-22.84) were associated with post-transplant dysfunction. FEV1 (p < 0.001) and FVC (p < 0.001) declined significantly by 12 months after HSCT and both remained below the pre-HSCT level at up to four yr post-transplantation. HSCT in childhood is associated with early and persistent restrictive impairment of pulmonary function. Patients with extensive chronic GvHD are particularly vulnerable to severe pulmonary dysfunction. Scheduled pulmonary function testing is warranted as part of the follow-up of survivors of HSCT in childhood.

Alemtuzumab induction in pediatric kidney transplantation

Recipient parenchymal lymphatic cells are crucial for direct and indirect pathways of allorecognition. We proposed that alemtuzumab, being infused several weeks pretransplant could eradicate peripheral lymphatic cells and promote donor-specific tolerance. We present here a single center, retrospective review of 101 consecutive living-donor kidney transplantations to pediatric patients aged from seven month to 18 yr, performed between September 2006 and April 2010. Immunosupression protocol included two 30 mg doses of alemtuzumab: first given 12–29 d prior to transplantation and second at the time of transplantation. Maintenance immunosupression was based on combination of low dose and wide range CNI and mycophenolate. Patients were followed for 3.8 ± 1.4 yr and protocol biopsies were taken one month, one, and three yr post transplant. The Kaplan–Meier graft and patient survival was 96% and 97% for one yr, 89% and 93% for three yr. Biopsy proven acute rejection developed in 26% patients at one yr and in 35% at two yr, no rejections occurred beyond two yr. We conclude that alemtuzumab pretreatment prior to living related donor kidney transplantation allows to reach satisfactory middle-term results in pediatric patients with wide range and low CNI concentrations.

HLA‐matched family hematopoetic stem cell transplantation in children with beta thalassemia major: The experience of the Turkish Pediatric Bone Marrow Transplantation Group

From January 1991 to June 2009, 245 children with beta thalassemia major who underwent their first allogeneic HSCT in Turkey and who were followed for a minimum of one yr post-transplantation were enrolled this study. The median age of the patients was 6.6 yr old (range, 1-22 yr). The distribution of Pesaro risk class I, II, and III categories was 41, 130, and 63 children, respectively. The median serum ferritin level was 2203 ng/mL. Eighty-eight patients received bone marrow (BM) stem cells; 137, peripheral blood (PB) stem cells; and 20, cord blood (CB) stem cells. The donors were HLA-matched siblings or parents. Median engraftment times were shorter in PBSCT patients compared with the BMT group (p < 0.001). Grade II-IV acute GvHD was observed in 33 children (13.5%), while cGvHD was observed in 28 patients (12.5%), eight of whom had the extensive form. Thalassemic reconstitution was observed in 43 (17%) of the transplant patients. Post-transplant aplasia occurred in three patients, and the TRM rate was 7.75%. Seventeen patients were lost after 100 days. The thalassemia-free survival and OS rates were 68% (95% CI, 61.8-74.2) and 85.0% (95% CI, 80.2-89.8), respectively. We believe that this study is important because it is the first multicenter national data for children with beta thalassemia major receiving HSCT.

Post‐transplantation lymphoproliferative disorder in pediatric kidney‐transplant recipients – A national study

PTLD is the most common malignancy in pediatric kidney-transplant recipients. We examined the prevalence, clinical features, and outcome of PTLD in Israel. Twelve (4.4%) of 272 pediatric (<19 yr) kidney-transplant recipients retrieved from a search of the NIKTR for 1991-2008 had acquired PTLD at a median of 3.2 yr post-transplantation. PTLD-affected patients were younger at transplantation (4.2 vs. 12.5 yr, p = 0.02), had a higher rate of OKT3 therapy for acute rejection (25% vs. 4%, p = 0.015), and 5/12 were EBV-seropositive at transplantation. Graft dysfunction was the presenting sign in six (50%). PTLD was predominantly abdominal (83%) and B-cell type (67%); T-cell PTLD occurred exclusively in EBV-seropositive patients. Treatment consisted of immunosuppression cessation (6/12, 50%), antiviral agents (7/12, 58%), anti-CD20 monoclonal antibodies (4/12, 33%), and chemotherapy (6/12, 50%). Survival was 100% in the EBV-naïve patients and 40% in the EBV-seropositive patients. Graft loss occurred in three of eight survivors (37.5%). PTLD-associated mortality risk was older age: 11.2 vs. 3.4 yr, longer dialysis: 15 vs. 6.5 months, T-cell type disease (75%), later PTLD onset: 6.35 vs. 1.9 yr post-transplantation and era of transplantation (43% mortality before vs. 20% after 2001). Pretransplantation EBV-seronegative status might confer a survival benefit with early detected PTLD. EBV-seropositive patients are at risk for aggressive late-onset lethal PTLD.

The impact of CMV prevention on long‐term recipient and graft survival in heart transplant recipients: analysis of the Scientific Registry of Transplant Recipients (SRTR) database

The association between cytomegalovirus immunoglobulin (CMVIG) and long-term clinical outcomes in heart transplantation has not been evaluated using data from large national databases. We examined the association between CMVIG, with and without antivirals, or antivirals alone, and long-term recipient and graft survival in heart transplantation using data from the Scientific Registry of Transplant Recipients. Recipients transplanted between January 1995 and October 2008, ≤80 yr old, of primary, single-organ heart transplants, recorded as receiving CMVIG with or without antivirals (n = 2112), antivirals without CMVIG (n = 12 089), or no prophylaxis (n = 14 661), at hospital discharge, were included. Kaplan-Meier analysis was used to examine death and graft loss at seven yr post-transplantation; Cox proportional hazards regression was used to estimate the adjusted risk of graft loss and death for prophylaxis vs. no prophylaxis. CMVIG use (± other antivirals) was associated with increased recipient (69% vs. 64%, p < 0.001) and graft (67% vs. 63%, p < 0.001) survival. Antivirals alone also demonstrated increased recipient (68% vs. 64%, p < 0.001) and graft survival (66% vs. 63%, p < 0.001). Cox models demonstrated that CMVIG (± other antivirals) was independently associated with decreased risk for death (hazard ratio, HR 0.79, p < 0.001) and graft loss (HR 0.78, p < 0.001) as were antivirals alone (mortality HR: 0.79, p < 0.001; graft loss: HR 0.78, p < 0.001).

292 ASSOCIATION OF HBSAG DECLINE WITH INNATE AND ADAPTIVE IMMUNE RESPONSES DURING ACUTE HEPATITIS B VIRUS INFECTION

In contrast, PBMCs from HCV rapid-fibrosers produced less IL-6 in response to TLR3 (p =0.007) and TLR9 stimulation (p =0.02), and less IFNa in response to TLR7/8 stimulation compared with HCV slow-fibrosers (p = 0.02). We confirmed these findings in a prospective cohort of 16 patients who had PBMCs collected and liver biopsy 1 yr post transplant. 8 (50%) had fibrosis progression (F1 or greater). Rapid fibrosers produced less IL-6 in response to TLR3 (p =0.05) and TLR9 stimulation (p =0.06) and less IFNa in response to TLR7/8 stimulation (p =0.01). Additionally, rapid fibrosers produced less TNFa in response to TLR3 stimulation (p =0.009). Conclusion: Rapid fibrosers demonstrate impaired cytokine and IFNa responses to stimulation of antiviral TLRs 3, 7/8 and 9. We postulate that this leads to impaired immune control of HCV and subsequent activation of fibrogenic pathways. These findings suggest impaired antiviral TLR signaling may be an important immune mechanism for aggressive HCV recurrence post transplant.

Exercise performance increases coincident to body weight over the first two years following cardiac transplantation

To determine whether exercise performance changed over time once patients stabilized after heart transplantation, metabolic stress testing was performed in patients one and two yr post-heart transplantation. The patient cohort includes those transplanted in our program who survived at least two yr and were able to perform metabolic stress tests during their one- and two-yr annual evaluations. Standard stress test parameters were assessed, including weight, body surface area, rest and exercise heart rate (HR) and blood pressure (BP), exercise time, anaerobic threshold (AT), and maximum VO2 (MVO2). Ejection fraction by echo was also collected. Each patient served as their own control and data were compared using paired t-testing. Fifty patients were included in the cohort, 48 of whom were able to exercise to at least AT. Patient weight increased from year 1 to year 2 (82.4 ± 15.1 vs. 85.0 ± 17.0 kg, p = 0.035). Systolic BP increased approximately 40 mmHg with exercise with no change in diastolic BP, and there was no difference between years 1 and 2. HR increased approximately 25 bpm with exercise. There was no difference in resting HR but exercise HR increased significantly between yrs (148 ± 15 bpm vs. 154 ± 18 bpm, p = 0.017). Both VO2 at AT and MVO2 increased significantly from year 1 to year 2 (1116 ± 347 mL/min vs. 1192 ± 313 mL/min, p = 0.049 and 1523 ± 337 mL/min vs. 1599 ± 356 mL/min, p = 0.012, respectively) but when corrected for body weight, there were no differences (VO2-AT 13.6 ± 4.0 mL/kg/min vs. 14.0 ± 4.0 mL/kg/min; MVO2 18.7 ± 4.2 mL/kg/min vs. 18.8 ± 4.1 mL/kg/min). All other measured parameters were not different. There was a weak but statistically significant correlation between change in peak HR and change in VO2 at AT between one and two yr post-transplantation (r = 0.30, p = 0.04). We conclude that exercise performance as measured by VO2 can increase over time post-heart transplantation and in our cohort appears to be related to both an increase in body weight and an increase in HR from years 1 and 2.

Serum phosphate and outcome at one year after deceased donor renal transplantation

Traditional risk factors do not adequately explain the increased prevalence of cardiovascular disease in renal patients. This study considered a "non-traditional" risk factor, serum phosphate and outcome in renal transplant recipients. Data from 377 patients who received a first deceased donor renal transplant between January 1, 1999, and December 31, 2008, were recorded; 10% (n=38) had diabetes, 16.7% (n=63) were smokers, and 18.8% (n=71) had a history of vascular disease. Three hundred and thirty-three patients were alive at the time of the analysis. Survivors were significantly younger, less likely to be smokers or diabetic, and had a higher estimated glomerular filtration rate at one yr post-transplantation. Serum phosphate was significantly lower in these patients (0.95 ± 0.23 vs. 1.04 ± 0.26, p = 0.031). Analysis of recipient survival, stratified by serum phosphate at one yr post-transplant, revealed that serum phosphate > 1.11 mMol/L was a significant predictor of all-cause mortality (p=0.006). Serum phosphate between 0.9 and 1.11 mMol/L afforded the best outcome. In multivariate analysis, serum phosphate remained a significant predictor of mortality (p=0.016). Serum phosphate at one yr after transplant seems to have a J-shaped relationship with mortality, and this effect is independent of traditional cardiovascular risk factors.

Analysis of clinical variables associated with tolerance in pediatric liver transplant recipients

Tolerance has been defined as stable graft function off IMS. We reviewed the data of 369 pediatric liver transplant patients to examine demographic differences that may have a PV of pediatric LT tolerance. Of the 369 patients, 280 patients were stable with detectable blood levels of IMS agents and with good graft function without biopsy proven REJ > 1 yr posttransplantation, 18 patients were noted to be TOL off IMS, 27 patients were taking MIS with drug levels below detectable range by standard laboratory parameters, and 44 patients developed one or more episodes of biopsy proven acute or chronic REJ > 1 yr post-transplantation. Variables, including percentage of biliary atresia, type of transplanted organ, history of EBV infection, patient and donor gender, and ABO blood type mismatch between recipient and donor did not have PV of tolerance. Average age in years was 1.37 ± 1.53 (0.3-4.9) for TOL, 1.14 ± 0.89 (0.4-3.1) for MIS and 3.35 ± 4.45 (0.3-16) for REJ. Age difference of TOL/MIS vs. REJ was significant (p =0.002) and TOL vs. REJ was significant (0.01). Age at the time of transplantation is an important predictor in the development of pediatric LT tolerance.

Comparative Analysis of An Azacytidine Versus Azacytidine-HSCT Approach for the Treatment of Older Patients with AML/MDS

AbstractAbstract 2375While allogeneic HSCT remains the only curative option for patients with MDS, it is associated with considerable morbidity and mortality. 5-azacytidine (5-aza) has been shown to improve the overall survival (OS) of patients with int-2/high risk MDS when compared with best supportive care and conventional chemotherapy. The feasibility of 5-aza in the pre-transplant setting has been demonstrated allowing disease remission induction whilst minimising the toxicity of “induction” chemotherapy. However the additional benefit gained by patients receiving HSCT post 5-aza as compared to patients who receive continuous 5-aza therapy remains to be determined.We report on our single centre experience on the use of 5-aza in a cohort of 71 patients receiving 5-aza as de-novo therapy for high risk MDS/AML. The patients were classified into 2 cohorts. 41 patients received 5-aza in a non-intensive group (defined as patients with advanced age or significant co-morbidities precluding them from HSCT) and 30 patients received 5-aza induction therapy with the intention of proceeding to an allogeneic HSCT (intensive group). Patients in the non-intensive group were significantly older at start of 5-aza therapy than the intensive group (median age: 72 yrs vs 62 yrs, p=<0.01). There was no difference in the proportion of patients with advanced disease (int-2/high IPSS or AML) between groups (non-intensive: 80% vs intensive: 76%, p=0.76). Similarly, there was no significant difference in blast percentage at diagnosis or karyotype risk group between the non-intensive and intensive groups.In the intensive group, the median no. of cycles of 5-aza administered was 7(range 1–30). Out of 30 patients, 15(50%) patients did not proceed to transplant. 14 of these patients had disease progression while on 5-aza, out of which 11 patients received conventional chemotherapy. None of these 11 patients proceeded to HSCT primarily as a result of refractory MDS/AML or chemotherapy toxicity. 15(50%) patients attained a morphological remission (<5% bone marrow blasts) post-5-aza and eventually received a RIC HSCT (including two patients who received umbilical cord blood transplants). All transplanted patients had durable engraftment and the incidence of GVHD at 1 year post-transplant was 50%. At last follow-up, 6 patients who received HSCT were still alive. The actuarial OS at 1 yr post transplant was 35%+/−7%. Among the 41 patients in the non-intensive group, the median number of cycles of 5-aza received was 7 (range:1-46). At last follow-up, 8 patients (19%) were alive with 7 patients receiving ongoing 5 aza. The main reason for cessation of therapy was disease progression.In summary, only 50% of patients commencing 5-aza in the intensive group were subsequently able to receive an allogeneic HSCT. While the non-intensive group consisted of older patients, the median OS from start of 5-azacytidine was 22 months for both intensive and non-intensive groups. The 1 yr and 2 yr actuarial OS was 57%+/−8% and 24%+/−8% for the non-intensive group and 76%+/−8% and 17%+/−8% for the intensive group (p=0.76). While the development of RIC regimens has facilitated the expansion of allogeneic HSCT to older patients with AML/MDS, these findings suggest that in certain patients with co-morbidities, non-intensive novel therapies may be a preferable therapeutic option. Further studies in older AML/MDS patients to evaluate the benefit of novel agents such as 5-azacytidine when compared with HSCT are warranted. Disclosures:Mufti: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

One-Year Post-Transplant Serum Ferritin Level Is a Predictor of Long-Term Survival Following Allogeneic Transplantation.

AbstractAbstract 3453Individuals undergoing allogeneic transplantation receive multiple red blood cell transfusions both as part of the transplant procedure and as part of the pre-transplant care of the underlying disease. Therefore these patients may be at risk for complications of transfusional iron overload. Several studies have noted that individuals entering the transplant with baseline elevated serum ferritin values have decreased overall survival and higher rates of disease relapse. Whether the iron is a direct contributor to inferior outcomes or is a marker of more advanced disease (thereby requiring greater transfusions) is unclear. Little is known about the incidence and consequences of iron overload among long-term survivors of allogeneic transplantation. Methods:Using Kaplan-Meier and Cox regression analyses, we performed a single center, retrospective cohort study of consecutive allogeneic transplants performed at Hackensack University Medical Center from January 2002 through June 30, 2009 to determine the association between serum ferritin (measured approximately 1 yr post allogeneic transplant) and overall survival. Results:During the study time frame, 637 allogeneic transplants (Donor Lymphocyte Infusion procedures excluded) were performed at our center and 342 (54%) survived ≥ one year. Among 1-year survivors 240 (70%) had post-transplant serum ferritin values available for review, including 132 (55%) allogeneic sibling, 68 (28%) matched unrelated, and 40 (17%) mismatched unrelated donor transplants. The median post-transplant ferritin value among 1-year survivors of allogeneic transplant was 628 ng/ml (95% CI 17, 5010), with 93 (39%) above 1000 ng/ml and 40 (17%) above 2500 ng/ml. The median post-transplant ferritin levels varied by underlying hematologic disease (aplastic anemia = 1147, acute leukemia = 1067, MDS = 944, CLL = 297, CML = 219, lymphoma = 123, multiple myeloma = 90). The Kaplan-Meier projected 5-year survival rate was 76% for the cohort that had survived one year and had available ferritin values. Fifty late deaths have occurred; causes of late death were disease relapse (n=37, 74%), GVHD (n=7, 14%), infection (n=4, 8%), cardiac (n=1, 2%) and second malignancy (n=1, 2%). The 1-year post-transplant serum ferritin value was a significant predictor of long term survival. Using a cut-off ferritin value of 1000 ng/ml, the 5-year projected survivals were 85% (95 CI 75%-91%) and 64% (95% CI 52–73%) for the low and high ferritin cohorts respectively (Figure, log-rank p<0.001), with a hazard ratio of 3.5 (95% CI 2–6.4, p<0.001). Similarly a serum ferritin value >2500 ng/ml was associated with inferior survival (HR 2.97, p<0.001). Underlying hematologic disease also correlated with 5-year projected survival including 70%, 83%, and 89% for acute leukemia/MDS, lymphoma/myeloma/CLL, and aplastic anemia/CML groupings, respectively (log-rank p<0.01 for leukemia/MDS vs other groupings). Patients receiving bone marrow grafts did better than those receiving peripheral blood stem cells (HR = 2.2; p = 0.03). Age, gender, donor type (sibling, matched unrelated, mismatch unrelated) and intensity of regimen (ablative vs. non-myeloablative) were not predictive of inferior survival in univariate analysis. In the multivariate Cox-regression analysis, elevated post-transplant ferritin >1000 ng/ml (HR 3.3, 95%CI 1.6–6.1; p<0.001) and diagnosis of acute leukemia/MDS (HR 4.5, 95%CI 1.1–18.7; p=0.04) remained independent predictors of inferior survival, even when adjusted for age, gender, type of graft, donor type, and intensity of conditioning regimen. Relapse deaths (25% vs. 9%; p<0.001) and GVHD deaths (6% vs 0.6%; p=0.03) were more common in the high ferritin cohort. Conclusions:Among patients who have survived one-year following allogeneic transplantation, a post-transplant serum ferritin value greater than 1000 ng/ml is a predictor of inferior long-term outcomes. To our knowledge this is the first report on the importance of late monitoring of serum ferritin, but it is in agreement with prior studies suggesting a pre-transplant ferritin value is a predictor of outcomes. Prospective studies attempting to modify outcomes by reducing post-transplant iron overload states are needed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The efficacy and safety of valganciclovir vs. oral ganciclovir in the prevention of symptomatic CMV infection in children after solid organ transplantation

Routine prophylaxis for CMV with valganciclovir is common in adult recipients but data to support its use in children are scarce. The aim of this study was to compare the efficacy and safety of valganciclovir vs. ganciclovir in a pediatric cohort. We performed a retrospective analysis of 92 children after KTx and/or LTx. All children have received IV ganciclovir for two wk, and then oral ganciclovir (TID; n = 41) before 2004, or valganciclovir (OD; n = 51) thereafter. Treatment was given for three months in R+/D+ or R+/D- recipients and for six months in R-/D+. Patients were followed for one yr post transplant. Both groups were comparable in their demographic and transplant-related history. Symptomatic CMV infection/disease developed in 13.7% vs. 19.5% of valganciclovir and ganciclovir groups, respectively (P-NS). Time-to-onset of CMV infection was comparable in both groups (P-NS); rates of acute allograft rejection were similar in both groups (3.9% vs. 9.8%). Risk factors for CMV infection included young age, serostatus of R-/D+, and allograft from cadaver donor. No significant side effects were noted in both groups. As in adults, valganciclovir appears to be as efficacious and safe as oral ganciclovir. Valganciclovir should be considered as a possible prophylactic treatment for CMV in pediatric recipients of KTx or LTx.